The Safety of Non-vitamin K Oral Anticoagulants Compared to Warfarin Early After Cardiac Surgery
Primary Purpose
Atrial Fibrillation
Status
Unknown status
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Non-vitamin K oral anticoagulants (NOACs)
Warfarin
Sponsored by
About this trial
This is an interventional treatment trial for Atrial Fibrillation focused on measuring postoperative anticoagulation, warfarin, NOAC, cardiac surgery, atrial fibrillation
Eligibility Criteria
Inclusion Criteria:
- Adults ≥18 years
Cardiac surgical procedures
- Coronary artery bypass grafting (on or off pump)
- Bioprosthetic aortic valve replacement
- Mitral valve repair
- Ascending aorta procedures
- Tricuspid valve repair
- Pulmonic valve procedures.
An indication for oral anticoagulation
- Pre-existing AF
- New post-operative atrial fibrillation
- Arterial embolism
- Venous thromboembolism.
Exclusion Criteria:
Cardiac surgical procedure
- Redo-sternotomy
- Bioprosthetic mitral valve replacement
- Mechanical valve replacement
- Transcatheter valve procedure
- Aortic arch procedures
- Pericardectomy
- Post-operative extracorporeal membrane oxygenation
- Heart transplant
- Ventricular assist devices
- Congenital heart procedures
- Stroke within 4 weeks prior to surgery or postoperatively prior to initiation of study drug
- Recent history of heparin-induced thrombocytopenia (less than 3 months)
- High risk for bleeding (e.g. major bleed [intracranial hemorrhage, gastrointestinal bleed] within past 3 months, unexplained drop in hemoglobin pre-operatively)
- Postoperative bleeding requiring return to operating room for exploration prior to randomization
- Perioperative severe renal failure, defined as any eGFR <30 mL/min/1.73m2 or requirement of dialysis
- Perioperative liver failure with alanine aminotransferase > 3x upper limit of normal
- Pregnant or lactating women
- Patient unable to consent
- Contraindication to any study drug (including use of concomitant strong P-glycoprotein or cytochrome P450 enzyme inducers/inhibitors).
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Non-Vitamin K Oral Anticoagulant (NOAC) Group
Warfarin Group
Arm Description
Anticoagulation with a NOAC (Apixaban, Dabigatran, Edoxaban, Rivaroxaban)
Anticoagulation with warfarin to target INR 2.5
Outcomes
Primary Outcome Measures
Successful recruitment rate
The percentage of eligible participants who can be successfully recruited in the study
Adherence rate to the anticoagulation protocol
The percentage of participants who are adherent to the pre-specified anticoagulation protocol (ie. day of initiation of NOAC or warfarin, indication and dosing of bridging) during index hospital stay
Composite safety endpoint
The percentage of participants who experience all-cause mortality, major bleeding, stroke or systemic embolism, pericardial effusion requiring intervention
Secondary Outcome Measures
Full Information
NCT ID
NCT05006287
First Posted
May 29, 2021
Last Updated
August 6, 2021
Sponsor
St. Paul's Hospital, Canada
1. Study Identification
Unique Protocol Identification Number
NCT05006287
Brief Title
The Safety of Non-vitamin K Oral Anticoagulants Compared to Warfarin Early After Cardiac Surgery
Official Title
A Randomized Trial of the Safety of Non-vitamin K Oral Anticoagulants Compared to Warfarin Early After Cardiac Surgery: a Pilot Study
Study Type
Interventional
2. Study Status
Record Verification Date
August 2021
Overall Recruitment Status
Unknown status
Study Start Date
October 1, 2021 (Anticipated)
Primary Completion Date
November 30, 2022 (Anticipated)
Study Completion Date
November 30, 2022 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
St. Paul's Hospital, Canada
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
A small pilot study comparing different blood thinners (non-vitamin K oral anticoagulants [NOACs] and warfarin) will be conducted in people at risk for blood clots after open-heart surgery. This study will help us design a much bigger study to test the effectiveness and safety of different blood thinners in people after open-heart surgery. The study will test the following hypotheses: (1) Our standardized use of different blood thinners is feasible in patients early after cardiac surgery. (2) NOACs are safe to use early after cardiac surgery.
