Dabigatran for Mitral Stenosis Atrial Fibrillation

Study Overview
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Brief Summary
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Atrial fibrillation (AF) is the most common sustained cardiac arrythmia encountered in clinical practice and patients suffer from this are at increased risk of ischemic stroke and systemic thromboembolism due to the formation and embolism of left atrial thrombi. Current international guidelines recommend non-vitamin K oral anticoagulants (NOACs) for stroke prevention amongst these patients with non-valvular AF at significant ischemic stroke risk, given the superior safety and comparable efficacy of NOACs over warfarin. However, warfarin therapy remains in the stroke prevention strategy for AF patients with mitral stenosis (MS) as NOACs lack of evidence for safety and efficacy amongst this group of patients. A local study is initiated to compare and evaluate the safety and efficacy among the two groups of anticoagulants - NOACs and traditional Warfarin therapy - in AF patients with underlying moderate to severe MS.

Detailed Description
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While the stroke risk amongst AF patients appears heterogeneous, patients with underlying valvular heart diseases particularly MS are at very high risk for stroke if left un-anticoagulated. However, this group of patients were typically excluded in randomized control trials. As a result, current international guidelines for management of AF do not recommend NOACs for stroke prevention in AF patients with underlying moderate or severe MS. In a stark contrast to developed countries, mitral stenosis remains prevalent in many Asian countries. Together with the much higher intracranial haemorrhage risk in Asians on Warfarin, NOACs appear to be a very attractive and promising alternative. Nonetheless off-label use of NOACs in patients with MS is not uncommon in the real world practice. This study refers as a prospective, randomized, open-label trial with blinded end-point adjudication, aiming at evaluating the safety and efficacy of Dabigatran for stroke prevention in AF patients with underlying moderate or severe mitral stenosis. Subjects enrolled in this study will be randomized into 2 groups in a 1:1 ratio, to receive either Dabigatran (150mg or 110mg according to creatinine clearance level, twice daily) or Warfarin (targeting in the international normalized ratio (INR) range 2-3) in an open-label design. Primary and secondary outcomes will be assessed, including ischemic stroke, systemic embolism, haemorrhagic stroke, intracranial haemorrhage, major bleeding and death. The estimated sample size is approximately 686 participants. The results will contribute to the stroke prevention strategy for patients with mitral stenosis and may be immediately translatable to real clinical practice. Ultimately, this study will provide the necessary evidence for establishing universal guidelines for this group of patients.

Official Title
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Rationale and Design of Dabigatran for Mitral Stenosis Atrial Fibrillation Trial

Conditions
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Atrial Fibrillation, Mitral Stenosis

Intervention / Treatment
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* Drug: Dabigatran etexilate
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with atrial fibrillation documented with standard 12-lead ECG documented atrial fibrillation on the day of screening or randomization Patients with age 18 years old or above Patients with moderate or severe mitral stenosis, i.e. mitral valvular area (MVA) <1.5cm2 Patients should be able to provide a written informed consent Patients should have all 4 inclusion-criteria fulfilled to be qualified for the study Exclusion Criteria: Patients with prosthetic valve, or with active endocarditis Patients with planned valvular intervention within 1 year Patients with left atrial appendage occlusive device Patients with planned AF ablation Patients with history of intracranial, intraocular, spinal, or retroperitoneal bleeding Unexplained anemia (haemoglobin level <10g/dL) or thrombocytopenia (platelet count <100x10*9/L) Need for anticoagulant therapy of disorders other than atrial fibrillation Patients receiving antiplatelet therapy for disorders other an atrial fibrillation Uncontrolled hypertension (systolic blood pressure >180mmHg and/or diastolic blood pressure >100mmHg) Estimated creatinine clearance equal to or less than 30mL/min Liver dysfunction of Child Pugh stage B or C Women who are pregnant or of childbearing potential who refuse to use a medically acceptable form of contraception throughout the study Patients considered unreliable by the investigator or have a life expectancy less than 1 year because of concomitant disease, or has any condition, which in the opinion of the investigator, would not allow safe participation in the study (e.g. drug addiction, alcohol abuse)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabigatran etexilate<br>Subjects randomized into this group will be prescribed with either Dabigatran 150mg or Dabigatran 110mg (twice daily) according to creatinine clearance level, twice daily) for stroke prevention. | Drug: Dabigatran etexilate<br>* Subjects will be randomized into 2 groups in a 1:1 ratio, to receive either Dabigatran or Warfarin for stroke prevention, in a open-label design.<br>* Other names: Pradaxa;|
| Active Comparator: Warfarin<br>Subjects randomized into this group will be prescribed with Warfarin with dosage adjustment according to INR level (targeting to INR 2-3) for stroke prevention. | Drug: Warfarin<br>* Subjects will be randomized into 2 groups in a 1:1 ratio, to receive either Dabigatran or Warfarin for stroke prevention, in a open-label design.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stroke | It is defined as a neurological deficit of sudden onset that persisted for more than 24 hours and corresponded to a vascular territory that cannot be explained by other causes. It will be further classified as ischemic stroke and haemorrhagic stroke according to computerized axial tomography or magnetic resonance imaging of the brain. | 1 year | 
| Systemic embolism | It is defined as an acute vascular occlusion of an extremity or organ other than the brain, documented by imaging, surgery, and/or autopsy. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ischemic stroke | It is diagnosed with computerized axial tomography or magnetic resonance imaging of the brain. | 1 year | 
| Haemorrhagic stroke | It is diagnosed with computerized axial tomography or magnetic resonance imaging of the brain. | 1 year | 
| Intracranial haemorrhage | It consists of haemorrhagic stroke (intracerebral haemorrhage and cerebellar haemorrhage), subdural haemorrhage, and subarachnoid haemorrhage, and will be confirmed with computerized axial tomography or magnetic resonance imaging of the brain. | 1 year | 
| Major bleeding | It is defined as a drop in the haemoglobin level of at least 2g/dL, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. Life-threatening bleeding includes fatal bleeding, symptomatic intracranial bleeding, bleeding with a haemoglobin drop of at least 5g/dL, or bleeding requiring transfusion of at least 4 units of blood or inotropic agents or requiring surgery. | 1 year | 
| Death | It is defined as medically certified cessation of life. | 1 year |