Effectiveness of Bridging Anticoagulation for Surgery (The BRIDGE Study)

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00786474
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 1,884
• Location: 1
• Arms: 2
• Duration (Months): 67.1
• Patients Per Site Per Month: 28.1

Study Details

Study Description

Brief Summary

Blood thinners, such as warfarin, prevent blood clots from forming, thereby reducing the risk of a stroke or heart attack. When people undergo surgery or certain procedures, they must stop using warfarin to prevent too much bleeding during and after the surgery or procedure. Some doctors prescribe a different blood thinner, one that works more quickly and wears off more quickly, to bridge the gap between starting and stopping warfarin. However, this short-term treatment is expensive, may increase the risk of bleeding, and has not been proven effective. This study will determine whether a bridging blood thinner called dalteparin is helpful or harmful for people with atrial fibrillation who stop taking warfarin in preparation for surgery or a procedure.

Condition or Disease	Intervention/Treatment	Phase
Arterial Thromboembolic Events; Atrial Fibrillation	Drug: Placebo; Drug: Dalteparin	Phase 3

Detailed Description

Approximately 2 million people in North America take the anticoagulant warfarin to prevent stroke, heart attack, and other events related to blood clots. Warfarin needs to be stopped before a person undergoes surgery or certain procedures because it can cause dangerous amounts of bleeding during and after surgery. Some doctors give a low molecular weight heparin (LMWH) to patients during the 2-week period when participants are without the effects of warfarin. The LMWH has the same effect as warfarin, but it acts and then leaves the system more quickly than warfarin. However, the LMWH is expensive, may increase the risk of bleeding, and has not been proven effective. This study will determine the safety and efficacy of an LMWH in adults with atrial fibrillation who stop warfarin in preparation for surgery.

Participation in this study will last between 36 and 67 days. Participation will involve nine points of contact with researchers, at least two of which will be in-person visits at the research clinic. The others will be conducted by phone. All points of contact will include assessments on possible bleeding and any new symptoms. The first two of these points of contact, will take place at the signing of the informed consent, which will involve a screening of medical records and random assignment of participants to receive either the LMWH dalteparin or placebo. Participants will self-administer a subcutaneous injection of their assigned treatment twice a day for 3 days before the surgery or procedure and for 6 days after. During the course of the study, when participants visit their primary physicians for regularly scheduled appointments, it will be recommended that they undergo two international normalized ratio (INR) tests of blood clotting ability between day 2 and 10 after the surgery or procedure. The remaining seven points of contact will occur sometime between the day before surgery and 37 days after surgery. One of the in-person visits will occur within the first week after surgery and will include assessments on possible bleeding, any new symptoms, and INR results.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1884 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo	Drug: Placebo; Normal saline solution, dosage determined by weight, self-administered by patient twice a day
Experimental: Dalteparin	Drug: Dalteparin; Low molecular weight heparin (LMWH), dosage determined by weight, self-administered by patient twice a day; Other Names: Fragmin

Outcome Measures

Primary Outcome Measures

1. Number of Arterial Thromboembolic Events [from subject signing of the consent until completed the study (Day -30 to Day +37)]

   The events are defined as arterial thromboembolism: stokes, transient ischemic attack and systemic embolism events were independently and blindly adjudicated

2. Major Bleeding [from subject signing of the consent until completed the study (Day -30 to Day +37)]

   Major bleeding is defined as symptomatic bleeding associated with transfusion of more than two units of packed red blood cells or whole blood, or death

Secondary Outcome Measures

1. Number of Subjects With Death, Acute Myocardial Infarction, Deep Vein Thrombosis, or Pulmonary Embolism [from subject signing of the consent until completed the study (Day -30 to Day +37)]

2. Number of Participants With Minor Bleeding [from subject signing of the consent until completed the study (Day -30 to Day +37)]

   Minor bleeding is defined as symptomatic or clinically-overt bleeding that does not satisfy the criteria for major bleeding

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Receiving warfarin therapy for at least 3 months, administered to achieve an international normalized ratio (INR) range of 2.0 to 3.0

• Requiring temporary interruption of warfarin for pre-specified elective procedure or surgery

• Presence of one of the following conditions:

1. Chronic (permanent or paroxysmal) nonvalvular atrial fibrillation, confirmed by at least one prior electrocardiography recording or pacemaker or acid citrate dextrose (ACD) interrogation

