Challenges in AnticoagulationChallenges in Anticoagulationand and ThromboembolismThromboembolism

Ethan Cumbler M.D.Ethan Cumbler M.D.Assistant Professor of MedicineAssistant Professor of Medicine

Hospitalist Medicine SectionHospitalist Medicine SectionUniversity of Colorado DenverUniversity of Colorado Denver

May 2010May 2010

No Conflicts of InterestNo Conflicts of Interest

ObjectivesObjectives1.1. Discuss data on prevention and treatment of upperDiscuss data on prevention and treatment of upper

extremity venous thrombosisextremity venous thrombosis

2.2. Use individualized risk assessment of Use individualized risk assessment of thrombothrombo-embolic-embolicevents and bleeding to design a events and bleeding to design a periperi-operative anti--operative anti-thrombotic bridging regimenthrombotic bridging regimen

3.3. Identify uncommon side effects of anti-thromboticIdentify uncommon side effects of anti-thromboticmedicationsmedications

Upper Extremity DVTUpper Extremity DVT

10% of all 10% of all DVTs DVTs occur in theoccur in theupper extremitiesupper extremities

Symptomatic upper ex DVTSymptomatic upper ex DVTwill complicate 12% of will complicate 12% of CVCsCVCs

–– Asymptomatic clot in up to 2/3Asymptomatic clot in up to 2/3pts with central linespts with central lines

Upper Extremity Deep Venous Thrombosis. Sem in Thromb and Hemostasis 2006;32:729-736Upper Extremity Deep Vein Thromosis. Intern Emerg Med 2009

Upper Extremity DVTUpper Extremity DVTRisk FactorsRisk Factors

PrimaryPrimary20%20%

–– Strenuous armStrenuous armexerciseexercise

““Effort thrombosisEffort thrombosis””

–– AnatomyAnatomyThoracic outletThoracic outletsyndromesyndrome

SecondarySecondary80%80%

–– CancerCancer

–– Surgery/trauma to armSurgery/trauma to arm

–– Cast immobilizationCast immobilization

–– Central LineCentral Line

–– PacemakerPacemaker

–– ThrombophiliaThrombophilia

–– OCPsOCPs

Does prophylaxis with Does prophylaxis with warfarinwarfarin work? work?

New research demonstrates fixed doseNew research demonstrates fixed dosewarfarinwarfarin to prevent CVC related to prevent CVC related DVTsDVTs in incancer patients is ineffectivecancer patients is ineffective

–– No significant reduction in DVT ratesNo significant reduction in DVT rates6% in no-6% in no-warfarinwarfarin

6% in 6% in warfarinwarfarin group group

Subgroup analysis suggested possible benefit inSubgroup analysis suggested possible benefit inadjusted dose adjusted dose warfarinwarfarin compared to fixed dose compared to fixed dose

–– No improvement in mortalityNo improvement in mortalityRandomized Placebo-Controlled Study of Low-Dose Warfarin for the Prevention of Central Venous Catheter–Associated Thrombosis in Patients With Cancer Journal of Clinical Oncology 2005;23:4063-4069 Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trialLancet 2009;373:567

Upper extremity Upper extremity DVTsDVTs are not benign are not benign

Risks of upper extremity DVTRisks of upper extremity DVT–– Post-Post-phlebiticphlebitic syndrome syndrome

20-27%20-27%

–– RecurrenceRecurrence1 in 101 in 10

–– PE in up to 36%PE in up to 36%line related has higher riskline related has higher risk

–– DeathDeath10-50% mortality rate10-50% mortality rate

largely due to underlying diseaselargely due to underlying disease

Clinical outcome of patients with an upper extremity deep vein thrombosis: results from the RIETE registry. Chest.2008;133(1):143-148

TreatmentTreatmentTreatment improves outcomesTreatment improves outcomes–– 12% PE rate with physical measures only12% PE rate with physical measures only

–– 7% PE rate with anticoagulation7% PE rate with anticoagulation

–– 1% PE rate with thrombolysis1% PE rate with thrombolysis

Recommendations for non-cancer associated DVT are to treatRecommendations for non-cancer associated DVT are to treatwith UFH/LMWH or with UFH/LMWH or fondaparinuxfondaparinux followed by oral followed by oralanticoagulation for at least 3 monthsanticoagulation for at least 3 months

For patients with catheter associated DVT the CHESTFor patients with catheter associated DVT the CHESTguidelines do NOT recommend removal so long as the line isguidelines do NOT recommend removal so long as the line isfunctioning and neededfunctioning and needed

Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2008;133:454S-545SWhat is the best approach to treat an upper extremity DVT? The Hospitalist;May 2009

Treatment of VTE in CancerTreatment of VTE in CancerPatientsPatients

LMWH is the preferred agent for initial andLMWH is the preferred agent for initial andlong term treatment of VTE in cancer patientslong term treatment of VTE in cancer patients

