DARING-AF: Comparison of Efficacy and Safety Among Dabigatran, Rivaroxaban, and Apixaban in Non-Valvular Atrial Fibrillation

Sponsor

National Cheng-Kung University Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT02666157

Collaborator

Tainan Municipal Hospital (Other), E-DA Hospital (Other), National Cheng-Kung University Hospital Dou-Liou Branch (Other), Ministry of Health and Welfare, Taiwan (Other)

3,672

Enrollment

Locations

Arms

Duration (Months)

734.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.
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.
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.
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.
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.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Drug: Dabigatran etexilate Drug: Rivaroxaban Drug: Apixaban	Phase 4

Detailed Description

participants

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)

blood sampling, genotyping, and measurement of biomarkers

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

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

3672 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Comparison of Efficacy and Safety Among DAbigatran, RIvaroxaban, and ApixabaN in Patients HavinG Non-Valvular Atrial Fibrillation in Taiwan (DARING-AF Study)

Study Start Date :

Jan 1, 2016

Anticipated Primary Completion Date :

Dec 1, 2018

Anticipated Study Completion Date :

Dec 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Dabigatran oral dabigatran etexilate capsule 110 or 150 mg (110 mg in specific population) bid for entire study period	Drug: Dabigatran etexilate this drug is administered twice per day for the entire study period Other Names: Pradaxa
Active Comparator: Rivaroxaban oral rivaroxaban film-coated tablet 15 or 20 mg (10 or 15 mg in specific population) qd for entire study period	Drug: Rivaroxaban this drug is administered once per day for the entire study period Other Names: Xarelto
Active Comparator: Apixaban oral apixaban 5 mg (2.5 mg in specific population) bid for entire study period	Drug: Apixaban this drug is administered twice per day for the entire study period Other Names: Eliquis

Arm

Intervention/Treatment

Active Comparator: Dabigatran

oral dabigatran etexilate capsule 110 or 150 mg (110 mg in specific population) bid for entire study period

Drug: Dabigatran etexilate

this drug is administered twice per day for the entire study period

Other Names:

Pradaxa

Active Comparator: Rivaroxaban

oral rivaroxaban film-coated tablet 15 or 20 mg (10 or 15 mg in specific population) qd for entire study period

Drug: Rivaroxaban

this drug is administered once per day for the entire study period

Other Names:

Xarelto

Active Comparator: Apixaban

oral apixaban 5 mg (2.5 mg in specific population) bid for entire study period

Drug: Apixaban

this drug is administered twice per day for the entire study period

Other Names:

Eliquis

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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
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

Other Outcome Measures

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
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Cheng Kung University Hospital	Tainan	Tainan City	Taiwan	704
2	Tainan Hospital Ministry of Health and Welfare	Tainan	Tainan City	Taiwan	704
3	National Cheng Kung University Hospital Dou-Liou Branch	Dou-Liou City		Taiwan	640
4	E-DA Hospital	Kaohsiung		Taiwan	824
5	Tainan Municipal Hospital	Tainan		Taiwan	701