Detailed Description
Patients undergoing cardiac surgery (CVS) have various indications for anticoagulation, with the most common being pre-existing atrial fibrillation (AF) or post-operative atrial fibrillation (POAF). The incidence of POAF is up to 42% and both pre-existing AF and POAF have been associated with 62% higher odds of stroke and 44% higher odds of mortality. Even though non-vitamin K oral anticoagulants (NOACs) have superseded warfarin as the choice anticoagulant for non-valvular AF based on the results of landmark trials, these trials generally excluded patients with recent CVS. Although recommendations on anticoagulation for POAF are extrapolated from general AF guidelines, there is hesitancy to use NOACs early after cardiac surgery due to concerns regarding hemorrhagic cardiac tamponade and the fast anticoagulant onset of these agents with limited access to reversal agents. The investigators recently conducted a systematic review of 7 studies evaluating NOACs in the post-CVS setting, which identified insufficient evidence regarding the safety and efficacy of NOACs versus warfarin. Despite there being 3 planned randomized controlled trials (RCT) comparing NOACs to warfarin early following cardiac surgery, none indicated a standardized bridging protocol, which is a significant limitation, as anticoagulation trials lacking in standardized bridging may significantly influence incidences of bleeding and embolic events. The investigators propose a multi-centered pilot RCT of 100 patients comparing NOACs to warfarin initiated early after cardiac surgery (ie. within the index hospitalization) to determine the feasibility of conducting a large, definitive RCT. Patients with an indication for anticoagulation (most common being pre-existing AF or POAF), will be randomized to receive a NOAC (starting on post-operative day [POD] 5 or later) or warfarin (starting on POD 1 or at time of diagnosis of indication for anticoagulation) and supported by a standardized bridging protocol with unfractionated heparin infusion or low molecular weight heparin as early as POD 3 in patients with high-risk of thrombosis and low risk of bleeding. The co-primary feasibility outcomes are (1) >70% of eligible patients recruited into the study, and (2) >80% adherence to the anticoagulation protocol (defined as adherence to the bridging protocol and the initiation of the study drug on the right POD). The primary scientific outcome is a composite of death, stroke or systemic embolism, major bleeding, or pericardial effusion requiring intervention. Follow up will be conducted at 1 and 3 months and corroborated by re-admission data. The results of this pilot RCT will inform the design and feasibility of a large definitive RCT.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Atrial Fibrillation
Keywords
postoperative anticoagulation, warfarin, NOAC, cardiac surgery, atrial fibrillation
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
a multi-center, prospective, randomized, open-label, blinded-endpoint (PROBE) pilot study
Masking
None (Open Label)
Allocation
Randomized
Enrollment
100 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Non-Vitamin K Oral Anticoagulant (NOAC) Group
Arm Type
Experimental
Arm Description
Anticoagulation with a NOAC (Apixaban, Dabigatran, Edoxaban, Rivaroxaban)
Arm Title
Warfarin Group
Arm Type
Active Comparator
Arm Description
Anticoagulation with warfarin to target INR 2.5
Intervention Type
Drug
Intervention Name(s)
Non-vitamin K oral anticoagulants (NOACs)
Other Intervention Name(s)
Apixaban, Dabigatran, Edoxaban, Rivaroxaban
Intervention Description
NOAC Group (Intervention):
Patients randomized to the NOAC group will receive a NOAC dosed according to the Canadian monograph for the respective indication. Patients receiving a NOAC before cardiac surgery will resume the same NOAC as pre-operatively, whereas patients not previously receiving a NOAC will preferentially receive apixaban according to local practice. The NOAC will be started no earlier than post-operative day 5 and based on the standard protocol depending on whether the patient has a pre-existing indication for anticoagulation or new indication (e.g. post-operative atrial fibrillation).
Patients at high risk of thrombosis and low risk of bleeding will receive a standardized bridging protocol as early as post-operative day 3 with unfractionated heparin infusion or low molecular weight heparin until the NOAC is initiated.
Intervention Type
Drug
Intervention Name(s)
Warfarin
Intervention Description
Warfarin Group (Comparator):
Patients randomized to the warfarin group will receive warfarin titrated to achieve a target International Normalized Ratio (INR) of 2.5 (range 2.0 to 3.0). Warfarin will be started as early as post-operative day 1 and based on the standard protocol depending on whether the patient has a pre-existing indication for anticoagulation or new indication (e.g. post-operative atrial fibrillation).
Patients at high risk of thrombosis and low risk of bleeding will receive a standardized bridging protocol as early as post-operative day 3 with unfractionated heparin infusion or low molecular weight heparin until INR is 2.0 or above.
Primary Outcome Measure Information:
Title
Successful recruitment rate
Description
The percentage of eligible participants who can be successfully recruited in the study
Time Frame
At study completion (ie. 3 months)
Title
Adherence rate to the anticoagulation protocol
Description
The percentage of participants who are adherent to the pre-specified anticoagulation protocol (ie. day of initiation of NOAC or warfarin, indication and dosing of bridging) during index hospital stay
Time Frame
At study completion (ie. 3 months)
Title
Composite safety endpoint
Description
The percentage of participants who experience all-cause mortality, major bleeding, stroke or systemic embolism, pericardial effusion requiring intervention
Time Frame
3 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Adults ≥18 years
Cardiac surgical procedures
Coronary artery bypass grafting (on or off pump)
Bioprosthetic aortic valve replacement
Mitral valve repair
Ascending aorta procedures
Tricuspid valve repair
Pulmonic valve procedures.
An indication for oral anticoagulation
Pre-existing AF
New post-operative atrial fibrillation
Arterial embolism
Venous thromboembolism.
Exclusion Criteria:
Cardiac surgical procedure
Redo-sternotomy
Bioprosthetic mitral valve replacement
Mechanical valve replacement
Transcatheter valve procedure
Aortic arch procedures
Pericardectomy
Post-operative extracorporeal membrane oxygenation
Heart transplant
Ventricular assist devices
Congenital heart procedures
Stroke within 4 weeks prior to surgery or postoperatively prior to initiation of study drug
Recent history of heparin-induced thrombocytopenia (less than 3 months)
High risk for bleeding (e.g. major bleed [intracranial hemorrhage, gastrointestinal bleed] within past 3 months, unexplained drop in hemoglobin pre-operatively)
Postoperative bleeding requiring return to operating room for exploration prior to randomization
Perioperative severe renal failure, defined as any eGFR <30 mL/min/1.73m2 or requirement of dialysis
Perioperative liver failure with alanine aminotransferase > 3x upper limit of normal
Pregnant or lactating women
Patient unable to consent
Contraindication to any study drug (including use of concomitant strong P-glycoprotein or cytochrome P450 enzyme inducers/inhibitors).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Erica HZ Wang, PharmD
Phone
6046822344
Ext
63198
Email
ewang@providencehealth.bc.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Jian Ye, MD
Phone
6048069349
Email
jye@providencehealth.bc.ca
12. IPD Sharing Statement
Plan to Share IPD
No
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The Safety of Non-vitamin K Oral Anticoagulants Compared to Warfarin Early After Cardiac Surgery
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