Rivaroxaban vs. Warfarin for Post Cardiac Surgery Atrial Fibrillation

Stroke Clinical Trial

— NEW-AF  

Official title:

Trial of New Oral Anticoagulants vs. Warfarin for Post Cardiac Surgery Atrial Fibrillation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03702582
• Other study ID #: 2018P002307
• Status: Completed
• Phase: Phase 3
• Start date: April 30, 2019
• Est. completion date: October 1, 2023

Study information

• Verified date: October 2023
• Source: Massachusetts General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This prospective, randomized, active-controlled, parallel arm study compares the safety and financial benefits of arterial thromboembolism prophylaxis with Warfarin vs. Rivaroxaban (A novel oral anticoagulant) in patients with new onset atrial fibrillation after sternotomy for cardiac operations.

Description:

New onset atrial fibrillation (NOAF) is a common occurrence following cardiac surgery, occurring in 20-30% of patients post-operatively. Historically, Vitamin K antagonist therapy with Warfarin has been the treatment of choice for prophylaxis against stroke and systemic arterial thromboembolism in NOAF. Warfarin inhibits the Vitamin K dependent factors involved in both the intrinsic and extrinsic coagulation cascades, thus decreasing systemic clotting. However, Warfarin therapy comes with many challenges including prolonged titration, tedious monitoring requirements and in some cases, increased bleeding risk.

The limitations associated with Warfarin may be mitigated by using new oral anticoagulants (NOACs) like Rivaroxaban which have no routine monitoring requirements. Rivaroxaban is a direct inhibitor of Factor Xa, a central reactant in both the intrinsic and extrinsic coagulation cascades. Studies in non-operative patients with atrial fibrillation have shown that Rivaroxaban is non-inferior to Warfarin for stroke prophylaxis with similar risk profiles. This study aims to compare the efficacy, safety and financial cost of these two drugs when used for the management of new onset atrial fibrillation that occurs after cardiac operations.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: October 1, 2023
• Est. primary completion date: October 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or Female = 18 years

• At least one of the following procedures: coronary artery bypass grafting, aortic valve repair, mitral valve repair, non-mechanical aortic valve replacement, any combination of these procedures

• Two or more episodes of New Onset Atrial Fibrillation (each lasting > 20 minutes) or persistent atrial fibrillation lasting > 24 hours (Or for >18 hours over a 24-hour interval)

• If female of child-bearing age, use of adequate contraception

Exclusion Criteria:

• Pre-existing paroxysmal atrial fibrillation before cardiac surgery

• Pre-existing indications for therapeutic anticoagulation (Including but not limited to PE, DVT, mechanical valve)

• Moderate-to-severe mitral valve stenosis not surgically corrected

• Pre-existing allergy to study medications

• Recent (< 1 year) or ongoing pregnancy (Urine pregnancy test will be obtained for women of child bearing age at the time of enrollment into the study)

• Stroke within 1 month prior to surgery or postoperatively prior to initiation of study drugs

• Postoperative bleeding episode prior to initiation of study drug

• Severe dysfunction of another organ system including GFR < 30 ml/min, baseline INR > 1.7, ileus or other gastrointestinal pathology hindering ability to absorb oral medications, and known coagulation pathway deficiencies

• Postoperative need for non-aspirin anti-platelet therapy that cannot be discontinued when therapeutic anticoagulation is initiated

• Patient taking medications with known major interactions with study drugs with no therapeutic alternatives)

Related Conditions & MeSH terms

• Atrial Fibrillation
• Bleeding
• Hemorrhage
• Stroke

Intervention

Drug:
• Rivaroxaban
Anticoagulant drug that works via direct inhibition of factor Xa. FDA approved for prophylaxis against stroke in non-valvular atrial fibrillation
• Warfarin
Anticoagulation drug that works via inhibition of vitamin K dependent clotting factors. FDA approved for prophylaxis against stroke in atrial fibrillation

Locations

Country	Name	City	State
United States	Massachusetts General Hospital	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Massachusetts General Hospital

Country where clinical trial is conducted

United States, 

References & 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. — View Citation

Butt JH, Xian Y, Peterson ED, Olsen PS, Rorth R, Gundlund A, Olesen JB, Gislason GH, Torp-Pedersen C, Kober L, Fosbol EL. Long-term Thromboembolic Risk in Patients With Postoperative Atrial Fibrillation After Coronary Artery Bypass Graft Surgery and Patients With Nonvalvular Atrial Fibrillation. JAMA Cardiol. 2018 May 1;3(5):417-424. doi: 10.1001/jamacardio.2018.0405. Erratum In: JAMA Cardiol. 2018 Jun 1;3(6):505. — View Citation

Charlton B, Adeboyeje G, Barron JJ, Grady D, Shin J, Redberg RF. Length of hospitalization and mortality for bleeding during treatment with warfarin, dabigatran, or rivaroxaban. PLoS One. 2018 Mar 28;13(3):e0193912. doi: 10.1371/journal.pone.0193912. eCollection 2018. — View Citation

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. Erratum In: N Engl J Med. 2010 Nov 4;363(19):1877. — View Citation

