Apixaban Versus Warfarin for the Management of Post-operative Atrial Fibrillation

NCT02889562 | Completed Phase 2 Results

• 1 other identifier: CV185-505
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

In this open-label, prospective, randomized pilot study, patients who develop atrial fibrillation after isolated coronary artery bypass grafting surgery will be identified. Patients with persistent atrial fibrillation (\>12 hours) or recurrent sustained atrial fibrillation (\>2 episodes of atrial fibrillation lasting longer than 30 minutes) will be candidates for inclusion. Upon meeting study inclusion and exclusion criteria, and after informed consent, patients will be randomized to either the standard of care (warfarin per protocol) or apixaban arms of the trial. Routine postoperative care after CABG will occur in both groups. Upon discharge, anticoagulation in both groups will be managed by the anticoagulation clinic. Patients will be followed for 30 days after surgery.

Conditions

Coronary Artery Bypass Grafting; Postoperative Atrial Fibrilation; Stroke; Systemic Embolism; Deep Venous Thrombosis

Keywords

apixaban; anticoagulant; CABG; thrombosis; fibrillation

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Strokes

  Efficacy will be measured by the freedom from stroke during the study period. Events relating to stroke will be adjudicated using pre-determined definitions by independent committee members that remain blinded to the patient's treatment arm.

  30 days

• Number of Participants With Thromboembolytic Events

  Efficacy will be measured by the freedom from thromboembolytic events during the study period. Events relating to thromboembolytic events will be adjudicated using pre-determined definitions by independent committee members that remain blinded to the patient's treatment arm.

  30 days

Secondary Outcomes (3)

• Units of Blood Given After Initiation of Anticoagulation Medication

  30 days

• Total Post-operative Length of Stay

  30 days

• Time in Therapeutic Range of INR, if on Warfarin

  30 days

Study Arms (2)

Apixaban

ACTIVE COMPARATOR

Apixaban is to be dosed at 5 mg by mouth twice daily, except in the case of the criteria listed below in "dose modifications". The duration of therapy will be at least 30 days. The patient's physician may determine that anticoagulation therapy should be continued after the study period, based on their examination of the patient at the 30-day post-operative examination.

Drug: Apixaban

Warfarin

ACTIVE COMPARATOR

While patients are hospitalized, warfarin will be dosed daily, with daily INR monitoring per hospital protocol. Daily doses may vary from 0.5mg to 15mg by mouth, as determined by patient specific factors such as patient size, hepatic function, INR, concomitant medications, diet, or other factors. Based on these factors or others not listed, there may also be days in which the patient is prescribed to not get does not receive a dose of warfarin. After discharge from the hospital, warfarin dosing will be subsequently managed by an anticoagulation clinic, per established protocols. All patients will have a goal INR of 2-3 during the duration of the study. The duration of therapy will be at least 30 days. The patient's physician may determine that anticoagulation therapy should be continued after the study period, based on their examination of the patient at the 30-day post-operative examination.

Drug: Warfarin

Interventions

Apixaban DRUG

Study arm that patient can be randomized to. Apixaban is a novel, orally active, potent, direct selective inhibitor of coagulation FXa that directly and reversibly binds to the active site of FXa and exerts anticoagulant and antithrombotic effects by diminishing the conversion of prothrombin to thrombin.

Also known as: Eliquis

Apixaban

Warfarin DRUG

Study arm that patient can be randomized to. Warfarin therapy has been the mainstay of therapy for patients with POAF. While the duration of therapy is usually short (3-4 weeks), complications of anticoagulation do occur. Additionally, warfarin therapy for POAF is associated with increased length of stay, need for monitoring, and bleeding complications.

Also known as: Coumadin

Warfarin

Eligibility Criteria

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

You may qualify if:

• Signed Written Informed Consent
• Patients diagnosed with new-onset persistent or recurrent atrial fibrillation after isolated CABG surgery. Persistent atrial fibrillation is defined as an episode of \>12 hours. Recurrent atrial fibrillation is defined as two or more episodes of atrial fibrillation lasting longer than 30 minutes.
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. Patients undergoing isolated CABG must have this tested and documented prior to the procedure, and this will be verified prior to randomization.
• Women must not be breastfeeding.
• WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s): 30 days of treatment plus 5 half-lives of study drug Apixaban (3 days) or warfarin (8 days) plus 30 days (duration of ovulatory cycle) for a total of 38 days post-treatment completion.
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s): 30 days of treatment plus 5 half-lives of study drug Apixaban (3 days) or warfarin (8 days) plus 90 days (duration of sperm turnover) for a total of 98 days post-treatment completion.

