NEW-AF: Rivaroxaban vs. Warfarin for Post Cardiac Surgery Atrial Fibrillation

Sponsor

Massachusetts General Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT03702582

Collaborator

(none)

300

Enrollment

Location

Arms

Anticipated Duration (Months)

6.2

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation Stroke Bleeding	Drug: Rivaroxaban Drug: Warfarin	Phase 3

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Cardiac surgery patients who meet study criteria and develop recurrent or persistent atrial fibrillation post-operatively will be randomized 1:1 to receive Warfarin or Rivaroxaban for prophylaxis against stroke or other systemic arterial embolismCardiac surgery patients who meet study criteria and develop recurrent or persistent atrial fibrillation post-operatively will be randomized 1:1 to receive Warfarin or Rivaroxaban for prophylaxis against stroke or other systemic arterial embolism

Masking:

None (Open Label)

Masking Description:

Statisticians performing comparative analyses of primary outcomes will be blinded as to the allocation designations of patients. Otherwise there will be no masking in the study.

Primary Purpose:

Prevention

Official Title:

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

Actual Study Start Date :

Apr 30, 2019

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

May 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rivaroxaban Rivaroxaban: Direct inhibitor of Factor Xa, an enzyme that stimulates the formation of thrombin from prothrombin (A critical step in both the intrinsic and extrinsic aspects of the coagulation cascade) Dosage form: Per Os (Oral) Dosage and Frequency: 20 mg every evening with the evening meal (No titration requirements). For patients with decreased glomerular filtration rate (GFR between 15 ml/min and 50 ml/min), dosing will be decreased to 15 mg every evening with the evening meal. Duration: 30 days (Possibility of continuation after post-operative cardiology clinic visit)	Drug: Rivaroxaban Anticoagulant drug that works via direct inhibition of factor Xa. FDA approved for prophylaxis against stroke in non-valvular atrial fibrillation Other Names: Xarelto Database of Molecules (PubChem CID): 6433119
Active Comparator: Warfarin Warfarin: Competitive inhibitor of vitamin K epoxide reductase complex 1, an important enzyme in the activation pathway for vitamin K dependent coagulation factors Dosage form: Per Os (Oral) Dosage and Frequency: Initial dose of 2 - 5 mg nightly after the evening meal (QHS) with appropriate titration to goal INR 2.0 - 3.0 (Initial dose based on weight, age, gender, co-morbidities and concurrent medications). INR will be checked daily to weekly depending on stability of dosing and medication regimen. Duration: 30 days (Possibility of continuation after post-operative Cardiology clinic visit)	Drug: Warfarin Anticoagulation drug that works via inhibition of vitamin K dependent clotting factors. FDA approved for prophylaxis against stroke in atrial fibrillation Other Names: Coumadin Database of Molecules (PubChem CID): 54678486

Arm

Intervention/Treatment

Experimental: Rivaroxaban

Rivaroxaban: Direct inhibitor of Factor Xa, an enzyme that stimulates the formation of thrombin from prothrombin (A critical step in both the intrinsic and extrinsic aspects of the coagulation cascade) Dosage form: Per Os (Oral) Dosage and Frequency: 20 mg every evening with the evening meal (No titration requirements). For patients with decreased glomerular filtration rate (GFR between 15 ml/min and 50 ml/min), dosing will be decreased to 15 mg every evening with the evening meal. Duration: 30 days (Possibility of continuation after post-operative cardiology clinic visit)

Drug: Rivaroxaban

Anticoagulant drug that works via direct inhibition of factor Xa. FDA approved for prophylaxis against stroke in non-valvular atrial fibrillation

Other Names:

Xarelto

Database of Molecules (PubChem CID): 6433119

Active Comparator: Warfarin

Warfarin: Competitive inhibitor of vitamin K epoxide reductase complex 1, an important enzyme in the activation pathway for vitamin K dependent coagulation factors Dosage form: Per Os (Oral) Dosage and Frequency: Initial dose of 2 - 5 mg nightly after the evening meal (QHS) with appropriate titration to goal INR 2.0 - 3.0 (Initial dose based on weight, age, gender, co-morbidities and concurrent medications). INR will be checked daily to weekly depending on stability of dosing and medication regimen. Duration: 30 days (Possibility of continuation after post-operative Cardiology clinic visit)

Drug: Warfarin

Anticoagulation drug that works via inhibition of vitamin K dependent clotting factors. FDA approved for prophylaxis against stroke in atrial fibrillation

Other Names:

Coumadin

Database of Molecules (PubChem CID): 54678486

Outcome Measures

Primary Outcome Measures

Postoperative Length of Stay [Up to 6 months following the cardiac operation]
Length of inpatient stay in days from time of departure from the operating room

Secondary Outcome Measures

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) [Up to 30 days after discharge from the initial postoperative hospitalization]
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
Cerebrovascular accident (CVA) [Up to 30 days after discharge from the initial postoperative hospitalization]
Rates of cerebrovascular accident including stroke and transient ischemic attack (TIA)
Other systemic embolism [Up to 30 days after discharge from the initial postoperative hospitalization]
Rates of non-neurological systemic arterial embolism involving any organ system
Deep venous thrombosis (DVT) and/or Pulmonary Embolism (PE) [Up to 30 days after discharge from the initial postoperative hospitalization]
Occurrence of pathologic venous thrombo-embolism including DVT and PE
Minor Bleeding [Up to 30 days after discharge from the initial postoperative hospitalization]
Minor bleeding defined as blood transfusions <= 2 units or drop in hemoglobin greater 3g/dL following administration of study drugs
Number of Transfusions [Up to 30 days after discharge from the initial postoperative hospitalization]
The number of units of blood transfused for each participant after initiation of study drugs
Hospital Readmission [Up to 30 days after discharge from the initial postoperative hospitalization]
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.
Therapy related costs of anticoagulation [Up to 30 days after discharge from the initial postoperative hospitalization]
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
Performance on the EUROQOL (EQ-5D) Quality of Life Instrument [Up to 30 days after discharge from the initial postoperative hospitalization]
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.
Average score on the Perception of Anticoagulant Treatment Questionnaire (PACT-Q2) [Up to 30 days after discharge from the initial postoperative hospitalization]
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.
Rate of ongoing atrial fibrillation [Up to 30 days after discharge from the initial postoperative hospitalization]
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.
Rate of Mortality [Up to 30 days after discharge from the initial postoperative hospitalization]
Mortality during study follow up will be documented and rates will compared across intervention groups. Cause of death will be documented
Rates of adverse clinical outcomes [Up to 30 days after discharge from the initial postoperative hospitalization]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

Massachusetts General Hospital

Investigators

Principal Investigator: Asishana A Osho, MD, MPH, Massachusetts General Hospital
Principal Investigator: Thoralf M Sundt, MD, Massachusetts General Hospital