Clinical trial NCT04284839: The Direct Oral Anticoagulation Versus Vitamin K Antagonist After Cardiac Surgery Trial
Official title: The Direct Oral Anticoagulation Versus Vitamin K Antagonist After Cardiac Surgery Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Bleeding Post Cardiac Surgery
Indication for Anticoagulation
Keywords: Direct Oral Anticoagulant
Vitamin K Antagonist
Bleeding
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: Hamilton Health Sciences Corporation
First posted: 2020-02-26
Enrollment: 3500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: The DANCE Trial is a multi-centre, randomized controlled trial comparing the safety of direct oral anticoagulants (DOAC) versus vitamin K antagonists (VKA) in the early period (30 days) after cardiac surgery in patients with atrial fibrillation requiring oral anticoagulation.

Detailed description: Approximately 36,000 Canadian adults undergo cardiac surgery annually. Of these patients, about 10% have a prior history of atrial fibrillation (AF). In the early post-operative period after cardiac surgery, 30-60% of patients develop AF and, by the time of discharge, 32% of patients who underwent cardiac surgery have an indication for oral anticoagulation (OAC). AF is associated with a significantly higher risk of stroke, even when transient, and OAC is the standard for thromboembolic prevention in these patients. In the post-operative period, the balance of benefits and risks of OAC may differ and the safest and most effective OAC in that patient population is uncertain.

Vitamin K antagonists (VKAs), such as warfarin or coumadin, are the most used anticoagulants after cardiac surgery. In the Left Atrial Appendage Occlusion Study (LAAOS) III that recruited 4811 patients from 105 centres in 27 countries, 77% of patients with AF on OAC were discharged on a VKA after cardiac surgery. Among patients taking a DOAC preoperatively, 55% were switched to a VKA after surgery. Over the first post-operative year, most of those patients were gradually transitioned back to a DOAC. Although effective, the use of VKAs is limited by a narrow therapeutic index requiring frequent international normalized ratio (INR) measurements to ensure appropriate levels of anticoagulation. This key limitation leads to non-compliance and discontinuation. In addition, in the first 3 months after cardiac surgery, time in the therapeutic range is low, even with close monitoring by experienced prescribers.

In the last decade, DOACs - inhibitors of factor Xa or thrombin- have become broadly used in patients with AF. Treatment with a DOAC in patients with AF has been demonstrated to yield a lower risk of stroke or systemic embolism and a similar risk of major bleeding when compared to VKAs during long-term follow-up. Moreover, DOACs are more convenient for both patients and clinicians. They have a rapid onset of effect, fixed dosage that obviates the need for regular monitoring, and few interactions with food and other medications. In the postoperative setting, DOACs may also lead to shorter length of stay and reduced costs.

The purpose of this study is to establish whether DOACs are as safe as VKAs in the first few weeks after heart surgery. The results of this study will impact the treatment of hundreds of thousands of patients in the world every year.

A subset of 910 DANCE participants with a recent bioprosthetic aortic and/or mitral valve replacement will be enrolled in the SUNDANCE substudy (Subclinical valve thrombosis in patients with surgical bioprosthetic valve replacement: An imaging substudy of the DANCE trial). SUNDANCE will examine the effects of DOACs versus VKAs on subclinical valve thrombosis and bioprosthetic valve function by conducting computed tomography (CT) scans and echocardiograms at 60 to 90 days after randomization.

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years at the time of enrolment,
2. Open heart surgery in the last 10 days,
3. Atrial fibrillation requiring anticoagulation (including pre-existing or post-operative atrial fibrillation),
4. Informed consent from either the patient or a substitute decision-maker.

