01-ortel-bridge (1)
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7/23/2019 01-Ortel-BRIDGE (1)
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Bridging Anticoagulation in Patients WRequire Temporary Interruption of War
Therapy for an Elective Procedure or Su
Thomas L. Ortel, MD, PhD,on behalf of the BRIDGE Investigators and Committees
The BRIDGE trial was funded by the U.S. National Heart, Lung, and Blood Institute of the U.S. National In
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Disclosures
Research support: NIH, CDC, Eisai, Glaxo-SmithKline, Instrumen
Laboratory, Stago.
Consultant activities: Daiichi Sankyo, Bristol-Myers/Squibb, Instru
Laboratory, CSL Behring.
Additional disclosures:• Current member, ABIM Hematology Board Exam Committee, 2
present. No exam material will be disclosed.
• Medical Director, Duke Anticoagulation Management Service
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Background
It has been estimated that approximately 250,000 paNorth America alone will require temporary interruptio
anticoagulant therapy for an operation or invasive pro
each year.
Uncertainty exists concerning whether bridging thera
low molecular weight heparin (LMWH) is indicated in
who need interruption of warfarin to minimize the risk
perioperative arterial thromboembolism.
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Hypotheses
We hypothesized that:
1) Forgoing bridging anticoagulation in patients with a
fibrillation (AF) who needed warfarin held for an ope
invasive procedure would be non-inferior to bridging
LMWH for the prevention of perioperative arterial
thromboembolism (ATE)
- and –
2) Forgoing bridging anticoagulation would be superio
bridging with respect to major bleeding
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Methods
Phase III, randomized, double-blind, placebo-controlled Warfarin stopped 5 days before procedure and resumed w
24 hours afterward
Patients randomized to receive either bridging anticoagula
therapy with LMWH (100 IU dalteparin per kg body weightmatching placebo twice daily for 3 days before and 5–10 d
elective operation/procedure
Follow-up continued for 30 days after the procedure
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Inclusion Criteria
18 years or older
Chronic (permanent or paroxysmal) AF
or atrial flutter, confirmed by
electrocardiography or pacemaker
interrogation
AF associated with valvular disease,
including mitral valve disease
Received warfarin therapy for 3 months
or longer, with a target INR therapeutic
range of 2.0–3.0
Undergoing an elective op
invasive procedure requiriinterruption
At least one of the followin
stroke risk factors:
– Congestive heart fai
ventricular dysfunctio – Hypertension
– 75 years or older
– Diabetes mellitus
– Previous ischemic st
systemic embolism,
ischemic attack (TIA
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Exclusion Criteria
Mechanical heart valve
Stroke, systemic embolism, or
TIA within previous 12 weeks
Major bleeding within previous
6 weeks
Venous thromboembolism
within the previous 12 weeks
Creatinine clearance<30 mL/min
Platelet count <100×
cubic millimeter
Planned cardiac, intror intraspinal surgery
Unable or unwilling to
informed consent
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TrialDesign
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Primary Outcomes
Arterial thromboembolism – Stroke, systemic embolism, or TIA
Major bleeding
Secondary Outcomes
Acute myocardial infarction, venous thromboembolism, or d
Minor bleeding
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Statistical Analysis - 1
Primary analysis of efficacy was a non-inferiority with a one-sided test at the 0.025 level
Sample-size estimate based upon the following:
• Estimated rate of ATE in the no-bridging group: 1.0
• Estimated rate of ATE in the bridging group: 1.0
• Non-inferiority margin: 1.0
Sample size of 1,641 patients per group would p
80% power to detect non-inferiority of no-bridging
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Statistical Analysis - 2
Primary analysis of safety was a superiority anala two-sided test at the 0.05 level
Sample-size estimate for safety based upon the
• Estimated rate of major bleeding in the no-bridging gro
• Estimated rate of major bleeding in the bridging group
Sample size of 1,641 patients per group would p
>99% power to detect superiority of no-bridging
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Sample Size Recalculation
After 850 patients were enrolled, the rate of ATE was <0.5total population
After 1,720 patients were enrolled, the rate of ATE was 0.4
the bleeding rate was 2.3% in the total population
A revised total sample size of 1,882 patients was calculate
provide nearly 90% power for the two primary endpoints
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Number of patients who
discontinued the study (n=32)
• Withdrew consent 23
• Lost to follow-up 3
• PI decision 2
• Other 4
Number of
discontinu
• Withdrew
• Lost to fo
