what is new for 2011:
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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
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