2. Chronic (permanent or paroxysmal) valvular atrial fibrillation with evidence of mitral valvular heart disease, confirmed by the same criteria as nonvalvular atrial fibrillation

• Presence of at least one of the following major stroke risk factors:

1. Older than 75 years of age

2. Hypertension

3. Diabetes mellitus

4. Congestive heart failure or left ventricular dysfunction

5. Previous ischemic stroke, systemic embolism, or transient ischemic attack (TIA)

Exclusion Criteria:

• Any mechanical prosthetic heart valve

• Stroke (ischemic or hemorrhagic), systemic embolism, or TIA within the past 12 weeks

• Venous thromboembolism (deep vein thrombosis and/or pulmonary embolism) within past 12 weeks

• Major bleeding within the past 6 weeks

• Severe renal insufficiency, measured through a calculated creatinine clearance of less than 30 mL/min

• Thrombocytopenia

• Life expectancy less than 1 month

• Condition that impairs compliance with trial protocol, such as cognitive impairment, an uncontrolled psychiatric condition, or geographic inaccessibility

• Pregnancy

• Allergy to heparin or history of heparin-induced thrombocytopenia

• Having one of the following surgeries or procedures during warfarin interruption:

1. Cardiac surgery, such as coronary artery bypass or heart valve replacement

2. Neurosurgery that is intracranial or intraspinal, such as tumor resection or aneurysm repair

3. High-risk non-surgical procedures, such as brain biopsy

• Other surgical or non-surgical procedure that, at the discretion of the surgeon, precludes administration of therapeutic-dose low molecular weight heparin (LMWH) at any time in the post-procedure period

• More than one surgery planned during the trial period

• Prior participation in this trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke Clinical Research Institute	Durham	North Carolina	United States	27715

Sponsors and Collaborators

• Duke University
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Thomas L. Ortel, MD, Duke University
• Principal Investigator: Victor Hasselblad, PhD, Duke Clinical Research Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00786474
• Other Study ID Numbers: Pro00017344; 1U01HL086755-01A1; 1U01HL087229
• First Posted: Nov 6, 2008
• Last Update Posted: Mar 7, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by Duke University: Bridging Anticoagulation
• Additional relevant MeSH terms: Atrial Fibrillation; Thromboembolism; Dalteparin; Tinzaparin; Heparin, Low-Molecular-Weight

Study Results

Participant Flow

Recruitment Details	6585 subjects were screened. 4701 were excluded, 1884 subjects enrolled and underwent randomization.

Arm/Group Title	Placebo	Dalteparin
Arm/Group Description	Placebo: Normal saline solution, dosage determined by weight, self-administered by patient twice a day	Dalteparin: Low molecular weight heparin (LMWH), dosage determined by weight, self-administered by patient twice a day
Period Title: Overall Study
STARTED	950	934
COMPLETED	913	891
NOT COMPLETED	37	43

Baseline Characteristics

Arm/Group Title	Placebo	Dalteparin	Total
Arm/Group Description	Placebo: Normal saline solution, dosage determined by weight, self-administered by patient twice a day	Dalteparin: Low molecular weight heparin (LMWH), dosage determined by weight, self-administered by patient twice a day	Total of all reporting groups
Overall Participants	950	934	1884
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.8 (8.74)	71.6 (8.88)	71.7 (8.8)
Sex: Female, Male (Count of Participants)
Female	254 26.7%	248 26.6%	502 26.6%
Male	696 73.3%	686 73.4%	1382 73.4%
Race/Ethnicity, Customized (participants) [Number]
White	860 90.5%	849 90.9%	1709 90.7%
Nonwhite	88 9.3%	82 8.8%	170 9%
Unknown	2 0.2%	3 0.3%	5 0.3%

Outcome Measures

1. Primary Outcome

Title	Number of Arterial Thromboembolic Events
Description	The events are defined as arterial thromboembolism: stokes, transient ischemic attack and systemic embolism events were independently and blindly adjudicated
Time Frame	from subject signing of the consent until completed the study (Day -30 to Day +37)

Outcome Measure Data

Analysis Population Description

Of the 1,884 subjects enrolled in the trial, 71 discontinued participation and did not provide outcome data.