CLOT trial-CLOT trial-–– 17% recurrent VTE rate with oral anticoagulation17% recurrent VTE rate with oral anticoagulation

–– 9% recurrent VTE rate in LMWH group9% recurrent VTE rate in LMWH group52% RRR (p=0.002)52% RRR (p=0.002)

Anticoagulation in the Treatment of Established Venous Thromboembolism in Patients with Cancer. J Clin Onc 2009;27:4895-4901Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Cancer Patients.NEJM 2003;349:146-153

Bridging AnticoagulationBridging Anticoagulation

ChallengeChallenge

Many pts needing procedures are onMany pts needing procedures are onchronic anticoagulationchronic anticoagulation–– Quarter of a million annuallyQuarter of a million annually

The hospitalist is frequently asked toThe hospitalist is frequently asked todetermine how to:determine how to:–– Minimize risk of bleeding with the procedureMinimize risk of bleeding with the procedure

–– Prevent Prevent periperi-op -op thromboembolic thromboembolic eventsevents

Fundamental ConceptFundamental ConceptBalance of RisksBalance of Risks

Chance of thrombosisChance of thrombosis

Severity of potential eventSeverity of potential event–– Periop Periop VTE= 4-9% fatalVTE= 4-9% fatal

–– Mechanical heart valveMechanical heart valvethrombosis = 15% mortalitythrombosis = 15% mortality

–– Periop Periop embolic stroke = 70%embolic stroke = 70%disability or deathdisability or death

Chance of bleedingChance of bleeding–– 1 in 10 major surgeries will1 in 10 major surgeries will

bleed if INR>2bleed if INR>2

–– Once bleeding occurs-Once bleeding occurs-longer delays to restartlonger delays to restartanticoagulationanticoagulation

Ability to achieveAbility to achievehemostasishemostasis

How to Reverse How to Reverse WarfarinWarfarinThree options:Three options:

Hold Hold Warfarin Warfarin 5 days5 days–– INR<1.5 in 93% of ptsINR<1.5 in 93% of pts

Vitamin KVitamin K–– low dose (2.5-5mg) low dose (2.5-5mg)

Fresh Frozen PlasmaFresh Frozen Plasma–– Plus low dose Vitamin KPlus low dose Vitamin K

How to BridgeHow to BridgePre-OpPre-Op

No BridgeNo Bridge

Full therapeutic heparinFull therapeutic heparin–– Requires hospitalizationRequires hospitalization–– Stop 4 hrs before procedureStop 4 hrs before procedure

Full therapeutic LMWHFull therapeutic LMWH–– Allows home therapyAllows home therapy

Last dose >24 hours before procedureLast dose >24 hours before procedureReduce final dose by 50% if using therapeutic LMWHReduce final dose by 50% if using therapeutic LMWH

No bridge?No bridge?

BridgeBridge

BridgeBridge

High

Embolic Risk

Medium

Low

Pre-Op Bridging AnticoagulationPre-Op Bridging Anticoagulation

High RiskHigh Risk

Thromboembolism Thromboembolism >10%>10%Mechanical mitral valvesMechanical mitral valves

Older aortic valve devicesOlder aortic valve devices

Afib Afib with CVA in last 3 months or CHADS2 of 5-6with CVA in last 3 months or CHADS2 of 5-6

VTE in last 3 months or severe VTE in last 3 months or severe thombophiliathombophilia–– Delay elective surgery if VTE in last monthDelay elective surgery if VTE in last month

Moderate RiskModerate Risk

Thromboembolism Thromboembolism 4-10%4-10%

Modern mechanical AVR + other risk factorsModern mechanical AVR + other risk factors

Afib Afib with CHADS2 of 3-4with CHADS2 of 3-4

VTE 3-12 months ago, recurrent VTE, orVTE 3-12 months ago, recurrent VTE, orcommon common thrombophiliasthrombophilias

Active cancerActive cancer

Low RiskLow Risk

Thromboembolism Thromboembolism <4%<4%

Modern mechanical AVR without other riskModern mechanical AVR without other riskfactorsfactors

Afib Afib with CHADS2 of 0-2with CHADS2 of 0-2

Prior VTE more than a year agoPrior VTE more than a year ago

How to BridgeHow to BridgePost-OpPost-Op

Resume oral anticoagulation 12-24 hrs post-opResume oral anticoagulation 12-24 hrs post-op–– Expect 2 days to restore INR > 1.5Expect 2 days to restore INR > 1.5