Exclusion Criteria:

1. Mechanical valve replacement,
2. Antiphospholipid syndrome (triple positive),
3. Severe renal failure (Cockcroft-Gault equation; creatinine clearance \<15 ml/min),
4. Known significant liver disease (Child-Pugh classification B and C),
5. Left ventricular thrombus,
6. Ongoing bleeding, hemorrhagic disorders, or bleeding diathesis,
7. Known contraindication for any DOAC or VKA,
8. Women who are pregnant, breastfeeding, or of childbearing potential,
9. Surgery including left ventricular assist device implantation or cardiac transplantation,
10. Previously enrolled in this trial,
11. Follow-up not possible,
12. History of moderate or severe mitral valvular lesion (stenosis or regurgitation) that is not corrected during index cardiac surgery.

Primary outcomes:
measure: Major Bleeding
timeFrame: 30-Days post-randomization
Secondary outcomes:
measure: Composite of stroke and non-central nervous system systemic arterial embolism at 30 and 90 days.
timeFrame: 30-Days and 90-Days post-randomization
measure: Major Bleeding
timeFrame: 90-Days post-randomization
measure: Pleural or pericardial effusion requiring drainage
timeFrame: 30-Days and 90-Days post-randomization
measure: Systemic arterial embolism
timeFrame: 30-Days and 90-Days post-randomization
measure: Ischemic stroke
timeFrame: 30-Days and 90-Days post-randomization
measure: Deep vein thrombosis
timeFrame: 30-Days and 90-Days post-randomization
measure: Pulmonary Embolism
timeFrame: 30-Days and 90-Days post-randomization
measure: Length of post-operative hospital stay
timeFrame: 30-Days and 90-Days post-randomization
measure: All-Cause Mortality
timeFrame: 6 Months post-randomization
Other outcomes:
measure: Minor Bleeding
timeFrame: 30-Days and 90-Days post-randomization
measure: All bleeding (major plus minor)
timeFrame: 30-Days and 90-Days post-randomization
measure: Myocardial Infarction
timeFrame: 30-Days and 90-Days post-randomization
measure: Valve Thrombosis
timeFrame: 30-Days and 90-Days post-randomization
measure: Hemorrhagic stroke
timeFrame: 30-Days and 90-Days post-randomization
measure: All Stroke
timeFrame: 30-Days and 90-Days post-randomization
measure: All Arterial Thrombosis/thromboembolism
timeFrame: 30-Days and 90-Days post-randomization
measure: Quality of Life - EQ-5D-5L
timeFrame: 30-Days and 90-Days post-randomization
measure: Patient Satisfaction with Anticoagulant treatment
timeFrame: 30-Days and 90-Days post-randomization
measure: Subclinical Valve Thrombosis on CT scan
timeFrame: 60 to 90-Days post-randomization
measure: Mean Aortic Valve g=Gradient on echocardiogram
timeFrame: 60 to 90-Days post-randomization
measure: Aortic Valve Reintervention
timeFrame: 60 to 90-Days post-randomization
measure: Association between subclinical valve thrombosis and clinically significant aortic valve thrombosis, stroke or systemic embolism
timeFrame: 90 days
Locations:
city: Fitzroy
country: Australia
facility: St Vincent's Hospital Melbourne
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital, University of Melbourne
state: Victoria
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Winnipeg
country: Canada
facility: St. Boniface Hospital
state: Manitoba
city: Saint John
country: Canada
facility: Saint John Regional Hospital
state: New Brunswick
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: Hôpital Sacré-Coeur de Montréal
state: Quebec
city: Montréal
country: Canada
facility: Montreal Heart Institute
state: Quebec
city: Quebec City
country: Canada
facility: IUCPQ-ULaval
state: Quebec
city: Leipzig
country: Germany
facility: Heart Center Leipzig
state: Saxony
city: Jena
country: Germany
facility: University Hospital Jena
state: Thuringen
city: Bonn
country: Germany
facility: University Hospital Bonn Heart Center
city: Essen
country: Germany
facility: West-German Heart and Vascular Center, University of Duisburg-Essen
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
Study officials:
affiliation: McMaster University
name: Emilie Belley-Cote, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: