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Uninterrupted Dabigatran Etexilate in Comparison to Uninterrupted Warfarin in Pulmonary Vein Ablation (RE-CIRCUIT)

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ClinicalTrials.gov Identifier: NCT02348723
Recruitment Status : Completed
First Posted : January 28, 2015
Results First Posted : November 14, 2017
Last Update Posted : January 29, 2018
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Atrial Fibrillation
Interventions Drug: Warfarin
Drug: Dabigatran Etexilate 150mg
Enrollment 678
Recruitment Details  
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.
Arm/Group Title Dabigatran Etexilate 150 mg Warfarin
Hide Arm/Group Description

Patients receiving Dabigatran Etexilate 150 mg capsule orally twice daily (BID);

1 capsule 150 mg twice daily (total daily dose 300 mg)

Patients receiving Warfarin tablet orally;

1, 3, and 5 mg (dose adjusted to International normalized ratio (INR) target range)

Period Title: Overall Study
Started 338 338
Completed 310 312
Not Completed 28 26
Reason Not Completed
No ablation             21             20
Non-compliant with Protocol             1             0
Lost to Follow-up             1             1
Consent withdrawn             1             3
Reason other than specified             1             1
Adverse Event             3             1
Arm/Group Title Dabigatran Etexilate 150 mg Warfarin Total
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Patients receiving Dabigatran Etexilate 150 mg capsule orally twice daily (BID);

1 capsule 150 mg twice daily (total daily dose 300 mg)

Patients receiving Warfarin tablet orally;

1, 3, and 5 mg (dose adjusted to International normalized ratio (INR) target range)

Total of all reporting groups
Overall Number of Baseline Participants 338 338 676
Hide Baseline Analysis Population Description
Treated set (TS): The treated set (TS) included all patients who were randomised and subsequently treated with at least 1 tablet/capsule.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 338 participants 338 participants 676 participants
59.2  (10.33) 59.4  (10.29) 59.3  (10.30)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 338 participants 338 participants 676 participants
Female
93
  27.5%
81
  24.0%
174
  25.7%
Male
245
  72.5%
257
  76.0%
502
  74.3%
1.Primary Outcome
Title Incidence of Major Bleeding Events (MBEs), as Defined by the International Society on Thrombosis and Haemostasis (ISTH)
Hide Description

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
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Hide Analysis Population Description
The ablation set (AS) was the primary analysis set and included all patients in the treated set (TS) who started the ablation procedure
Arm/Group Title Dabigatran Etexilate 150 mg Warfarin
Hide Arm/Group Description:

Patients receiving Dabigatran Etexilate 150 mg capsule orally twice daily (BID);

1 capsule 150 mg twice daily (total daily dose 300 mg)

Patients receiving Warfarin tablet orally;

1, 3, and 5 mg (dose adjusted to International normalized ratio (INR) target range)

Overall Number of Participants Analyzed 317 318
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
1.6
(0.2 to 2.9)
6.9
(4.1 to 9.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dabigatran Etexilate 150 mg, Warfarin
Comments The risk difference between dabigatran etexilate vs. warfarin, its 2-sided 95% CI, and corresponding p-value are presented.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0009
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD) %
Estimated Value -5.3
Confidence Interval (2-Sided) 95%
-8.4 to -2.2
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Incidence of the Composite of Stroke, Systemic Embolism, or Transient Ischemic Attack (TIA)
Hide Description

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
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Hide Analysis Population Description
AS
Arm/Group Title Dabigatran Etexilate 150 mg Warfarin
Hide Arm/Group Description:

Patients receiving Dabigatran Etexilate 150 mg capsule orally twice daily (BID);

1 capsule 150 mg twice daily (total daily dose 300 mg)

Patients receiving Warfarin tablet orally;

1, 3, and 5 mg (dose adjusted to International normalized ratio (INR) target range)

Overall Number of Participants Analyzed 317 318
Measure Type: Number
Unit of Measure: percentage of participants
0.0 0.3
3.Secondary Outcome
Title Incidence of Minor Bleeding Events
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
AS
Arm/Group Title Dabigatran Etexilate 150 mg Warfarin
Hide Arm/Group Description:

Patients receiving Dabigatran Etexilate 150 mg capsule orally twice daily (BID);

1 capsule 150 mg twice daily (total daily dose 300 mg)

Patients receiving Warfarin tablet orally;

1, 3, and 5 mg (dose adjusted to International normalized ratio (INR) target range)

Overall Number of Participants Analyzed 317 318
Measure Type: Number
Unit of Measure: percentage of participants
18.6 17.0
4.Secondary Outcome
Title Incidence of ISTH MBE, Stroke, Systemic Embolism, or TIA (Composite Endpoint Combining Safety and Efficacy
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
AS
Arm/Group Title Dabigatran Etexilate 150 mg Warfarin
Hide Arm/Group Description:

Patients receiving Dabigatran Etexilate 150 mg capsule orally twice daily (BID);

1 capsule 150 mg twice daily (total daily dose 300 mg)

Patients receiving Warfarin tablet orally;

1, 3, and 5 mg (dose adjusted to International normalized ratio (INR) target range)

Overall Number of Participants Analyzed 317 318
Measure Type: Number
Unit of Measure: percentage of participants
1.6 7.2
Time Frame All Adverse Events (AEs) which occurred after the first dose of trial medication up to 6 days after the last dose of trial medication; up to 225 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Dabigatran Etexilate 150 mg Warfarin
Hide Arm/Group Description

Patients receiving Dabigatran Etexilate 150 mg capsule orally twice daily (BID);

1 capsule 150 mg twice daily (total daily dose 300 mg)

Patients receiving Warfarin tablet orally;

1, 3, and 5 mg (dose adjusted to International normalized ratio (INR) target range)

All-Cause Mortality
Dabigatran Etexilate 150 mg Warfarin
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Dabigatran Etexilate 150 mg Warfarin
Affected / at Risk (%) Affected / at Risk (%)
Total   63/338 (18.64%)   75/338 (22.19%) 
Blood and lymphatic system disorders     
Anaemia  1  0/338 (0.00%)  1/338 (0.30%) 
Cardiac disorders     
Atrial fibrillation  1  6/338 (1.78%)  13/338 (3.85%) 
Atrial flutter  1  20/338 (5.92%)  19/338 (5.62%) 
Atrial tachycardia  1  2/338 (0.59%)  1/338 (0.30%) 
Atrial thrombosis  1  2/338 (0.59%)  1/338 (0.30%) 
Bradycardia  1  1/338 (0.30%)  1/338 (0.30%) 
Cardiac failure  1  1/338 (0.30%)  0/338 (0.00%) 
Cardiac failure acute  1  0/338 (0.00%)  1/338 (0.30%) 
Cardiac failure congestive  1  3/338 (0.89%)  2/338 (0.59%) 
Cardiac tamponade  1  1/338 (0.30%)  4/338 (1.18%) 
Coronary artery disease  1  1/338 (0.30%)  0/338 (0.00%) 
Palpitations  1  1/338 (0.30%)  0/338 (0.00%) 
Pericardial effusion  1  1/338 (0.30%)  1/338 (0.30%) 
Pericardial haemorrhage  1  0/338 (0.00%)  1/338 (0.30%) 
Pericarditis  1  2/338 (0.59%)  1/338 (0.30%) 
Right ventricular failure  1  1/338 (0.30%)  0/338 (0.00%) 
Sinus arrest  1  1/338 (0.30%)  1/338 (0.30%) 
Sinus node dysfunction  1  2/338 (0.59%)  0/338 (0.00%) 
Supraventricular tachycardia  1  1/338 (0.30%)  0/338 (0.00%) 
Tachycardia  1  1/338 (0.30%)  0/338 (0.00%) 
Congenital, familial and genetic disorders     
Atrial septal defect  1  0/338 (0.00%)  1/338 (0.30%) 
Eye disorders     
Conjunctival haemorrhage  1  1/338 (0.30%)  0/338 (0.00%) 
Gastrointestinal disorders     
Abdominal discomfort  1  1/338 (0.30%)  0/338 (0.00%) 
Abdominal pain  1  0/338 (0.00%)  1/338 (0.30%) 
Colitis ulcerative  1  1/338 (0.30%)  0/338 (0.00%) 
Gastritis erosive  1  0/338 (0.00%)  1/338 (0.30%) 
Gastrointestinal haemorrhage  1  0/338 (0.00%)  1/338 (0.30%) 
Impaired gastric emptying  1  1/338 (0.30%)  0/338 (0.00%) 
Oesophageal pain  1  1/338 (0.30%)  0/338 (0.00%) 
Small intestinal obstruction  1  0/338 (0.00%)  1/338 (0.30%) 
Upper gastrointestinal haemorrhage  1  1/338 (0.30%)  0/338 (0.00%) 
General disorders     
Chest pain  1  1/338 (0.30%)  3/338 (0.89%) 
Malaise  1  0/338 (0.00%)  1/338 (0.30%) 
Polyp  1  0/338 (0.00%)  1/338 (0.30%) 
Pyrexia  1  0/338 (0.00%)  1/338 (0.30%) 
Hepatobiliary disorders     
Cholelithiasis  1  0/338 (0.00%)  1/338 (0.30%) 
Infections and infestations     
Anal abscess  1  1/338 (0.30%)  0/338 (0.00%) 
Bacteraemia  1  1/338 (0.30%)  0/338 (0.00%) 
Erysipelas  1  0/338 (0.00%)  1/338 (0.30%) 
Groin abscess  1  0/338 (0.00%)  1/338 (0.30%) 
Lower respiratory tract infection  1  1/338 (0.30%)  0/338 (0.00%) 
Lung infection  1  1/338 (0.30%)  0/338 (0.00%) 
Pneumonia  1  1/338 (0.30%)  0/338 (0.00%) 
Injury, poisoning and procedural complications     
Acetabulum fracture  1  1/338 (0.30%)  0/338 (0.00%) 
Cardiac function disturbance postoperative  1  0/338 (0.00%)  1/338 (0.30%) 
Cardiac procedure complication  1  0/338 (0.00%)  1/338 (0.30%) 