Gillinov AM, Bagiella E, Moskowitz AJ, Raiten JM, Groh MA, Bowdish ME, Ailawadi G, Kirkwood KA, Perrault LP, Parides MK, Smith RL 2nd, Kern JA, Dussault G, Hackmann AE, Jeffries NO, Miller MA, Taddei-Peters WC, Rose EA, Weisel RD, Williams DL, Mangusan RF, Argenziano M, Moquete EG, O'Sullivan KL, Pellerin M, Shah KJ, Gammie JS, Mayer ML, Voisine P, Gelijns AC, O'Gara PT, Mack MJ; CTSN. Rate Control versus Rhythm Control for Atrial Fibrillation after Cardiac Surgery. N Engl J Med. 2016 May 19;374(20):1911-21. doi: 10.1056/NEJMoa1602002. Epub 2016 Apr 4. — View Citation

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. — View Citation

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. — View Citation

Hawks MK, Bryce C. Rivaroxaban vs. Warfarin for Anticoagulation in Patients with Atrial Fibrillation Undergoing Ablation and Cardioversion. Am Fam Physician. 2016 Oct 1;94(7):Online. No abstract available. — View Citation

Megens MR, Churilov L, Thijs V. New-Onset Atrial Fibrillation After Coronary Artery Bypass Graft and Long-Term Risk of Stroke: A Meta-Analysis. J Am Heart Assoc. 2017 Dec 22;6(12):e007558. doi: 10.1161/JAHA.117.007558. — View Citation

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. — View Citation

Spyropoulos AC, Ageno W, Albers GW, Elliott CG, Halperin JL, Hiatt WR, Maynard GA, Steg PG, Weitz JI, Suh E, Spiro TE, Barnathan ES, Raskob GE; MARINER Investigators. Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. doi: 10.1056/NEJMoa1805090. Epub 2018 Aug 26. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Postoperative Length of Stay	Length of inpatient stay in days from time of departure from the operating room	Up to 6 months following the cardiac operation
Secondary	Episode of Major Bleeding (Defined as the occurrence of any of several events listed in the description. No specific scale, questionnaire or instrument will be used)	Major bleeding defined as re-operation or other therapeutic intervention for bleeding (including but not limited to colonoscopy, upper endoscopy and urologic procedures for hematuria), development of any intracranial bleeding, cessation of study drug for bleeding concerns, reversal of study drug for bleeding concerns and/or new transfusion requirement > 2 units of blood after drug administration	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Cerebrovascular accident (CVA)	Rates of cerebrovascular accident including stroke and transient ischemic attack (TIA)	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Other systemic embolism	Rates of non-neurological systemic arterial embolism involving any organ system	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Deep venous thrombosis (DVT) and/or Pulmonary Embolism (PE)	Occurrence of pathologic venous thrombo-embolism including DVT and PE	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Minor Bleeding	Minor bleeding defined as blood transfusions <= 2 units or drop in hemoglobin greater 3g/dL following administration of study drugs	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Number of Transfusions	The number of units of blood transfused for each participant after initiation of study drugs	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Hospital Readmission	Readmissions will be counted in this calculation if patients are admitted to the hospital. Emergency room visits without admission and outpatient visits will not count toward this calculation of readmission rates.	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Therapy related costs of anticoagulation	Specific drug related costs will be estimated in dollars for patients in each intervention arm. This will include costs of all administered drug doses as well as costs of associated laboratory studies and mileage based costs of travel to INR testing centers	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Performance on the EUROQOL (EQ-5D) Quality of Life Instrument	Participants will be administered the EUROQOL-5D-3L (5 dimensions, 3 levels) questionnaire to derive an estimate of the health state. This is comprised of a 5 questions survey and a single visual analog scale highlighting perceived health levels; For the 5 questions survey, each question related to mobility, selfcare, mood, pain and/or functionality is answered on a three point scale with higher number representing worse outcomes. The entire dataset is used to generate a health state based on the unique pattern of answers. These health states are then compared against standardized country-based value sets which provide an assessment of quality of life based on societal preferences.; The visual analog scale is single answer between 0 and 100 representing the patient's perception of their health state. 0 represents the worst health imaginable and 100 represents the best.	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Average score on the Perception of Anticoagulant Treatment Questionnaire (PACT-Q2)	Participants will be administered the PACT-Q2 questionnaire which is comprised of a convenience subscale and a satisfaction subscale.; For the convenience subscale, each of 13 questions is answered on a 1-5 rating scale with higher numbers representing worse outcomes. A sub-scale score is generated by inverting the score from each element and calculating the sum. Range on the inverted scale is 13 - 65. Higher scores represent better outcomes.; For the satisfaction subscale, each of 7 questions is answered on a 1-5 rating scale with higher numbers representing better outcomes. The total score on this subscale is generated by adding up scores from all elements. Range on this subscale is 7-35. Higher scores represent better outcomes.; A composite score is generated by adding up scores from both subscales and recalibrating on a 0-100 scale by adding the scores together and applying the formula: COMPOSITE SCORE=100×(Sum-20)/80. Higher scores represent more favorable outcomes.	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Rate of ongoing atrial fibrillation	EKGs will be obtained at various time points during the study to determine whether participants remain in atrial fibrillation during the follow up period. From each EKG, existence of p-waves, regularity of the overall wave form and heart rate will be evaluated to determine if patients remain in atrial fibrillation or if they have spontaneously converted to a normal sinus rhythm.	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Rate of Mortality	Mortality during study follow up will be documented and rates will compared across intervention groups. Cause of death will be documented	Up to 30 days after discharge from the initial postoperative hospitalization
Secondary	Rates of adverse clinical outcomes	Other adverse clinical outcomes will be documented and rates compared between intervention arms including: Acute Kidney Injury, Infection, Heart Failure, Pericardial Effusion, Myocardial infarction, Pleural Effusion and Hepatic dysfunction	Up to 30 days after discharge from the initial postoperative hospitalization