Management of Anticoagulation Therapy in the

Peri-operative Period

J. Christian Barrett, MDAssistant Professor, Division of Hematology-Oncology

Virginia Commonwealth University

Management of Anticoagulation Therapy Peri-operatively

• What are the issues?– Risk of thrombosis vs. bleeding

• Variable indications for the therapy

• Variable procedural risks

– Reversal of Therapy

• Lack of conclusive evidence

Weighing the Risks

HEMORRHAGE

THROMBOSIS

•Venous

•5-10% fatal

•<5% disabling

•Arterial

•20-40% fatal

•20-50% disabling

•Major bleeding

•9-13% fatal

•Rarely disabling

Case #1

• 70 year old male with a history of atrial fibrillation and CHF (EF 30%) on chronic warfarin therapy with a therapeutic INR of 2.4

• Going for a routine screening colonoscopy

• Asks what he should do with his warfarin for the procedure.

Thrombotic Risk: Non-Valvular Heart Disease

• Non-valvular Atrial Fibrillation– 4.5% per year risk of arterial thromboembolism (range

1-20% based on individual risk factors)

– Warfarin reduces risk by 66%

• Left Ventricular Dysfunction– 18% increase stroke risk for every 5% decrease in LV

EF

– Warfarin reduces risk by 81%

– Aspirin reduces risk by 56%

Archives Internal Medicine 1994;154:1449

Colonoscopy Risk?• American Society for Gastrointestinal Endoscopy

Guidelines…– Low-risk procedures

• EGD, Flex sig, and colonoscopy with/without biopsy• EUS and push enteroscopy• ERCP and biliary stent placement without sphincterotomy

– High-risk procedures• Gastric (4%) or colonoscopic (1%-2.5%) polypectomy• Laser ablation and coagulation (<6%)• Endoscopic sphincterotomy (2.5%-5%)• EUS-guided biopsy• Percutaneous gastrostomy• Stricture dilation

ASGE Guideline• Recommendation for low risk procedure: No adjustments

in anticoagulation need be made irrespective of the underlying condition.

• Recommendation for high risk procedure: Warfarin should be discontinued 3-5 days before the scheduled procedure. – In patients, with high risk conditions, bridging with heparin or

LMWH may be individualized. – If to resume after procedure, heparin may resume 2-6 hours after

procedure and warfarin that night.**extra caution if s/p sphincterotomy where major hemorrhage risk is 10%-

15% if reinstituted within first 3 days (or if s/p large sessile polyp removal where caution in order up to 2 weeks.)

Polypectomy Risk

• Retrospective review of 6617 colorectal polypectomies in 3138 consecutive patients– Delayed hemorrhage defined as bloody feces reported

on >2 occasions• 37 patients (1.2%) or 38 polypectomies (0.57%)

• At second endoscopy, 15 patients had stopped and 22 patients required endoscopic hemostasis.

• Only 1 patient required blood transfusion

– Anticoagulation use was prohibited for 7 days post-procedure per the protocol

Watabe H et al. Gastointest Edosc 2006;64:73-78

Polypectomy Risk

• Multivariate analysis– Polyp-related factors

• Polyp size >1 cm (OR 4.5 with 95% CI 2.0-10.3)

– Patient-related factors• Hypertension control (OR 5.6 with 95% CI 1.8-17.2)

– Associated with a longer interval of recognition of bleeding

Polypectomy on Anticoagulation• Retrospective review of 1657 consecutive patients

with colonoscopic polypectomy– Immediate hemorrhage defined as bleeding sufficient to

require endoscopic interventions judged by the endoscopist

• 32 patients (1.9%)• 31/32 were classified as MILD (drop<4 g/dL and no blood)

– Delayed hemorrhage defined as rectal bleeding within 30 days of procedure of sufficient severity to require hospitalization for management

• 5 patients (0.3%)—all transfused• Did not report warfarin use specifically among this subgroup

Hui AJ et. Gastrointest Endosc 2004;59:44-48

Polypectomy on Anticoagulation

• Among those with bleeding …– No difference seen related to anti-platelet agent

use– Warfarin use was significantly associated with

risk of hemorrhage (p<0.001)• 4 patients (10.8%) among the 37 with hemorrhage

– Median INR 1.41 [range 1.09-2.86]

• 13 patients (0.8%) among the 1620 without hemorrhage

– Median INR 1.38 [range 1.08-1.84]

Polypectomy on Anticoagulation

• Retrospective review of 21 patients undergoing 41 colonoscopic polypectomies– Held warfarin evening before procedure only

• Median INR 2.0 [range 1.4-4.9]

– Polypectomy with prophylactic clips if <1 cm• No concomitant anti-platelet agent use• No immediate hemorrhage (all <10 mL)• No delayed hemorrhage reported at follow-up (3-8

weeks)

Friedland and Soetikno. Gastrointest Endosc 2006;64:98-100

Cataract Surgery on Anticoagulation

• Reviewed medication use among 19,282 cataract surgeries on a RCT– 4588 patients used aspirin (23.8%)

• 13.8% advised to stop use before the procedure

• 22.5% actually did so

– 752 patients used warfarin (3.9%)• 10.5% advised to stop use before the procedure

• 28.3% actually did so

Katz J et al. Ophthalmology 2003;110:1784-1788

Cataract Surgery on Anticoagulation

• Among the aspirin users …– No difference seen in ocular hemorrhage events

• 0.56% among those with no routine use• 0.59% among those who continued aspirin

– Increased incidence of medical events seen …• Myocardial Infarction

– 0.84% among those with no routine use– 4.16% among those who continued aspirin

• TIA– 0% among those with no routine use– 1.19% among those who continued aspirin

Cataract Surgery on Anticoagulation

• Among the warfarin users …– No difference seen in ocular hemorrhage events

• 0.55% among those with no routine use

• 0% among those who continued warfarin

– Increased incidence of medical events seen …• Myocardial Infarction

– 1.43% among those with no routine use

– 5.7% among those who continued aspirin

Recommendation

• Minor procedure: Should be able to proceed without any adjustments in anticoagulation perioperatively– If endoscopist unwilling, hold warfarin for 3-4 days

before procedure and resume warfarin same day without use of heparin

– If polyp found, second procedure could be scheduled off warfarin

• Though some data suggests may be safe to proceed at initial procedure if <1cm, small numbers and unconfirmed.

Case #2

• 44 year old female with a St Jude (bileaflet) mitral valve on warfarin with an INR of 2.9 (goal 2.5-3.5)

• Is scheduled to have a laparoscopic cholecystectomy

• Asks what she should do with her anticoagulation therapy for the surgery.

Thrombotic Risk: Valvular Heart Disease

• 4% per year risk of major* arterial thromboembolism with a mechanical valve – plus 1.8% per year risk of valve thrombosis

• 2.2% per year with antiplatelet therapy – plus 1.6% per year risk of valve thrombosis

• 1% per year with warfarin• 0.8% per year with an aortic valve• 1.3% per year with a mitral valve

– plus 0.2% per year risk of valve thrombosis

*major=death, neurologic deficit or requiring surgery

Cannegieter SC et al. Circulation 1994;89(2):635-41

ESC Guidelines

• Recommendation for low risk procedure: No adjustments in anticoagulation need be made.

• Recommendation for high risk procedure: Warfarin should be discontinued 3-4 days before the scheduled procedure. – In patients, with high risk factors for thrombosis,

bridging with heparin* is recommended stopping 4 hours before the procedure.

– After procedure, heparin* may resume within 6-12 hours after procedure and warfarin as soon as possible.

*LMWH is not included in the ESC guidelines

High Risk Factors

• Mechanical valve in the mitral position• High risk prostheses

– Starr Edward, Lillehei Kaster, Omniscience

• Atrial fibrillation• LVEF < 30%• Prior thromboembolism• Hypercoagulable state• Surgery for malignancy or infection

Bridging with Heparin

• Refers to the use of therapeutic doses of UFH or LMWH to cover the interval when warfarin dosing is subtherapeutic

• LMWH has been demonstrated to be cost-effective in cost models compared with UFH

• Data is limited

Bridging Heparin:Preoperative Planning

• UFH– Start 36-60 hours after

last warfarin dose

– Stop 6 hours before surgery

• LMWH– Once or twice daily

dosing starting 36 hours after last warfarin dose

– Stop before surgery…• >18 hours with twice

daily dosing

• >30 hours with once daily dosing

Heparin BridgingPostoperative Planning

• UFH– No load and not greater

than 18 u/kg/hr starting ~12 hours post-op

– 1st PTT 12hours after start infusion

• LMWH– Start ~24 hours after

surgery• If thrombosis risk is high

can consider starting prophylactic dosing within 12 hours and “step up” the next day

Additional factors to consider …

1. Post-operative risk of thrombosis (venous not arterial risk increased)

2. Post-operative bleeding risk*

*If the operative bleeding risk is moderate or high, consider prophylactic dosing instead of full bridging doses.