Arm/Group Title	Placebo	Dalteparin
Arm/Group Description	Placebo: Normal saline solution, dosage determined by weight, self-administered by patient twice a day	Dalteparin: Low molecular weight heparin (LMWH), dosage determined by weight, self-administered by patient twice a day
Measure Participants	918	895
Stroke	2	3
Transient Ischemic Attack	2	0
Systemic embolism	0	0

2. Primary Outcome

Title	Major Bleeding
Description	Major bleeding is defined as symptomatic bleeding associated with transfusion of more than two units of packed red blood cells or whole blood, or death
Time Frame	from subject signing of the consent until completed the study (Day -30 to Day +37)

Outcome Measure Data

Analysis Population Description

Of the 1,884 subjects enrolled in the trial, 71 discontinued participation and did not provide outcome data.

Arm/Group Title	Placebo	Dalteparin
Arm/Group Description	Placebo: Normal saline solution, dosage determined by weight, self-administered by patient twice a day	Dalteparin: Low molecular weight heparin (LMWH), dosage determined by weight, self-administered by patient twice a day
Measure Participants	918	895
Number [participants]	12 1.3%	29 3.1%

3. Secondary Outcome

Title	Number of Subjects With Death, Acute Myocardial Infarction, Deep Vein Thrombosis, or Pulmonary Embolism
Time Frame	from subject signing of the consent until completed the study (Day -30 to Day +37)

Outcome Measure Data

Analysis Population Description

Of the 1,884 subjects enrolled in the trial, 71 discontinued participation and did not provide outcome data.

Arm/Group Title	Placebo	Dalteparin
Arm/Group Description	Placebo: Normal saline solution, dosage determined by weight, self-administered by patient twice a day	Dalteparin: Low molecular weight heparin (LMWH), dosage determined by weight, self-administered by patient twice a day
Measure Participants	918	895
Death	5 0.5%	4 0.4%
Myocardial infarction	7 0.7%	14 1.5%
Deep-vein thrombosis	0 0%	1 0.1%
pulmonary embolism	0 0%	1 0.1%

4. Secondary Outcome

Title	Number of Participants With Minor Bleeding
Description	Minor bleeding is defined as symptomatic or clinically-overt bleeding that does not satisfy the criteria for major bleeding
Time Frame	from subject signing of the consent until completed the study (Day -30 to Day +37)

Outcome Measure Data

Analysis Population Description

Of the 1,884 subjects enrolled in the trial, 71 discontinued participation and did not provide outcome data

Arm/Group Title	Placebo	Dalteparin
Arm/Group Description	Placebo: Normal saline solution, dosage determined by weight, self-administered by patient twice a day	Dalteparin: Low molecular weight heparin (LMWH), dosage determined by weight, self-administered by patient twice a day
Measure Participants	918	895
Number [participants]	110 11.6%	187 20%

