Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation

James D Douketis, Alex C Spyropoulos, Scott Kaatz, Richard C Becker, Joseph A Caprini, Andrew S Dunn, David A Garcia, Alan Jacobson, Amir K Jaffer, David F Kong, Sam Schulman, Alexander G G Turpie, Vic Hasselblad, Thomas L Ortel, BRIDGE Investigators, Thomas Ortel, Vic Hasselblad, Sam Schulman, Alex Spyropoulos, Mark Blostein, Benoit Coutu, James Douketis, Francois Grondin, Peter Gross, Marc Jolicoeur, Bernard Thibault, Yves Pesant, Thomas Rebane, Jennifer Ringrose, Bruce Ritchie, Simon Robinson, Peter Klinke, Reginald Smith, Frederick Spencer, Erik Yeo, Patricia Schoch, Joon Ahn, J Jeffrey Marshall, Charles Allen 3rd, Alpesh Amin, Mary Anderson, Tammy Anthony, Mark Antonishen, Gowthami Arepally, Michael Baker, Anthony Bartkowiak Jr, Kim Baty, Leon Menajovsky, Carlos Bayron, Seth Bilazarian, Kevin Browne Jr, David Buccigrossi, A Bleakley Chandler Jr, Nathan Clark, Dan Witt, Barry Clemson, Steven Cohn, Amir Jaffer, Vincent Colucci, Jean Connors, Stephen Culp, Mark Donahue, Gowthami Arepally, Gregory Eberhart, Richard Primm, Matthew Eisen, Steven Eisenberg, Georg Emlein, Bishoy Faltas, Steven Forman, William French, David Garcia, Steven Georgeson, Douglas Geraets, Santosh Gill, Eve Gillespie, Robert Glover, Swapna Goday, Margaret Kennedy, Joel Gore, Jaspal Gujral, Anjan Gupta, Tariq Haddad, Monica Hazelrigg, Steven Herson, Stephan Hoeing, William Herzog Jr, Robert Hill, Marie Iacona, Alan Jacobson, Gerhard Johnson, Kenneth Kellick, Muhammad Khan, Nicholas Kondo, Rekha Lakshmanan, Joel Landzberg, Thomas LeGalley, Satyaprakash Makam, Amit Malhotra, Frank McGrew, William Martin, Brent McLaurin, Daniel Meyer, Freny Mody, Visala Muluk, Wayne Old, Brian Peek, Robert Pendleton, John Petersen, Arnold Pfahnl, Kurt Pfeifer, Guna Raj, Vijay Rao, David Rater, Cheryl Ray, Mary Zimmerman, Charles Russo, Joseph Sacco, Abraham Salacata, Jorge Saucedo, Suman Rathbun, Brian Schietinger, Matthew Sackett, Ricky Schneider, Vinay Shah, Scott Kaatz, Tatjana Sljapic, Carlos Sotolongo, Shawn Speirs, Daniel Sporn, Kishore Harjai, Alex Spyropoulos, Michael Staab, Robert Stein, Carl Sufit, Steven Mitnick, Darren Traub, Annabelle Volgman, Stuart Rosenbush, Robert Watson 3rd, Keattiyoat Wattanakit, Barry Clemson, Roy McRae Jr, Richard White, Robert Williams, Brian Williamson, James D Douketis, Alex C Spyropoulos, Scott Kaatz, Richard C Becker, Joseph A Caprini, Andrew S Dunn, David A Garcia, Alan Jacobson, Amir K Jaffer, David F Kong, Sam Schulman, Alexander G G Turpie, Vic Hasselblad, Thomas L Ortel, BRIDGE Investigators, Thomas Ortel, Vic Hasselblad, Sam Schulman, Alex Spyropoulos, Mark Blostein, Benoit Coutu, James Douketis, Francois Grondin, Peter Gross, Marc Jolicoeur, Bernard Thibault, Yves Pesant, Thomas Rebane, Jennifer Ringrose, Bruce Ritchie, Simon Robinson, Peter Klinke, Reginald Smith, Frederick Spencer, Erik Yeo, Patricia Schoch, Joon Ahn, J Jeffrey Marshall, Charles Allen 3rd, Alpesh Amin, Mary Anderson, Tammy Anthony, Mark Antonishen, Gowthami Arepally, Michael Baker, Anthony Bartkowiak Jr, Kim Baty, Leon Menajovsky, Carlos Bayron, Seth Bilazarian, Kevin Browne Jr, David Buccigrossi, A Bleakley Chandler Jr, Nathan Clark, Dan Witt, Barry Clemson, Steven Cohn, Amir Jaffer, Vincent Colucci, Jean Connors, Stephen Culp, Mark Donahue, Gowthami Arepally, Gregory Eberhart, Richard Primm, Matthew Eisen, Steven Eisenberg, Georg Emlein, Bishoy Faltas, Steven Forman, William French, David Garcia, Steven Georgeson, Douglas Geraets, Santosh Gill, Eve Gillespie, Robert Glover, Swapna Goday, Margaret Kennedy, Joel Gore, Jaspal Gujral, Anjan Gupta, Tariq Haddad, Monica Hazelrigg, Steven Herson, Stephan Hoeing, William Herzog Jr, Robert Hill, Marie Iacona, Alan Jacobson, Gerhard Johnson, Kenneth Kellick, Muhammad Khan, Nicholas Kondo, Rekha Lakshmanan, Joel Landzberg, Thomas LeGalley, Satyaprakash Makam, Amit Malhotra, Frank McGrew, William Martin, Brent McLaurin, Daniel Meyer, Freny Mody, Visala Muluk, Wayne Old, Brian Peek, Robert Pendleton, John Petersen, Arnold Pfahnl, Kurt Pfeifer, Guna Raj, Vijay Rao, David Rater, Cheryl Ray, Mary Zimmerman, Charles Russo, Joseph Sacco, Abraham Salacata, Jorge Saucedo, Suman Rathbun, Brian Schietinger, Matthew Sackett, Ricky Schneider, Vinay Shah, Scott Kaatz, Tatjana Sljapic, Carlos Sotolongo, Shawn Speirs, Daniel Sporn, Kishore Harjai, Alex Spyropoulos, Michael Staab, Robert Stein, Carl Sufit, Steven Mitnick, Darren Traub, Annabelle Volgman, Stuart Rosenbush, Robert Watson 3rd, Keattiyoat Wattanakit, Barry Clemson, Roy McRae Jr, Richard White, Robert Williams, Brian Williamson

