Atrial Fibrillation
Conditions
Brief summary
The primary objective of this trial is to assess the safety of an uninterrupted dabigatran etexilate periprocedural anticoagulant regimen compared to an uninterrupted warfarin regimen in Non-Valvular Atrial Fibrillation (NVAF) patients undergoing Atrial Fibrillation (AF) ablation in a PROBE (Prospective, randomized, open label, blinded end point) active controlled study. Secondary objectives are to assess additional safety endpoints and efficacy in this clinical setting. It is not intended to assess confirmatory hypothesis, this is an exploratory study.
Interventions
DRUGWarfarin
Patients receiving Warfarin to keep International Normalized Ratio (INR)between 2.0 - 3.0
Patients receiving Dabigatran Etexilate 150mg twice daily dosing (BID)
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients aged \>= 18 years. * Patients eligible for treatment with dabigatran etexilate 150 mg b.i.d. according to local label. * Treatment naïve patients or patients on oral anticoagulant treatment with a Vitamin K Antagonist (VKA), dabigatran etexilate, rivaroxaban, apixaban or edoxaban. * Patient with paroxysmal or persistent NVAF with a planned catheter ablation for AF unless it is performed an investigational ablation technique. * AF must have been documented at least once either by ECG, Holter monitoring, loop recorder, telemetry, trans-telephonic monitoring, pacemaker or cardiac defibrillator read outs within 24 months prior to screening (Visit 1). * The patient must be able to give informed consent in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and local legislation and/or regulations.
Exclusion criteria
* Patients with permanent AF. * Patients with AF felt to be secondary to an obvious reversible cause such as, but not limited to, an acute myocardial infarction, pulmonary embolism, recent surgery, pericarditis or thyrotoxicosis. * Patients with Left Atrium (LA) size \>= 60 mm * Patients with contraindications to systemic anticoagulation with heparin, warfarin or dabigatran etexilate * Patients with a known allergy to warfarin tablets and it excipients or to dabigatran etexilate or its excipients * Mechanical or biological heart valve prosthesis * Severe renal impairment (estimated Creatinine Clearance (CrCl) calculated by Cockcroft-Gault equation) \<30mL/min at screening * Stroke within 1 month prior to screening visit * Major surgery per investigator judgement within the previous month prior to screening. * Patient has received an organ transplant or is on a waiting list for an organ transplant * History of intracranial haemorrhage, intraocular, spinal, retroperitoneal or non-traumatic intra-articular bleeding * Gastrointestinal haemorrhage within one month prior to screening, unless, in the opinion of the investigator, the cause has been permanently eliminated (e.g. by surgery). * Major bleeding episode (ISTH definition) one month prior to the screening visit. * Haemorrhagic disorder or bleeding diathesis (e.g. von Willebrand disease, haemophilia A or B or other hereditary bleeding disorder, history of spontaneous intra-articular bleeding, history of prolonged bleeding after surgery/intervention) * Anaemia (haemoglobin \<10g/dL) or thrombocytopenia including heparin-induced thrombocytopenia (platelet count \<100 x 10\^9/L) at screening * Recent malignancy or radiation therapy (\<=6 months prior to screening) unless, in the opinion of the Investigator, the estimated life expectancy is greater than 36 months * Active liver disease as indicated by at least one of the following: \-- Prior and persistent alanine aminotransferase or Aspartate transaminase or alkaline phosphatase \>3x upper limit of normal and/or -- Known active hepatitis C and/or -- Known active hepatitis B and/or -- Known active hepatitis A * Need for continued treatment with systemic ketoconazole, itraconazole, posaconazole, cyclosporine, tacrolimus, dronedarone, rifampicin, phenytoin, carbamazepine, St. John's Wort or any cytotoxic/myelosuppressive therapy. * Pre-menopausal (last menstruation \<=1 year prior to screening) who: * Are pregnant or breast-feeding or plan to become pregnant during study or * Are not surgically sterile or * Are of child bearing potential and not practising two acceptable method of birth control, or do not plan to continue practising an acceptable method of birth control throughout the trial * Patients who have participated in another trial with an investigational drug or device within the past 30 days preceding the screening visit or are participating in another trial (patients participating in an observational study only will not be excluded) * Patients not willing or able to comply with the protocol requirements or considered unreliable by the Investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, who have a life expectancy less than the expected duration of the trial due to concomitant disease and/or subjects who are institutionalised due to official or court orders and/or vulnerable subjects who are dependent on the Sponsor or the Investigator or the site, or patients who have any condition which in the opinion of the Investigator, would not allow safe participation in the study (e.g. drug addiction, alcohol abuse).