Contusion  1  0/338 (0.00%)  1/338 (0.30%) 
Craniocerebral injury  1  0/338 (0.00%)  1/338 (0.30%) 
Fall  1  0/338 (0.00%)  1/338 (0.30%) 
Injury  1  0/338 (0.00%)  1/338 (0.30%) 
Road traffic accident  1  0/338 (0.00%)  1/338 (0.30%) 
Tendon rupture  1  1/338 (0.30%)  0/338 (0.00%) 
Vascular access site haemorrhage  1  1/338 (0.30%)  0/338 (0.00%) 
Vascular pseudoaneurysm  1  0/338 (0.00%)  4/338 (1.18%) 
Vascular pseudoaneurysm ruptured  1  0/338 (0.00%)  1/338 (0.30%) 
Investigations     
Bleeding time prolonged  1  0/338 (0.00%)  1/338 (0.30%) 
Haemoglobin decreased  1  0/338 (0.00%)  1/338 (0.30%) 
Metabolism and nutrition disorders     
Diabetic ketoacidosis  1  1/338 (0.30%)  0/338 (0.00%) 
Hypoglycaemia  1  1/338 (0.30%)  0/338 (0.00%) 
Hyponatraemia  1  0/338 (0.00%)  1/338 (0.30%) 
Musculoskeletal and connective tissue disorders     
Arthritis  1  0/338 (0.00%)  1/338 (0.30%) 
Compartment syndrome  1  0/338 (0.00%)  1/338 (0.30%) 
Gouty arthritis  1  1/338 (0.30%)  0/338 (0.00%) 
Intervertebral disc protrusion  1  1/338 (0.30%)  0/338 (0.00%) 
Musculoskeletal chest pain  1  0/338 (0.00%)  1/338 (0.30%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Bladder cancer  1  1/338 (0.30%)  0/338 (0.00%) 
Central nervous system neoplasm  1  0/338 (0.00%)  1/338 (0.30%) 
Laryngeal squamous cell carcinoma  1  1/338 (0.30%)  0/338 (0.00%) 
Squamous cell carcinoma of lung  1  1/338 (0.30%)  0/338 (0.00%) 
Nervous system disorders     
Facial paralysis  1  1/338 (0.30%)  0/338 (0.00%) 
Intraventricular haemorrhage  1  0/338 (0.00%)  1/338 (0.30%) 
Ischaemic stroke  1  0/338 (0.00%)  1/338 (0.30%) 
Neurological symptom  1  0/338 (0.00%)  1/338 (0.30%) 
Peripheral nerve paresis  1  0/338 (0.00%)  1/338 (0.30%) 
Phrenic nerve paralysis  1  1/338 (0.30%)  1/338 (0.30%) 
Transient ischaemic attack  1  1/338 (0.30%)  0/338 (0.00%) 
Renal and urinary disorders     
Acute kidney injury  1  1/338 (0.30%)  1/338 (0.30%) 
Renal impairment  1  1/338 (0.30%)  0/338 (0.00%) 
Urinary retention  1  2/338 (0.59%)  0/338 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Dyspnoea  1  0/338 (0.00%)  1/338 (0.30%) 
Epistaxis  1  1/338 (0.30%)  0/338 (0.00%) 
Pulmonary hypertension  1  2/338 (0.59%)  0/338 (0.00%) 
Pulmonary oedema  1  3/338 (0.89%)  1/338 (0.30%) 
Respiratory distress  1  0/338 (0.00%)  1/338 (0.30%) 
Sleep apnoea syndrome  1  0/338 (0.00%)  1/338 (0.30%) 
Skin and subcutaneous tissue disorders     
Skin haemorrhage  1  0/338 (0.00%)  1/338 (0.30%) 
Vascular disorders     
Deep vein thrombosis  1  0/338 (0.00%)  1/338 (0.30%) 
Haematoma  1  0/338 (0.00%)  6/338 (1.78%) 
Haemorrhage  1  0/338 (0.00%)  1/338 (0.30%) 
Hypertensive crisis  1  0/338 (0.00%)  1/338 (0.30%) 
Orthostatic hypotension  1  0/338 (0.00%)  1/338 (0.30%) 
Peripheral artery occlusion  1  0/338 (0.00%)  1/338 (0.30%) 
Thrombophlebitis  1  0/338 (0.00%)  1/338 (0.30%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Dabigatran Etexilate 150 mg Warfarin
Affected / at Risk (%) Affected / at Risk (%)
Total   68/338 (20.12%)   65/338 (19.23%) 
Cardiac disorders     
Atrial fibrillation  1  40/338 (11.83%)  38/338 (11.24%) 
Palpitations  1  16/338 (4.73%)  19/338 (5.62%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  18/338 (5.33%)  14/338 (4.14%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02348723     History of Changes
Other Study ID Numbers: 1160.204
2014-003890-40 ( EudraCT Number )
First Submitted: January 27, 2015
First Posted: January 28, 2015
Results First Submitted: October 16, 2017
Results First Posted: November 14, 2017
Last Update Posted: January 29, 2018