• PI decisio
• Other
Screen fai
• MD deci
• Failed in
• Reasons
Number of patients who died
(n=5)
Number o
PatientPopulation
Number of patients screened (n=6585)
Number of patients who completed
the study (n=913)
Number of patients who
completed the study (n=891)
Randomized to placebo (n=950) Randomized to dalteparin (n=93
Number of patients enrolled (n=1884)
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PatientCharacteristics
Characteristic No Bridging (N=950) B
Age, yr 71.8±8.74
Male sex, no. (%) 696 (73.3)
Race, no. (%)
White 860 (90.5)
Nonwhite 88 (9.3)
Unknown 2 (0.2)
Weight, kg 96.2±24.87
CHADS2 score
Mean 2.3±1.03
Distribution, no. (%)
0 1 (0.1)
1 216 (22.7)
2 382 (40.2)
3 229 (24.1)
4 96 (10.1)
5 23 (2.4)
6 3 (0.3)
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PatientCharacteristics
Characteristic
No Bridging
(N=950)
CHF or left ventricular
dysfunction, no. (%)
289 (30.4)
Hypertension, no. (%) 833 (87.7)
Diabetes mellitus, no. (%) 390 (41.1)
Stroke, no. (%) 79 (8.3)
TIA, no. (%) 79 (8.3)
Mitral valve disease, no. (%) 165 (17.4)
Stenosis 19 (2.0)
Regurgitation 142 (14.9)
Prolapse 13 (1.4)
Laboratory values
INR 2.4±0.57
Creatinine clearance, mL/min 88.1±39.50
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Surgeries andProcedures*
Surgery/Procedure Type No Bridging
Minor, no. (%) (n=781)
Gastrointestinal 391 (50.1) Cardiothoracic 139 (17.8)
Orthopedic 54 (6.9)
Urologic 41 (5.3)
Other 156 (19.9)
Major, no. (%) (n=94)
Orthopedic 29 (30.9)
Urologic 26 (27.7)
General surgery 16 (17.0)
Other 23 (24.5)
* Initial classification of
surgery/procedure was not
always aligned to post-
procedure bleeding risk
designation
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Perioperative Anticoagulant Management
Variable
No Bridging
(N=950)
Brid
(N=Warfarin treatment
Preprocedure time not
taking warfarin
Patients with data, no. 872 83
Mean, days 5.2±1.4 5.3±
Time to first postprocedure
warfarin dose
Patients with data, no. 735 69
Mean, days 1.5 (1.3) 1.4
Aspi rin treatment , no./total no. (%)
Interruption ≥7 days before procedure 92/324 (28.4) 92/329
Interruption <7 days before procedure 41/324 (12.7) 33/329
No interruption 191/324 (59.0) 204/32
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Perioperative Anticoagulant Management
VariableNo Bridging
(N=950)
Brid
(N=
LMWH or placebo
Preprocedure dose Patients with data, no. 796 76
Mean no. of doses 5.0±0.7 5.0±
Patients in whom last dose was taken on the morning
of the day before the procedure, no./total no. 778/796 (97.7) 734/76
Time to first postprocedure dose
Major surgery/procedure
(high bleeding risk)
Patients with data, no. 235 22
Mean, hr 53.3±31.6 51.3±
Minor surgery/procedure
(low bleeding risk)
Patients with data, no. 526 49
Mean, hr 21.1±2.3 21.0
Postprocedure doses Patients with data, no. 764 72
Mean no. of doses 15.7±7.4 16.1
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PrimaryOutcomes
Outcome
No. (%)
No Bridging
(N=918)
Bridging
(N=895)
ATE 4 (0.4) 3 (0.3)
Stroke 2 (0.2) 3 (0.3)
TIA 2 (0.2) 0 (0)
Systemic embolism 0 (0) 0 (0)
Major bleeding 12 (1.3) 29 (3.2)
* The mean CHADS2 score in patients who sustained a thromboembolic event was 2.6
The median time to an arterial thromboembolic event was 19.0 days (IQR, 6.0-23.0 d
The median time to a major bleeding event after a procedure was 7.0 days (IQR, 4.0-
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SecondaryOutcomes
Outcome
No. (%)
No Bridging
(N=918)
Bridging
(N=895)
Death 5 (0.5) 4 (0.4) Myocardial infarction 7 (0.8) 14 (1.6)
Deep vein thrombosis 0 (0) 1 (0.1)
Pulmonary embolism 0 (0) 1 (0.1)
Minor bleeding 110 (12.0) 187 (20.9
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Limitations
Few patients had a high CHADS2
score (e.g., 5–6)
Most patients underwent low-risk procedures, such as colo
or ambulatory surgery
Overall rate of ATE was lower than initial projections
Findings should not be applied to patients with mechanicavalves or venous thromboembolism
Findings are not applicable to patients with AF treated with
oral anticoagulant
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Conclusion
For patients with AF who require temporary interruption of
treatment for an elective operation or invasive procedure, a
of forgoing bridging anticoagulation was non-inferior to per
bridging with LMWH for prevention of arterial thromboemb
Forgoing bridging treatment also decreased the risk of maj
bleeding compared to perioperative bridging with LMWH
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Acknowledgements
NHLBI and Andrei L. Kindzelski, MD, PhD, NIH Project Off
Eisai Co., Ltd.: provided dalteparin
Jill Lynch, University of Iowa Pharmaceuticals: manufactur
matching placebo
James Bernstein, Live Oak Pharmaceuticals Consulting: pconsultancy regarding the manufacture of the matching pla
packaging the study drug kits for distribution to the trial site
Participating sites, committee members, and patients
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