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Major Bleeding Events (MBEs), as Defined by the International Society on Thrombosis and Haemostasis (ISTH) | during and up to 2 months post-ablation | Major bleeds were defined according to the ISTH definition of a major bleed, as follows * Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or * Bleeding associated with a reduction in haemoglobin of at least 2 g/dL (1.24 mmol/L), or leading to transfusion of 2 or more units of blood or packed cells. and/or * Fatal bleed These are based on adjudicated data (blinded evaluation) Point estimates for the incidence of ISTH MBEs and their 2-sided 95% confidence intervals (CI), based on the normal approximation of independent binomial distribution without stratification, are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of the Composite of Stroke, Systemic Embolism, or Transient Ischemic Attack (TIA) | during and up to 2 months post-ablation | Stroke was defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of haemorrhage or infarction. Systemic embolism was defined as an acute vascular occlusion of the extremities or any organ (kidneys, mesenteric arteries, spleen, retina or grafts) and was to be documented by angiography, surgery, scintigraphy or autopsy. Transient ischemic attack was defined as a transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischemia, without acute infarction. These are based on adjudicated data (blinded evaluation). Percentage of patients with composite of stroke, systemic embolism, or transient ischemic attack (TIA) is presented |
| Incidence of Minor Bleeding Events | during and up to 2 months post-ablation | Minor bleeds were clinical bleeds that did not fulfil the criteria for major bleeds. Percentage of patients with Minor bleeding events are presented. These are based on adjudicated data (blinded evaluation) |
| Incidence of ISTH MBE, Stroke, Systemic Embolism, or TIA (Composite Endpoint Combining Safety and Efficacy | during and up to 2 months post-ablation | Percentage of patients with ISTH MBE, stroke, systemic embolism, or TIA (composite endpoint combining safety and efficacy) are presented. These are based on adjudicated data (blinded evaluation) |
Countries
Belgium, Canada, France, Germany, Italy, Japan, Netherlands, Russia, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Patients were randomly assigned to dabigatran etexilate 150 mg twice daily or warfarin in a 1:1 ratio and remained on this treatment for the duration of the trial. 678 subjects were randomised and 676 were treated.
Participants by arm
| Arm | Count |
|---|---|
| Dabigatran Etexilate 150 mg Patients receiving Dabigatran Etexilate 150 mg capsule orally twice daily (BID);
1 capsule 150 mg twice daily (total daily dose 300 mg) | 338 |
| Warfarin Patients receiving Warfarin tablet orally;
1, 3, and 5 mg (dose adjusted to International normalized ratio (INR) target range) | 338 |
| Total | 676 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Consent withdrawn | 1 | 3 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | No ablation | 21 | 20 |
| Overall Study | Non-compliant with Protocol | 1 | 0 |
| Overall Study | Reason other than specified | 1 | 1 |
Baseline characteristics
| Characteristic | Dabigatran Etexilate 150 mg | Warfarin | Total |
|---|---|---|---|
| Age, Continuous | 59.2 years STANDARD_DEVIATION 10.33 | 59.4 years STANDARD_DEVIATION 10.29 | 59.3 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 93 Participants | 81 Participants | 174 Participants |
| Sex: Female, Male Male | 245 Participants | 257 Participants | 502 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 68 / 338 | 65 / 338 |
| serious Total, serious adverse events | 63 / 338 | 75 / 338 |
Outcome results
Primary
Incidence of Major Bleeding Events (MBEs), as Defined by the International Society on Thrombosis and Haemostasis (ISTH)
Major bleeds were defined according to the ISTH definition of a major bleed, as follows * Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome and/or * Bleeding associated with a reduction in haemoglobin of at least 2 g/dL (1.24 mmol/L), or leading to transfusion of 2 or more units of blood or packed cells. and/or * Fatal bleed These are based on adjudicated data (blinded evaluation) Point estimates for the incidence of ISTH MBEs and their 2-sided 95% confidence intervals (CI), based on the normal approximation of independent binomial distribution without stratification, are presented.