Adverse Events

Time Frame	from subject signing of the consent until completed the study from Day -30 to Day +37
Adverse Event Reporting Description	Study only collected and reported serious adverse events
Arm/Group Title	Placebo		Dalteparin
Arm/Group Description	Placebo: Normal saline solution, dosage determined by weight, self-administered by patient twice a day		Dalteparin: Low molecular weight heparin (LMWH), dosage determined by weight, self-administered by patient twice a day
All Cause Mortality
	Placebo		Dalteparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Dalteparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/950 (6.9%)		133/934 (14.2%)
Blood and lymphatic system disorders
Coagulopathy	0/950 (0%)		1/934 (0.1%)
Hypocoagulable State	0/950 (0%)		1/934 (0.1%)
Cardiac disorders
Acute Coronary Syndrome	0/950 (0%)		1/934 (0.1%)
Acute Myocardial Infarction	0/950 (0%)		3/934 (0.3%)
Angina Pectoris	1/950 (0.1%)		1/934 (0.1%)
Atrial Fibrillation	2/950 (0.2%)		3/934 (0.3%)
Atrial Flutter	1/950 (0.1%)		1/934 (0.1%)
Atrioventricular Block Second Degree	0/950 (0%)		1/934 (0.1%)
Bradycardia	1/950 (0.1%)		0/934 (0%)
Cardiac Arrest	0/950 (0%)		1/934 (0.1%)
Cardiac Failure	1/950 (0.1%)		1/934 (0.1%)
Cardiac Failure Congestive	4/950 (0.4%)		5/934 (0.5%)
Coronary Artery Disease	0/950 (0%)		1/934 (0.1%)
Ischaemic Cardiomyopathy	0/950 (0%)		1/934 (0.1%)
Myocardial Infarction	2/950 (0.2%)		2/934 (0.2%)
Pericardial Effusion	0/950 (0%)		1/934 (0.1%)
Pericarditis	1/950 (0.1%)		0/934 (0%)
Sick Sinus Syndrome	0/950 (0%)		1/934 (0.1%)
Ventricular Fibrillation	0/950 (0%)		1/934 (0.1%)
Ventricular Tachycardia	0/950 (0%)		2/934 (0.2%)
Endocrine disorders
Adrenal Haemorrhage	0/950 (0%)		1/934 (0.1%)
Gastrointestinal disorders
Ascites	1/950 (0.1%)		0/934 (0%)
Duodenal Ulcer Perforation	0/950 (0%)		1/934 (0.1%)
Dysphagia	1/950 (0.1%)		0/934 (0%)
Gastric Perforation	0/950 (0%)		1/934 (0.1%)
Gastrointestinal Haemorrhage	0/950 (0%)		4/934 (0.4%)
Haematochezia	0/950 (0%)		1/934 (0.1%)
Ileus	1/950 (0.1%)		0/934 (0%)
Inguinal Hernia	1/950 (0.1%)		0/934 (0%)
Intestinal Obstruction	0/950 (0%)		1/934 (0.1%)
Intestinal Perforation	0/950 (0%)		1/934 (0.1%)
Lower Gastrointestinal Haemorrhage	1/950 (0.1%)		1/934 (0.1%)
Pancreatic Haemorrhage	0/950 (0%)		1/934 (0.1%)
Rectal Haemorrhage	1/950 (0.1%)		6/934 (0.6%)
Retroperitoneal Haemorrhage	0/950 (0%)		1/934 (0.1%)
Vomiting	0/950 (0%)		1/934 (0.1%)
General disorders
Cardiac Death	1/950 (0.1%)		0/934 (0%)
Chest Pain	0/950 (0%)		1/934 (0.1%)
Influenza Like Illness	0/950 (0%)		1/934 (0.1%)
Multi-Organ Failure	1/950 (0.1%)		0/934 (0%)
Non-Cardiac Chest Pain	1/950 (0.1%)		0/934 (0%)
Oedema Peripheral	0/950 (0%)		1/934 (0.1%)
Pyrexia	0/950 (0%)		1/934 (0.1%)
Cholangitis	0/950 (0%)		1/934 (0.1%)
Hepatobiliary disorders
Cholecystitis	1/950 (0.1%)		0/934 (0%)
Cholecystitis Acute	0/950 (0%)		1/934 (0.1%)
Gallbladder Fistula	0/950 (0%)		1/934 (0.1%)
Hepatic Cirrhosis	1/950 (0.1%)		0/934 (0%)
Arthritis Bacterial	0/950 (0%)		1/934 (0.1%)
Infections and infestations
Arthritis Infective	1/950 (0.1%)		0/934 (0%)
Bronchitis	0/950 (0%)		1/934 (0.1%)
Cellulitis	0/950 (0%)		2/934 (0.2%)
Gastroenteritis	1/950 (0.1%)		0/934 (0%)
Infection	0/950 (0%)		1/934 (0.1%)
Influenza	0/950 (0%)		1/934 (0.1%)
Lower Respiratory Tract Infection	0/950 (0%)		1/934 (0.1%)
Osteomyelitis	0/950 (0%)		1/934 (0.1%)