Recommendation

• High risk of arterial thrombosis with a minor surgical bleeding risk– Stop the warfarin 5 days before the surgery

– Start therapeutic dose LMWH with the AM dose 3 days before surgery

– Stop LMWH after the AM dose day before surgery

– Resume therapeutic dose LMWH the next day along with the warfarin at prior steady state dose

– Stop LMWH once INR >2 on 2 consecutive days

Case #3

• 59 year-old female with a history of …– DVT following her 2nd pregnancy at age 35

treated– DVT with PTE at age 55 years at which time

noted to be heterozygous for FVL – On chronic anticoagulation since the 2nd event

with an INR 2.6

• Scheduled for a right-sided hemicolectomy (non-malignant indication)

Thrombotic Risk: Venous Thomboembolism

• Risk reduces with longer duration of warfarin– 50% risk of recurrence within three months without

anticoagulation• 40% risk during the first month

• 10% risk during the next two months

– 5% after three months of anticoagulation• 10-15% per year risk of recurrence among those with history

of recurrent venous thrombosis without continued anticoagulation

Venous Thrombosis

• Pre-operatively– Time from prior venous event– Time of surgery– Mobility of the patient

• Post-operatively– Time from prior venous event– Operative risk of thrombosis– Operative risk of hemorrhage

Venous Thrombosis

• Pre-operative recommendation– Stop warfarin 4-5 days before the surgery with

no bridging or prophylactic dosing of heparin

• Post-operatively recommendation– Prophylactic dose LMWH and steady state dose

of warfarin starting 12-24 hours after surgery if hemostasis achieved and continued until warfarin is therapeutic

Case #4

• 38 year-old male discharged 8 days ago following a DVT returns off LMWH on warfarin with an INR of 3.2 with a gun shot wound requiring emergent exploratory surgery of the abdomen. Surgeons are lining up the OR and asking for recommendations.

Warfarin Reversal

• Warfarin Discontinuation

• Vitamin K

• Fresh Frozen Plasma

• Recombinant VIIa

Warfarin Discontinuation

• Wide variability—especially among elderly

• Generalizations to achieve INR <1.2 at surgery if steady state …– INR 2-3 hold 4 doses preoperatively– INR 3-4 hold 5 doses preoperatively

White RH et al. Annals of Internal Medicine 1995;122:40-42

Vitamin K

• Subcutaneous administration inferior to oral or IV which appear equivalent

• IV associated with a risk of hypotension and/or anaphylaxis

• Effects seen starting 12-24 hours after administration

Fresh Frozen Plasma

• Can be infused rapidly if patient can tolerate volume

• Cheaper and more widely/rapidly available at many centers than rVIIa

• Calculate dose to achieve prothrombin complex level of 40% normal plasma– If subtherapeutic INR, 10mL/kg (3 units in 70 kg pt)– If therapeutic INR, 25mL/kg (7 units in 70 kg pt)– If supratherapeutic INR, 35mL/kg (10 units in 70 kg pt)

Recombinant Factor VIIa

• Warfarin reversal—not approved indication• Candidates for consideration

– Life-threatening bleed with INR > 2.0 (+ INR >1.5 though Vit K / FFP preferable)

– Emergent surgery unable to be delayed 24+ hours

• Other factors to consider– Fibrinogen > 120 mg/dL– MI/angina/stroke ongoing or within prior 4 weeks– Active DVT or other thrombotic disorder

• Optimal dose is uncertain

Recommendations

• Because of the emergent nature of surgery– Hold warfarin

– Give dose of vitamin K (5-10mg orally or slow IV)

– Fresh frozen plasma 25-35 mL/kg

or

Recombinant factor VIIa 10-20 mcg/kg (rounded to nearest full vial dose)

– IVC filter placed intraoperatively