Time frame: during and up to 2 months post-ablation
Population: The ablation set (AS) was the primary analysis set and included all patients in the treated set (TS) who started the ablation procedure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 150 mg | Incidence of Major Bleeding Events (MBEs), as Defined by the International Society on Thrombosis and Haemostasis (ISTH) | 1.6 percentage of participants |
| Warfarin | Incidence of Major Bleeding Events (MBEs), as Defined by the International Society on Thrombosis and Haemostasis (ISTH) | 6.9 percentage of participants |
Comparison: The risk difference between dabigatran etexilate vs. warfarin, its 2-sided 95% CI, and corresponding p-value are presented.p-value: 0.000995% CI: [-8.4, -2.2]Chi-squared
Secondary
Incidence of ISTH MBE, Stroke, Systemic Embolism, or TIA (Composite Endpoint Combining Safety and Efficacy
Percentage of patients with ISTH MBE, stroke, systemic embolism, or TIA (composite endpoint combining safety and efficacy) are presented. These are based on adjudicated data (blinded evaluation)
Time frame: during and up to 2 months post-ablation
Population: AS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 150 mg | Incidence of ISTH MBE, Stroke, Systemic Embolism, or TIA (Composite Endpoint Combining Safety and Efficacy | 1.6 percentage of participants |
| Warfarin | Incidence of ISTH MBE, Stroke, Systemic Embolism, or TIA (Composite Endpoint Combining Safety and Efficacy | 7.2 percentage of participants |
Secondary
Incidence of Minor Bleeding Events
Minor bleeds were clinical bleeds that did not fulfil the criteria for major bleeds. Percentage of patients with Minor bleeding events are presented. These are based on adjudicated data (blinded evaluation)
Time frame: during and up to 2 months post-ablation
Population: AS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 150 mg | Incidence of Minor Bleeding Events | 18.6 percentage of participants |
| Warfarin | Incidence of Minor Bleeding Events | 17.0 percentage of participants |
Secondary
Incidence of the Composite of Stroke, Systemic Embolism, or Transient Ischemic Attack (TIA)
Stroke was defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of haemorrhage or infarction. Systemic embolism was defined as an acute vascular occlusion of the extremities or any organ (kidneys, mesenteric arteries, spleen, retina or grafts) and was to be documented by angiography, surgery, scintigraphy or autopsy. Transient ischemic attack was defined as a transient episode of focal neurological dysfunction caused by brain, spinal cord, or retinal ischemia, without acute infarction. These are based on adjudicated data (blinded evaluation). Percentage of patients with composite of stroke, systemic embolism, or transient ischemic attack (TIA) is presented
Time frame: during and up to 2 months post-ablation
Population: AS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dabigatran Etexilate 150 mg | Incidence of the Composite of Stroke, Systemic Embolism, or Transient Ischemic Attack (TIA) | 0.0 percentage of participants |
| Warfarin | Incidence of the Composite of Stroke, Systemic Embolism, or Transient Ischemic Attack (TIA) | 0.3 percentage of participants |