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

NCT02666157 | Unknown Phase 4

• 1 other identifier: A-BR-104-049
• Study Type: interventional
• Target: 3,672
• Locations: 1 country
• Sites: 5

Brief Summary

1. 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. 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. 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. 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. 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.

Conditions

Atrial Fibrillation

Keywords

atrial fibrillation; stroke; systemic embolism; bleeding; oral anticoagulant

Outcome Measures

Primary Outcomes (1)

• Time to the occurrence of the major embolic events

  a composite of stroke (ischemic or hemorrhagic), transient ischemic attack or systemic embolism

  up to 36 months

Secondary Outcomes (3)

• Time to the occurrence of the major embolic events and death

  up to 36 months

• Time to the occurrence of the major embolic and vascular events

  up to 36 months

• Time to the occurrence of all clinically relevant bleeding events

  up to 36 months

Other Outcomes (18)

• Time to the occurrence of all stroke

  up to 36 months

• Time to the occurrence of systemic embolism

  up to 36 months

• Time to the occurrence of transient ischemic attack

  up to 36 months

Study Arms (3)

Dabigatran

ACTIVE COMPARATOR

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

Drug: Dabigatran etexilate

Rivaroxaban

ACTIVE COMPARATOR

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

Drug: Rivaroxaban

Apixaban

ACTIVE COMPARATOR

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

Drug: Apixaban

Interventions

Dabigatran etexilate DRUG

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

Also known as: Pradaxa

Dabigatran

Rivaroxaban DRUG

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

Also known as: Xarelto

Rivaroxaban

Apixaban DRUG

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

Also known as: Eliquis

Apixaban

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cheng-Kung University Hospital: lead
• Tainan Municipal Hospital: collaborator
• E-DA Hospital: collaborator
• National Cheng-Kung University Hospital Dou-Liou Branch: collaborator
• Ministry of Health and Welfare, Taiwan: collaborator

Study Sites (5)

National Cheng Kung University Hospital

Tainan, Tainan City, 704, Taiwan

RECRUITING

Tainan Hospital Ministry of Health and Welfare

Tainan, Tainan City, 704, Taiwan

NOT YET RECRUITING

National Cheng Kung University Hospital Dou-Liou Branch

Dou-Liou City, 640, Taiwan

NOT YET RECRUITING

E-DA Hospital

Kaohsiung City, 824, Taiwan

NOT YET RECRUITING

Tainan Municipal Hospital

Tainan, 701, Taiwan

RECRUITING

Related Publications (17)

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  PMID: 22240753 BACKGROUND

• Chiang CE, Wang KL, Lip GY. Stroke prevention in atrial fibrillation: an Asian perspective. Thromb Haemost. 2014 May 5;111(5):789-97. doi: 10.1160/TH13-11-0948. Epub 2014 Feb 6.

  PMID: 24500243 BACKGROUND

• Lin LJ, Cheng MH, Lee CH, Wung DC, Cheng CL, Kao Yang YH. Compliance with antithrombotic prescribing guidelines for patients with atrial fibrillation--a nationwide descriptive study in Taiwan. Clin Ther. 2008 Sep;30(9):1726-36. doi: 10.1016/j.clinthera.2008.09.010.

  PMID: 18840379 BACKGROUND

• Chang CH, Yang YH, Chen JH, Lin LJ. Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation in Taiwan. Thromb Res. 2014 May;133(5):782-9. doi: 10.1016/j.thromres.2014.02.024. Epub 2014 Mar 3.

  PMID: 24642004 BACKGROUND

• Lip GY, Wang KL, Chiang CE. Non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in Asian patients with atrial fibrillation: time for a reappraisal. Int J Cardiol. 2015 Feb 1;180:246-54. doi: 10.1016/j.ijcard.2014.11.182. Epub 2014 Nov 26.

  PMID: 25463377 BACKGROUND

• Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30.

  PMID: 19717844 BACKGROUND

• Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638. Epub 2011 Aug 10.

  PMID: 21830957 BACKGROUND

• Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. doi: 10.1056/NEJMoa1107039. Epub 2011 Aug 27.

  PMID: 21870978 BACKGROUND

• Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.

  PMID: 24251359 BACKGROUND

• Hori M, Connolly SJ, Zhu J, Liu LS, Lau CP, Pais P, Xavier D, Kim SS, Omar R, Dans AL, Tan RS, Chen JH, Tanomsup S, Watanabe M, Koyanagi M, Ezekowitz MD, Reilly PA, Wallentin L, Yusuf S; RE-LY Investigators. Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation. Stroke. 2013 Jul;44(7):1891-6. doi: 10.1161/STROKEAHA.113.000990. Epub 2013 Jun 6.

  PMID: 23743976 BACKGROUND

• Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014 Mar 15;383(9921):955-62. doi: 10.1016/S0140-6736(13)62343-0. Epub 2013 Dec 4.

  PMID: 24315724 BACKGROUND

• Lip GY, Larsen TB, Skjoth F, Rasmussen LH. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2012 Aug 21;60(8):738-46. doi: 10.1016/j.jacc.2012.03.019. Epub 2012 May 9.

  PMID: 22575324 BACKGROUND

• Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S, Oldgren J, Themeles E, Wallentin L, Yusuf S. Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009 May;157(5):805-10, 810.e1-2. doi: 10.1016/j.ahj.2009.02.005.

  PMID: 19376304 BACKGROUND

• ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010 Mar;159(3):340-347.e1. doi: 10.1016/j.ahj.2009.11.025.

  PMID: 20211293 BACKGROUND

• Lopes RD, Alexander JH, Al-Khatib SM, Ansell J, Diaz R, Easton JD, Gersh BJ, Granger CB, Hanna M, Horowitz J, Hylek EM, McMurray JJ, Verheugt FW, Wallentin L; ARISTOTLE Investigators. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010 Mar;159(3):331-9. doi: 10.1016/j.ahj.2009.07.035.

  PMID: 20211292 BACKGROUND

• Ruff CT, Giugliano RP, Antman EM, Crugnale SE, Bocanegra T, Mercuri M, Hanyok J, Patel I, Shi M, Salazar D, McCabe CH, Braunwald E. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 2010 Oct;160(4):635-41. doi: 10.1016/j.ahj.2010.06.042.

  PMID: 20934556 BACKGROUND

• Wang KL, Lip GY, Lin SJ, Chiang CE. Non-Vitamin K Antagonist Oral Anticoagulants for Stroke Prevention in Asian Patients With Nonvalvular Atrial Fibrillation: Meta-Analysis. Stroke. 2015 Sep;46(9):2555-61. doi: 10.1161/STROKEAHA.115.009947. Epub 2015 Jul 30.

  PMID: 26304863 BACKGROUND

MeSH Terms

Conditions

Atrial Fibrillation; Stroke; Hemorrhage

Interventions

Dabigatran; Rivaroxaban; apixaban

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Thiophenes; Sulfur Compounds; Organic Chemicals; Morpholines; Oxazines

Study Officials

• Ting-Hsing Chao, MD

  National Cheng-Kung University Hospital

  STUDY CHAIR

Central Study Contacts

Ting-Hsing Chao, MD

CONTACT

886-6-2353535; chaoth@mail.ncku.edu.tw

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 24, 2016
• First Posted: January 28, 2016
• Study Start: January 1, 2016
• Primary Completion: December 1, 2018
• Study Completion: December 1, 2018
• Last Updated: February 17, 2016

Record last verified: 2016-02

Locations

TW (5)