You may not qualify if:

• Atrial fibrillation due to a reversible cause other than recent surgery
• Patients diagnosed with persistent or paroxysmal atrial fibrillation chronically before undergoing surgery
• Patients with mechanical heart valves
• Patients currently experiencing active bleeding precluding initialization of anticoagulation therapy in the opinion of their managing physician, or with increased bleeding risk (as determined by the attending surgeon) believed to be a contraindication to anticoagulation at the time of randomization Planned major surgery requiring stoppage of anticoagulation therapy during trial period
• Stroke within the previous 7 days
• Moderate or severe mitral stenosis
• Conditions other than atrial fibrillation that required anticoagulation (prosthetic mechanical heart valve)
• Patients taking warfarin, apixaban, rivaroxaban, dabigatran, edoxaban, clopidogrel, ticagrelor, or enoxaparin at home for any indication in the 15 days prior to surgery
• Patients requiring the use of clopidogrel or ticagrelor during the study period
• Severe renal insufficiency (serum creatinine level of \>2.5 mg/dL or CrCL\<25 ml/min) for consecutive measurements
• Allergies to warfarin or apixaban, or components of warfarin or apixaban

Sponsors & Collaborators

• Sanford Health: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Sanford Health

Fargo, North Dakota, 58122, United States

Location

Related Publications (11)

• Anderson E, Johnke K, Leedahl D, Glogoza M, Newman R, Dyke C. Novel oral anticoagulants vs warfarin for the management of postoperative atrial fibrillation: clinical outcomes and cost analysis. Am J Surg. 2015 Dec;210(6):1095-102; discussion 1102-3. doi: 10.1016/j.amjsurg.2015.07.005. Epub 2015 Sep 18.

  PMID: 26482512 BACKGROUND

• Schulman S, Angeras U, Bergqvist D, Eriksson B, Lassen MR, Fisher W; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 2010 Jan;8(1):202-4. doi: 10.1111/j.1538-7836.2009.03678.x. Epub 2009 Oct 30.

  PMID: 19878532 BACKGROUND

• Piccini JP, Zhao Y, Steinberg BA, He X, Mathew JP, Fullerton DA, Hegland DD, Hernandez AF, Mills RM, Klaskala W, Peterson ED. Comparative effectiveness of pharmacotherapies for prevention of atrial fibrillation following coronary artery bypass surgery. Am J Cardiol. 2013 Oct 1;112(7):954-60. doi: 10.1016/j.amjcard.2013.05.029. Epub 2013 Jul 11.

  PMID: 23850476 BACKGROUND

• Lahiri MK, Fang K, Lamerato L, Khan AM, Schuger CD. Effect of race on the frequency of postoperative atrial fibrillation following coronary artery bypass grafting. Am J Cardiol. 2011 Feb 1;107(3):383-6. doi: 10.1016/j.amjcard.2010.09.032.

  PMID: 21257002 BACKGROUND

• Rostagno C, La Meir M, Gelsomino S, Ghilli L, Rossi A, Carone E, Braconi L, Rosso G, Puggelli F, Mattesini A, Stefano PL, Padeletti L, Maessen J, Gensini GF. Atrial fibrillation after cardiac surgery: incidence, risk factors, and economic burden. J Cardiothorac Vasc Anesth. 2010 Dec;24(6):952-8. doi: 10.1053/j.jvca.2010.03.009. Epub 2010 May 31.

  PMID: 20570180 BACKGROUND

• Raiten JM, Ghadimi K, Augoustides JG, Ramakrishna H, Patel PA, Weiss SJ, Gutsche JT. Atrial fibrillation after cardiac surgery: clinical update on mechanisms and prophylactic strategies. J Cardiothorac Vasc Anesth. 2015;29(3):806-16. doi: 10.1053/j.jvca.2015.01.001. No abstract available.

  PMID: 26009291 BACKGROUND

• Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, Halperin JL, Kay GN, Klein WW, Levy S, McNamara RL, Prystowsky EN, Wann LS, Wyse DG, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Russell RO, Smith SC Jr, Klein WW, Alonso-Garcia A, Blomstrom-Lundqvist C, de Backer G, Flather M, Hradec J, Oto A, Parkhomenko A, Silber S, Torbicki A; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation); North American Society of Pacing and Electrophysiology. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation. 2001 Oct 23;104(17):2118-50. No abstract available.

  PMID: 11673357 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

• 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

• Chapin TW, Leedahl DD, Brown AB, Pasek AM, Sand MG, Loy ML, Dyke CM. Comparison of Anticoagulants for Postoperative Atrial Fibrillation After Coronary Artery Bypass Grafting: A Pilot Study. J Cardiovasc Pharmacol Ther. 2020 Nov;25(6):523-530. doi: 10.1177/1074248420929483. Epub 2020 Jun 1.

  PMID: 32476465 DERIVED

Related Links

• Apixaban. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO.
• Rivaroxaban. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO.
• Dabigatran Etexilate Mesylate. DrugPoints Summary. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO.

MeSH Terms

Conditions

Stroke; Venous Thrombosis; Thrombosis

Interventions

apixaban; Warfarin

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Embolism and Thrombosis

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

Limited by sample size.

Results Point of Contact

• Title: Todd Chapin PharmD
• Organization: Sanford Health

todd.chapin@sanfordhealth.org

701-417-2351

Study Officials

• Cornelius Dyke, MD

  Sanford Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2016
• First Posted: September 5, 2016
• Study Start: September 1, 2016
• Primary Completion: May 11, 2019
• Study Completion: May 11, 2019
• Last Updated: January 22, 2021
• Results First Posted: January 22, 2021

Record last verified: 2020-12

Locations

US (1)