Abstract

Background: It is uncertain whether bridging anticoagulation is necessary for patients with atrial fibrillation who need an interruption in warfarin treatment for an elective operation or other elective invasive procedure. We hypothesized that forgoing bridging anticoagulation would be noninferior to bridging with low-molecular-weight heparin for the prevention of perioperative arterial thromboembolism and would be superior to bridging with respect to major bleeding.

Methods: We performed a randomized, double-blind, placebo-controlled trial in which, after perioperative interruption of warfarin therapy, patients were randomly assigned to receive bridging anticoagulation therapy with low-molecular-weight heparin (100 IU of dalteparin per kilogram of body weight) or matching placebo administered subcutaneously twice daily, from 3 days before the procedure until 24 hours before the procedure and then for 5 to 10 days after the procedure. Warfarin treatment was stopped 5 days before the procedure and was resumed within 24 hours after the procedure. Follow-up of patients continued for 30 days after the procedure. The primary outcomes were arterial thromboembolism (stroke, systemic embolism, or transient ischemic attack) and major bleeding.

Results: In total, 1884 patients were enrolled, with 950 assigned to receive no bridging therapy and 934 assigned to receive bridging therapy. The incidence of arterial thromboembolism was 0.4% in the no-bridging group and 0.3% in the bridging group (risk difference, 0.1 percentage points; 95% confidence interval [CI], -0.6 to 0.8; P=0.01 for noninferiority). The incidence of major bleeding was 1.3% in the no-bridging group and 3.2% in the bridging group (relative risk, 0.41; 95% CI, 0.20 to 0.78; P=0.005 for superiority).

Conclusions: In patients with atrial fibrillation who had warfarin treatment interrupted for an elective operation or other elective invasive procedure, forgoing bridging anticoagulation was noninferior to perioperative bridging with low-molecular-weight heparin for the prevention of arterial thromboembolism and decreased the risk of major bleeding. (Funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health; BRIDGE ClinicalTrials.gov number, NCT00786474.).

Conflict of interest statement

No other potential conflict of interest relevant to this article was reported.

Figures

Figure 1. BRIDGE Study Design
Figure 1. BRIDGE Study Design
Screening visits occurred between 30 days and 5 days before the planned procedure, and randomization (R) occurred 5 days before the procedure. Warfarin treatment was discontinued 5 days before the procedure, and administration of the study drug was initiated 3 days before the procedure. It was recommended that the international normalized ratio (INR) be measured 1 day before the procedure; if the INR was greater than 1.8, oral vitamin K (1.0 to 2.5 mg) was recommended; if the INR was 1.5 to 1.8, oral vitamin K was optional. If the procedure or surgery was delayed up to 3 days, administration of the study drug was continued until 24 hours before the procedure. Warfarin treatment was restarted on the evening of or the day after the procedure, and the study drug was restarted 12 to 24 hours after a minor (or low-bleeding-risk) procedure and 48 to 72 hours after a major (or high-bleeding-risk) procedure. Administration of the study drug was continued after the procedure until the INR was 2.0 or higher on one occasion. The final patient follow-up occurred 30 days after the procedure. LMWH denotes low-molecular-weight heparin.
Figure 2
Figure 2
Screening, Randomization, and Follow-up.

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