Perirectal Abscess	0/950 (0%)		1/934 (0.1%)
Peritonsillar Abscess	1/950 (0.1%)		0/934 (0%)
Pneumonia	1/950 (0.1%)		5/934 (0.5%)
Postoperative Wound Infection	1/950 (0.1%)		0/934 (0%)
Sepsis	0/950 (0%)		2/934 (0.2%)
Urinary Tract Infection	1/950 (0.1%)		2/934 (0.2%)
Urosepsis	0/950 (0%)		1/934 (0.1%)
Injury, poisoning and procedural complications
Fall	1/950 (0.1%)		0/934 (0%)
Incision Site Haemorrhage	0/950 (0%)		1/934 (0.1%)
Joint Dislocation	1/950 (0.1%)		0/934 (0%)
Laceration	0/950 (0%)		1/934 (0.1%)
Limb Injury	0/950 (0%)		1/934 (0.1%)
Post Procedural Haematoma	1/950 (0.1%)		5/934 (0.5%)
Post Procedural Haemorrhage	3/950 (0.3%)		4/934 (0.4%)
Procedural Haemorrhage	0/950 (0%)		1/934 (0.1%)
Road Traffic Accident	1/950 (0.1%)		1/934 (0.1%)
Spinal Compression Fracture	1/950 (0.1%)		0/934 (0%)
Splenic Rupture	0/950 (0%)		1/934 (0.1%)
Traumatic Fracture	1/950 (0.1%)		0/934 (0%)
Traumatic Haematoma	1/950 (0.1%)		0/934 (0%)
Urinary Retention Postoperative	1/950 (0.1%)		0/934 (0%)
Vaginal Laceration	1/950 (0.1%)		0/934 (0%)
Investigations
Blood Culture Positive	0/950 (0%)		1/934 (0.1%)
Electrocardiogram Qt Prolonged	0/950 (0%)		1/934 (0.1%)
Haemoglobin Decreased	2/950 (0.2%)		1/934 (0.1%)
Metabolism and nutrition disorders
Dehydration	1/950 (0.1%)		1/934 (0.1%)
Gout	0/950 (0%)		1/934 (0.1%)
Hyperglycaemia	0/950 (0%)		1/934 (0.1%)
Hyperkalaemia	0/950 (0%)		1/934 (0.1%)
Hyperosmolar State	0/950 (0%)		1/934 (0.1%)
Hyponatraemia	1/950 (0.1%)		0/934 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal Chest Pain	1/950 (0.1%)		0/934 (0%)
Soft Tissue Haemorrhage	0/950 (0%)		1/934 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Of Colon	0/950 (0%)		1/934 (0.1%)
Bladder Neoplasm	1/950 (0.1%)		0/934 (0%)
Endometrial Adenocarcinoma	0/950 (0%)		1/934 (0.1%)
Hepatic Cancer	1/950 (0.1%)		0/934 (0%)
Intraductal Proliferative Breast Lesion	1/950 (0.1%)		0/934 (0%)
Oesophageal Carcinoma	0/950 (0%)		1/934 (0.1%)
Nervous system disorders
Cerebrovascular Accident	0/950 (0%)		3/934 (0.3%)
Dizziness	0/950 (0%)		1/934 (0.1%)
Embolic Stroke	1/950 (0.1%)		0/934 (0%)
Ischaemic Stroke	1/950 (0.1%)		0/934 (0%)
Migraine	1/950 (0.1%)		0/934 (0%)
Presyncope	0/950 (0%)		1/934 (0.1%)
Syncope	3/950 (0.3%)		2/934 (0.2%)
Transient Ischaemic Attack	2/950 (0.2%)		1/934 (0.1%)
Psychiatric disorders
Delirium	1/950 (0.1%)		0/934 (0%)
Renal and urinary disorders
Haematuria	1/950 (0.1%)		5/934 (0.5%)
Renal Failure	0/950 (0%)		1/934 (0.1%)
Renal Failure Acute	1/950 (0.1%)		1/934 (0.1%)
Urethral Obstruction	1/950 (0.1%)		0/934 (0%)
Urinary Bladder Rupture	0/950 (0%)		1/934 (0.1%)
Urinary Retention	1/950 (0.1%)		0/934 (0%)
Urinary Tract Obstruction	0/950 (0%)		1/934 (0.1%)
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	2/950 (0.2%)		3/934 (0.3%)
Haemoptysis	0/950 (0%)		1/934 (0.1%)
Pleural Effusion	0/950 (0%)		1/934 (0.1%)
Pulmonary Embolism	0/950 (0%)		1/934 (0.1%)
Respiratory Failure	0/950 (0%)		2/934 (0.2%)
Vascular disorders
Deep Vein Thrombosis	0/950 (0%)		2/934 (0.2%)
Haematoma	1/950 (0.1%)		1/934 (0.1%)
Haemorrhage	0/950 (0%)		1/934 (0.1%)
Hypertensive Crisis	0/950 (0%)		1/934 (0.1%)
Hypotension	0/950 (0%)		2/934 (0.2%)
Other (Not Including Serious) Adverse Events
	Placebo		Dalteparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT 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.