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

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ClinicalTrials.gov Identifier: NCT02666157
Recruitment Status : Unknown
Verified February 2016 by National Cheng-Kung University Hospital.
Recruitment status was:  Recruiting
First Posted : January 28, 2016
Last Update Posted : February 17, 2016
Sponsor:
Collaborators:
Tainan Municipal Hospital
E-DA Hospital
National Cheng-Kung University Hospital Dou-Liou Branch
Ministry of Health and Welfare, Taiwan
Information provided by (Responsible Party):
National Cheng-Kung University Hospital

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.

Condition or disease Intervention/treatment Phase
Atrial Fibrillation Drug: Dabigatran etexilate Drug: Rivaroxaban Drug: Apixaban Phase 4

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

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : January 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018


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 Name: 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 Name: 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 Name: Eliquis




Primary Outcome Measures :
  1. Time to the occurrence of the major embolic events [ Time Frame: up to 36 months ]
    a composite of stroke (ischemic or hemorrhagic), transient ischemic attack or systemic embolism


Secondary Outcome Measures :
  1. Time to the occurrence of the major embolic events and death [ Time Frame: up to 36 months ]
    a composite of all stroke (including hemorrhagic), systemic embolism, and death

  2. Time to the occurrence of the major embolic and vascular events [ Time Frame: up to 36 months ]
    a composite of all stroke, systemic embolism, pulmonary embolism, acute myocardial infarction, and vascular death

  3. Time to the occurrence of all clinically relevant bleeding events [ Time Frame: up to 36 months ]
    a composite of major bleeding or clinically relevant non-major bleeding events


Other Outcome Measures:
  1. Time to the occurrence of all stroke [ Time Frame: 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

  2. Time to the occurrence of systemic embolism [ Time Frame: up to 36 months ]
    embolic events excluding stroke, pulmonary embolism or venous thromboembolism

  3. Time to the occurrence of transient ischemic attack [ Time Frame: up to 36 months ]
    a transient focal loss of neurological function caused by an ischemic event with complete recovery within 24 hours after onset

  4. Time to the occurrence of death [ Time Frame: up to 36 months ]
    all-cause death includes vascular and non-vascular causes

  5. Time to the occurrence of pulmonary embolism [ Time Frame: up to 36 months ]
    clinical diagnosis of pulmonary embolism should be confirmed by an image study

  6. Time to the occurrence of acute myocardial infarction [ Time Frame: up to 36 months ]
    acute myocardial infarction is defined in accordance with the universal definition proposed in 2012

  7. Time to the occurrence of vascular death [ Time Frame: 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

  8. Time to the occurrence of hospitalization for congestive heart failure [ Time Frame: up to 36 months ]
    decompensated congestive heart failure requiring hospitalization for stabilization

  9. Time to the occurrence of advanced chronic kidney disease [ Time Frame: up to 36 months ]
    defined as estimated glomerular filtration rate <30 mL/min/1.73m2 confirmed by 2 separate laboratory tests within 3 months

  10. Time to the occurrence of cardiogenic shock [ Time Frame: 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

  11. Time to the occurrence of any revascularization for peripheral artery disease [ Time Frame: up to 36 months ]
    percutaneous transluminal angioplasty or bypass surgery for low extremity artery disease

  12. Time to the occurrence of any revascularization for coronary artery disease [ Time Frame: up to 36 months ]
    percutaneous coronary intervention or coronary artery bypass grafting for obstructive coronary artery disease

  13. Time to occurrence of any revascularization for carotid or vertebral artery stenosis [ Time Frame: up to 36 months ]
    endovascular therapy, endarterectomy or bypass surgery for carotid or vertebral artery stenosis

  14. Time to the occurrence of major bleeding events [ Time Frame: 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)

  15. Time to the occurrence of life-threatening bleeding events [ Time Frame: 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

  16. Time to the occurrence of minor bleeding events [ Time Frame: up to 36 months ]
    non-major or non-life-threatening bleeding events

  17. Time to the occurrence of clinically relevant non-major bleeding events [ Time Frame: 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

  18. Time to the occurrence of major or minor bleeding events [ Time Frame: up to 36 months ]
    major or minor bleeding



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02666157


Contacts
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Contact: Ting-Hsing Chao, MD 886-6-2353535 ext 2382 chaoth@mail.ncku.edu.tw

Locations
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Taiwan
National Cheng Kung University Hospital Recruiting
Tainan, Tainan City, Taiwan, 704
Contact: Ting-Hsing Chao, MD    886-6-2353535 ext 2382    chaoth@mail.ncku.edu.tw   
Principal Investigator: Ting-Hsing Chao, MD         
Sub-Investigator: Ju-Yi Chen, MD and PhD         
Sub-Investigator: Cheng-Han Lee, MD and PhD         
Sub-Investigator: Chih-Chan Lin, MD         
Sub-Investigator: Chih-Hung Chen, MD         
Sub-Investigator: Liang-Miin Tsai, MD         
Sub-Investigator: Li-Jen Lin, MD         
Sub-Investigator: Wei-Chuan Tsai, MD         
Sub-Investigator: Ping-Yen Liu, MD and PhD         
Tainan Hospital Ministry of Health and Welfare Not yet recruiting
Tainan, Tainan City, Taiwan, 704
Contact: Li-Dan Yang, MD    886-6-2200055 ext 9    litannyang@yahoo.com.tw   
Principal Investigator: Li-Dan Yang, MD         
National Cheng Kung University Hospital Dou-Liou Branch Not yet recruiting
Dou-Liou City, Taiwan, 640
Contact: Yang-Cheh Hsueh, MD    886-5-5332121 ext 5101    p308378@dou6.hosp.ncku.edu.tw   
Principal Investigator: Yang-Cheh Hsueh, MD         
Sub-Investigator: Yuen-Ting Sung, MD and PhD         
E-DA Hospital Not yet recruiting
Kaohsiung, Taiwan, 824
Contact: Wei-Kung Tseng, MD and PhD    886-7-6150011 ext 5005    arthurtseng@me.com   
Principal Investigator: Wei-Kung Tseng, MD and PhD         
Tainan Municipal Hospital Recruiting
Tainan, Taiwan, 701
Contact: I-Chih Chen, MD    886-6-2609926 ext 212045    ichih1230@yahoo.com.tw   
Principal Investigator: I-Chih Chen, MD         
Sub-Investigator: Ruei-Chang Zeng, MD         
Sponsors and Collaborators
National Cheng-Kung University Hospital
Tainan Municipal Hospital
E-DA Hospital
National Cheng-Kung University Hospital Dou-Liou Branch
Ministry of Health and Welfare, Taiwan
Investigators
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Study Chair: Ting-Hsing Chao, MD National Cheng-Kung University Hospital

Publications:

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Responsible Party: National Cheng-Kung University Hospital
ClinicalTrials.gov Identifier: NCT02666157     History of Changes
Other Study ID Numbers: A-BR-104-049
First Posted: January 28, 2016    Key Record Dates
Last Update Posted: February 17, 2016
Last Verified: February 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by National Cheng-Kung University Hospital:
atrial fibrillation
stroke
systemic embolism
bleeding
oral anticoagulant
Additional relevant MeSH terms:
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Dabigatran
Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Rivaroxaban
Apixaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants