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

NCT ID: NCT02666157

Last Updated: 2016-02-17

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE4

Total Enrollment

3672 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-01-31

Study Completion Date

2018-12-31

Brief Summary

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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

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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

Conditions

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Atrial Fibrillation

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Dabigatran

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

Group Type ACTIVE_COMPARATOR

Dabigatran etexilate

Intervention Type DRUG

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

Rivaroxaban

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

Group Type ACTIVE_COMPARATOR

Rivaroxaban

Intervention Type DRUG

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

Apixaban

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

Group Type ACTIVE_COMPARATOR

Apixaban

Intervention Type DRUG

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

Interventions

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Dabigatran etexilate

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

Intervention Type DRUG

Rivaroxaban

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

Intervention Type DRUG

Apixaban

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

Intervention Type DRUG

Other Intervention Names

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Pradaxa Xarelto Eliquis

Eligibility Criteria

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Inclusion 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

* 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
Minimum Eligible Age

20 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Tainan Municipal Hospital

OTHER

Sponsor Role collaborator

E-DA Hospital

OTHER

Sponsor Role collaborator

National Cheng-Kung University Hospital Dou-Liou Branch

UNKNOWN

Sponsor Role collaborator

Ministry of Health and Welfare, Taiwan

OTHER_GOV

Sponsor Role collaborator

National Cheng-Kung University Hospital

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Ting-Hsing Chao, MD

Role: STUDY_CHAIR

National Cheng-Kung University Hospital

Locations

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National Cheng Kung University Hospital

Tainan City, Tainan City, Taiwan

Site Status RECRUITING

Tainan Hospital Ministry of Health and Welfare

Tainan City, Tainan City, Taiwan

Site Status NOT_YET_RECRUITING

National Cheng Kung University Hospital Dou-Liou Branch

Dou-Liou City, , Taiwan

Site Status NOT_YET_RECRUITING

E-DA Hospital

Kaohsiung City, , Taiwan

Site Status NOT_YET_RECRUITING

Tainan Municipal Hospital

Tainan City, , Taiwan

Site Status RECRUITING

Countries

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Taiwan

Central Contacts

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Ting-Hsing Chao, MD

Role: CONTACT

886-6-2353535 ext. 2382

Facility Contacts

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Ting-Hsing Chao, MD

Role: primary

886-6-2353535 ext. 2382

Li-Dan Yang, MD

Role: primary

886-6-2200055 ext. 9

Yang-Cheh Hsueh, MD

Role: primary

886-5-5332121 ext. 5101

Wei-Kung Tseng, MD and PhD

Role: primary

886-7-6150011 ext. 5005

I-Chih Chen, MD

Role: primary

886-6-2609926 ext. 212045

References

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Chiang CE, Zhang S, Tse HF, Teo WS, Omar R, Sriratanasathavorn C. Atrial fibrillation management in Asia: from the Asian expert forum on atrial fibrillation. Int J Cardiol. 2013 Mar 20;164(1):21-32. doi: 10.1016/j.ijcard.2011.12.033. Epub 2012 Jan 10.

Reference Type BACKGROUND
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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.

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PMID: 24500243 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 18840379 (View on PubMed)

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.

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PMID: 24642004 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25463377 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19717844 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 21830957 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 21870978 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24251359 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23743976 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24315724 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 22575324 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19376304 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 20211293 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 20211292 (View on PubMed)

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.

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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.

Reference Type BACKGROUND
PMID: 26304863 (View on PubMed)

Other Identifiers

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A-BR-104-049

Identifier Type: -

Identifier Source: org_study_id

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