What is New for 2011:Anticoagulation in

Older Surgical Patients

Laurie G. Jacobs, MDProfessor of Clinical Medicine

Peri-OperativeAnticoagulation

• New Anticoagulants• VTE prophylaxis

• Chronic anticoagulation for AF andimplications for peri-operative care

• Peri-operative management

Xa

Prothrombin (II)

Fibrinogen

X

Warfarin

Thrombin (IIa)

Fibrin

Hirudin, bivalirudin,Argatroban, dabigatran

Plateletactivation

Points of Actionof Anticoagulants

apixaban, rivaroxaban, edoxaban,otamixaban, betrixaban, YM150, TAK 442

Fondaparinux

Heparin, LMWH

venousthrombosis

arterialthrombosis

Dabigatran RivaroxabanTarget Thrombin(II) FactorXaBioavailability 6.5% 86%Peakplasmaconcentration

0.5–2hrsafterpointake

2–4hrs

Halflife 12-17hrs(biddosing) 7-11hrs(qdtobid)

Metabolism Hepaticglucuronidation CYP3A4

Renalclearance 80% 65%(25%forapixaban)

Druginteractions Verapamil,amiodarone,macrolides

CYP3A4,Pgpinhibitors,Verapamil,macrolides,proteaseinhibitors,azoleantifungals,etc

New Oral Anticoagulants

Independent Risk Factorsfor First VTE

RISK FACTOR Adj. pop. Attrib. risk* 95% CI

Hospitalization or nursing homeHospitalization with surgeryHospitalization without surgeryNursing home

Active malignant neoplasmTraumaCongestive heart failurePrior central venous catheter or pacemakerNeurological disease w/extremity paresisPrior superficial vein thrombosis

58.823.821.513.318.012.09.59.16.95.4

53.4-64.220.3-27.317.3-25.69.9-16.8

13.4-22.69.0-14.93.3-15.85.7-12.63.5-10.23.0-7.7

Heit JA, et al. Arch Intern Med. 2002;162:1245-1248. *age, sex, yr

Risk Factors for VTE• Stasis

• Advanced age• Immobility (bed rest > 4 d)••••••

CHF, severe COPDStroke, paralysis, castingSpinal cord InjuryIncreased viscosityObesityVaricose veins

• Endothelial Damage•

Surgery, esp. orthopedic

•

Prior DVT, PE

•

Central lines, devices

•

Trauma

• Hypercoagulability••••••

Advanced ageActive cancerHigh estrogen statesThrombophiliaInflammatory statesSurgery

• Increased blood viscosity

Perc

enta

ge

21- 30

25

20

15

10

5

031- 40 41- 50 51- 60 61- 70 71- 80 81- 90 >901- 20

Age (years)

Piazza G, et al. Chest. 2007;132:554-561.

Hospitalized Nonmedical Patients

Age Distribution ofDVT Patients

30Hospitalized Medical Patients

Peri-operativeHypercoagulability• VTE risk factors prevalent in surgical patients• VTE Risk is 100X greater than in non-operative

periodPlasminogen activator inhibitor-1Hypercoagulability

StasisEndothelial damage

• “Rebound Hypercoagulability” with discontinuationof oral anticoagulants

thrombin-AT [TAT] complexesd-dimer

prothrombin fragments F1 & 2fibrinopeptide Afactor VIII

VTERiskGroup Prophylaxis

LOW<10%•Mobilemedical•Surgical(lowrisk,arthroscopic,laparoscopic,spine;vascular;GU)

Earlyambulation

MODERATE10-40%•Mostgeneral,openGYN,GU,CABG,Cancersurgery,etc•Medical,bedrestorsick•ModVTErisk,highbleedingrisk

LMWHLDUHFondaparinuxMechanical??FactorXaorIIinhibitors

HIGH40-80%•THR,TKR,HFS•Majortrauma,SCI•HighVTErisk,highbleedrisk

LMWHFondaparinuxWarfarin(INR2-3)plusmech.??FactorXaorIIinhibitors

VTE Risk & Prophylaxis

Geerts WH. CHEST 2008; 133:381S

DVT Prophylaxis

• Non-pharmacologicalMethods

••••

compression stockingsleg elevationearly mobilizationintermittent pneumaticcompression

• Foot pumps

• Anticoagulants• Heparins

– SC UF Heparin– LMWH– fondaparinux

• Warfarin• New agents:

– Factor Xa inhibitors– Direct Thrombin inhibitors

35dPx;thenbilateralvenogram

Apixaban*(n=1949)

Enoxaparin**(n=1917)

PValue

AllVTE+death 1.4%(n=27) 3.9%(n=74) <0.001

MajorVTE 0.5%(n=10) 1.1%(n=25) 0.01

Majorbleed 0.8%(n=22) 0.7%(n=18) 0.54

Clinicallyrelevantnonmajorbleed

4.8%(n=129) 5.0%(n=134) 0.72

VTE Prophylaxis in THR

*Apixaban 2.5 mg po bid; 12-24 h postop**Enoxaparin 40 mg sc 12 h preop, then postopADVANCE-3; pts. Followed 60+ days after last dose

Lassen MR, et al. N Engl J Med 2010:363:2487-98

VTE Prophylaxis:General Surgery Bleeding Risk

Meta-analysis: 52 RCTs VTE px (33,813 pts)

Leonardi MJ et al. Arch Surg 2006; 141:790-99.

ProphylaxisInjection site bruising 6.9%Wound hematoma 5.7%Drain site bleeding 2.0%Hematuria 1.6%GI bleeding 0.2%Retroperitoneal bleeding < 0.1%Discontinuation 2%Surgical intervention 0.7%

Control2.8%0.8%0.6%01.9%000.7%

Indications forChronic Anticoagulation

• Arterial Disease• Atrial fibrillation• Recurrent Systemic

Embolism• Mechanical Heart

Valves• Rheumatic mitral

disease (& hx SE, AF orLA diam.> 5.5 cm)

• Venous Disease• Prophylaxis of VTE• Secondary Prevention

(Treatment) of VTE– Deep venous

thrombosis– Pulmonary embolism

Dabigitran*n=6076%/yr(n)

Warfarinn=6022%/yr(n)

Dabigatranvs.WarfarinRR(95%CI)pvalue

StrokeorSE 1.1(134) 1.7(199) 0.66(0.53-0.82) <0.001

Death 3.6(438) 4.1(487) 0.88(0.77-1.00) 0.051

Cum

ulat

ive

haza

rd ra

te

Warfarin v. Dabigatranfor AF Stroke or SE (Re-Ly)

Connolly SJ et al. N Engl J Med 2009;361:1139-1151

months

Dabigitran 150 mg; TTR 44-70%; Reductions in composite cardiovascular endpoints and mortalitybtwn dabigatran and warfarin are attenuated by INR control

Randomized Evaluation of Long Term Anticoagulation Therapy

Peri-Op Decision-Making:Chronic Anticoagulation

Thromboembolic Risk• Indication

– Mech heart valve– Atrial fibrillation– Venous thrombosis

• Individual risk factors• Surgical risk factors

Bleeding Risk• Individual bleeding risk• Surgical risk for bleeding

Risk Mech.HeartValve

AtrialFib. VTE

High>10%/yrofATEor>10%/mo.VTE

anyMitralvalve,Oldervalve,RecentstrokeorTIA

CHADS2=5or6RecentstrokeTIAorRHD

VTE<3mo.Severe

thrombophilia

Moderate4-10%/yrofATEor4-10%/mo.VTE

BileafletAVandCHADS1point

CHADS2=3or4 VTE3-12mo.RecurrentVTEActivecancer

Low<4%/yrofATEor<4%/mo.VTE

BileafletAV CHADS2=0–2(nostrokeorTIA)

SingleVTE>12mo.ago

Risk Stratification forThromboembolism

Geerts et al. Chest 2001:119:132S-175S; Douketis et al. Chest 2008;133:299-339

Risk ACCPRecommendationHIGH Bridging(Grade1C)

•TherapeuticSCLMWH(preferred)•IVUFH

MOD Bridging(Grade2C)•TherapeuticSCLMWH(preferred)•IVUFH•LowdoseSCLMWH

LOW •Bridging-LowdoseSCLMWH•NoBridging(Grade2C)

Peri-Op Anticoagulationin NonCardiac Surgery

Douketis et al. Chest 2008;133:299-339

Peri-operative Eventswith Anticoagulation

• Mechanical Heart Valve Study1• 556 pts/580 procedures: 372 Ao, 136 Mitral, 48 multiple; warfarin

d/c 4-5 days prior, restarted after hemostasis, bridging. At 3 mos:

• 0.9% thromboembolism• 3.6% major bleeding• no difference bwtn bridging, and type of ac

• General Surgery Study of AC Patients2• 603 surgical patients on warfarin, the majority of whom did not have

interruption of therapy prior to surgery

• Peri-operative major bleeding 9.5% (7.1–12.1)• Odds ratio 1.6 (0.4–4.0) if INR 3.0 vs. 2.0

1 Daniels R, et al. Thromb Res 2009;124:300-5; 2 Torn M et al. Br J Haematol 2003; 123:676–82

LowerRiskSurgeryonAC

ProceduresUndertakenwithCautiononAC

Highrisk

•Dental•Dermatolological•Opthalmic•Endoscopy,colonoscopyw/obx

•rxnofcolonicpolyps•prostateorkidneybx•pacemakerordefibrillatorimplant

•CABGorvalverepl.•Intracranialorspinal•majorvascsurgery•majororthosurgery•reconstructiveplasticsurgery•majorcancersurgery•prostateorbladdersurgery

Guidelines for Surgeryon AC

Interruption of OralAnticoagulation:Elective Surgery• Discontinue warfarin 5 days prior to surgery

– may need to discontinue earlier with mechanical valvesas INR falls from a greater level

– INR falls more slowly in the elderly

• CHECK INR before surgery; INR fallsexponentially with wide variability betweenpatients, slower with age

• If INR > 1.5 pre-op day 1 - 2, administer 1 – 2 mgoral vitamin K (comes as 5 mg tab, thus wouldgive ½ tab or sc dose)

Douketis et al. Chest 2008;133:299-339

Resumption ofAnticoagulant Therapy

• May resume 12 - 24 hours post-op (evening of, orday after) or when hemostasis is established

• ~ 48 hrs required for a partial anticoagulant effect(INR > 1.5)• If resume at patient’s prior dose, ~ 5.1 + 1.1 days

to achieve a therapeutic INR• If resume with double patient’s usual dose for day

1–2, a therapeutic INR is achieved at 4.6 days

Bridge TherapyPre-operative Period• If pre-op INR 2-3, last dose warfarin 5 days before surgery

(hold 4 doses);• If pre-op INR 3-4.5 (or elderly), last dose 6 days before

surgery (hold 5 doses)• Start LMWH 36 hrs after last warfarin dose

– Enoxaparin 1 mg/kg sc or Dalteparin 100 IU/Kg q12– Last dose ½ dose LMWH ~24 h prior to procedure

• Written plan for patient, internist, surgeon, anesthesiologist• Phone number for questions or an emergency

Jaffer et al. CCJM 2003; 70:973 White RH et al. Ann Intern Med 1995;122:40-2

Bridge TherapyPost-op

• After discussion with surgeon, restart LMWH ~24 hrspost-operatively (with hemostatic control)– full doses for minor surgeries– prophylactic doses for day 1-2 if high bleeding risk

• After discussion with surgeon, start warfarin at pre-opdose on post-op day 1

• Daily PT/INR until discharge and periodically thereafteruntil INR is therapeutic (ongoing)

• CBC with Platelet count day 3 and 7 (HIT screening)• Discontinue LMWH when INR is in therapeutic range for

two consecutive days (often INR 2 -3)

LMWH & RegionalAnesthesia (or Analgesia)

• Pre-operatively• Other anticoagulants held (and clopidogrel, perhaps also

asa)• Needle placement

– 12 hrs after prophylactic LMWH– 24 hrs after LMWH if dose >1 mg/kg

• Post-operatively••••

Indwelling catheter removed prior to twice daily LMWHRemove catheter 12-24 hrs after last dose LMWHFirst dose LMWH 2 hrs after catheter removalIf using once daily LMWH, first dose 6-8 hrs post-op,second dose 24 hrs later

Horlocker T. Reg Anesth Pain Med 2003;28:172-97ASRA.com American Society of Regional Anesthesia and Pain Medicine

Anti-Platelet Agentsand Surgery

• Aspirin– Irreversibly inhibits platelet cyclooxygenase– Circulating platelet pool replaced 7 – 10 days– Acts within minutes

• Clopidogrel (thienopyridines)– Inhibits ADP receptor-mediated platelet activation and aggregation– Stop 7 days before surgery– May require loading on restarting 300-600 mg; takes 3 – 7 days to

reach peak anti-platelet aggregation activity on 75 mg dose

• NSAIDS– Reversibly inhibit platelet cyclooxygenase; COX-2 inhibitors haveless effect– Inhibit renal prostaglandin synthesis so can worsen renal failure withother drugs

Antiplatelet Agents andPerioperative Risk• Cannot easily measure bleeding risk with antiplatelets• Individual variability in bleeding risk with antiplatelets• If low cardiac risk, no stents, noncardiac surgery, may

elect to stop ASA or clopidogrel 7 – 10 days preop;resume 24 hrs postop with adequate hemostasis

• For high cardiac risk, noncardiac surgery, continue ASAto, and after surgery

• For cardiac surgery, or for patients with coronary stents,consult cardiology and guidelines (ACCP, ACC/AHA)

New Anticoagulantsand Surgery• New Agents

• May not substantially change thrombotic risks;however if adherence is poor, this may increase

• May not substantially change bleeding risk• May eliminate the need for monitoring• May eliminate the need for bridging when

patients can take p.o. medications• May increase the number of patients on chronic

anticoagulation due to ease of therapy