Effectiveness of Bridging Anticoagulation for Surgery (The BRIDGE Study)

• ClinicalTrials.gov Identifier: NCT00786474
• Recruitment Status: Completed
• First Posted: November 6, 2008
• Results First Posted: March 7, 2016
• Last Update Posted: March 7, 2016
• Sponsor: Duke University
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Duke University

Tracking Information

• First Submitted Date: November 5, 2008
• First Posted Date: November 6, 2008
• Results First Submitted Date: January 6, 2016
• Results First Posted Date: March 7, 2016
• Last Update Posted Date: March 7, 2016
• Study Start Date: July 2009
• Actual Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 8, 2016)

• Number of Arterial Thromboembolic Events [ Time Frame: 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
• Major Bleeding [ Time Frame: 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

Original Primary Outcome Measures (submitted: November 5, 2008)

• Arterial thromboembolic events, defined as an ischemic stroke, transient ischemic attack, or systemic embolis [ Time Frame: Measured throughout the study ]
• Major bleeding, symptomatic bleeding associated with transfusion of more than two units of packed red blood cells or whole blood, or death [ Time Frame: Measured throughout the study ]

Current Secondary Outcome Measures (submitted: February 8, 2016)

• 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) ]
• Number of Participants With Minor Bleeding [ Time Frame: 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

Original Secondary Outcome Measures (submitted: November 5, 2008)

• Acute myocardial infarction (with ST- and non-ST-elevation), deep vein thrombosis, or pulmonary embolism [ Time Frame: Measured throughout the study ]
• Minor bleeding [ Time Frame: Measured throughout the study ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effectiveness of Bridging Anticoagulation for Surgery (The BRIDGE Study)
• Official Title: Bridging Anticoagulation in Patients Who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery
• 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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• Arterial Thromboembolic Events
• Atrial Fibrillation

Intervention

• Drug: Placebo
  Normal saline solution, dosage determined by weight, self-administered by patient twice a day
• Drug: Dalteparin
  Low molecular weight heparin (LMWH), dosage determined by weight, self-administered by patient twice a day
  Other Name: Fragmin

Study Arms

• Placebo Comparator: Placebo
  Intervention: Drug: Placebo
• Experimental: Dalteparin
  Intervention: Drug: Dalteparin

Publications *

• Wight JM, Columb MO. Perioperative bridging anticoagulation for atrial fibrillation-the first randomised controlled trial. Perioper Med (Lond). 2016 Jun 7;5:14. doi: 10.1186/s13741-016-0040-5. eCollection 2016.
• Douketis JD, Spyropoulos AC, Kaatz S, Becker RC, Caprini JA, Dunn AS, Garcia DA, Jacobson A, Jaffer AK, Kong DF, Schulman S, Turpie AG, Hasselblad V, Ortel TL; BRIDGE Investigators. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med. 2015 Aug 27;373(9):823-33. doi: 10.1056/NEJMoa1501035. Epub 2015 Jun 22.
• Assaad B, Sesi VK, Figari R, Schultz L, Thummala N, Rehman M, Chandok A, Silverman A, Silver B. Antithrombotic management of stroke patients before colonoscopy. J Stroke Cerebrovasc Dis. 2013 Aug;22(6):733-6. doi: 10.1016/j.jstrokecerebrovasdis.2011.12.006. Epub 2012 Jan 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 27, 2015): 1884
• Original Estimated Enrollment (submitted: November 5, 2008): 3626
• Actual Study Completion Date: February 2015
• Actual Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00786474
• Other Study ID Numbers: Pro00017344; 1U01HL086755-01A1 ( U.S. NIH Grant/Contract ); 1U01HL087229 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Duke University
• Original Responsible Party: Thomas Ortel, MD and Victor Hasselblad, PhD, Duke Clinical Research Institute
• Current Study Sponsor: Duke University
• Original Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: 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

• PRS Account: Duke University
• Verification Date: January 2016