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


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)


Mean, hr 53.3±31.6 51.3±

Minor surgery/procedure

(low bleeding risk)


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

7/23/2019 01-Ortel-BRIDGE (1)


01-ortel-bridge (1)

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