–– 5 days to full therapeutic5 days to full therapeutic

Add prophylactic dose heparin/LMWHAdd prophylactic dose heparin/LMWH

Start full therapeutic heparin/LMWHStart full therapeutic heparin/LMWH–– New guidelines allow delay of full bridging forNew guidelines allow delay of full bridging for

patients at high surgical bleeding riskpatients at high surgical bleeding risk

Bleeding RiskBleeding Risk

High RiskHigh RiskCardiac surgeryCardiac surgery

Vascular surgeryVascular surgery

NeurosurgeryNeurosurgery

Hip/knee replacementHip/knee replacement

Major urologic surgeryMajor urologic surgery

Use lower doseUse lower dose

Delay initiation of bridging by 2-3 daysDelay initiation of bridging by 2-3 days

low doselow doseLMWHLMWH

oror

no bridgeno bridge

low doselow doseLMWHLMWH

oror

no bridgeno bridge

low doselow doseLMWHLMWH

oror

no bridgeno bridge

Full doseFull dose

preferred overpreferred overlow doselow doseLMWHLMWH

ChoicesChoices

Low doseLow doseLMWH anLMWH anoption overoption over

full dosefull dose

Full doseFull doseanticoagulationanticoagulation

Full doseFull doseanticoagulationanticoagulation

Full doseFull doseanticoagulationanticoagulation

High

Embolic Risk

Medium

Low

High Medium Low

Bleeding Risk

Case 1Case 1Mechanical Heart ValveMechanical Heart Valve

A 72 y/o woman with a modern mitral bi-leaf mechanical heartA 72 y/o woman with a modern mitral bi-leaf mechanical heartvalve is to have ankle surgery.valve is to have ankle surgery.How would you handle the How would you handle the perioperative perioperative anticoagulation?anticoagulation?

High risk for embolismHigh risk for embolismIntermediate risk for bleedingIntermediate risk for bleeding

Rec Rec hold hold warfarin warfarin 5 days with full dose LMWH 5 days with full dose LMWH preoppreopFull dose bridging Full dose bridging postoppostop–– Full dose LMWH or therapeutic UFHFull dose LMWH or therapeutic UFH

–– Start 24 hrs post-opStart 24 hrs post-op

Resume Resume warfarin warfarin POD1POD1

Case 2Case 2Atrial Atrial FibrillationFibrillation

45 y/o with 45 y/o with Afib Afib and HTN scheduled for and HTN scheduled for nephrectomynephrectomy

Low risk for embolic eventLow risk for embolic event–– CHADS2=1 point so 1.5% annual riskCHADS2=1 point so 1.5% annual risk–– Predicts 0.004% daily risk of embolic eventPredicts 0.004% daily risk of embolic event–– Actual rate may be 10X higher Actual rate may be 10X higher (surgery is (surgery is prothromboticprothrombotic))

–– Taking this into account- 8 day risk is only 0.3%Taking this into account- 8 day risk is only 0.3%

High risk for BleedingHigh risk for Bleeding

Rec Rec hold hold warfarin warfarin 5 days pre-op without bridge5 days pre-op without bridgeNo bridging post-op No bridging post-op oror using prophylactic dose LMWH using prophylactic dose LMWHRestart Restart warfarin warfarin POD1 (if good POD1 (if good hemostasishemostasis))

Case 3Case 3Prior VTEPrior VTE

67 year old man with history of PE 4 months ago is67 year old man with history of PE 4 months ago isscheduled for lap scheduled for lap choly choly for gallstone pancreatitisfor gallstone pancreatitis

Intermediate risk for venous embolic eventIntermediate risk for venous embolic eventIntermediate risk for bleedingIntermediate risk for bleeding

Rec Rec Hold Hold Warfarin Warfarin 5 days pre-op5 days pre-op——Full dose LMWH bridgeFull dose LMWH bridgeStarting low dose LMWH day after surgeryStarting low dose LMWH day after surgeryIf no bleeding increase to therapeutic LMWH in 2-3 daysIf no bleeding increase to therapeutic LMWH in 2-3 daysRestart Restart warfarin warfarin POD1POD1

low dose LMWHlow dose LMWH

oror

no bridgeno bridge

low dose LMWHlow dose LMWH

oror

no bridgeno bridge

No bridgeNo bridge

Full doseFull dose

versusversus

low dose LMWH low dose LMWHChoicesChoices

Low dose LMWHLow dose LMWH

versusversus

full dosefull dosedelayed 2-3 daysdelayed 2-3 days

Full doseFull doseanticoagulationanticoagulationstarting 24starting 24hours posthours postprocedureprocedure

Full doseFull doseanticoagulationanticoagulation

may delay untilmay delay untilday 2day 2

Full doseFull doseanticoagulationanticoagulationdelayed 2-3 daysdelayed 2-3 days

(Consider low(Consider lowdose initially)dose initially)

High

Embolic Risk

Medium

Low

High Medium Low

Bleeding RiskFuture Studies to Watch For:-BRIDGE-PERIOP 2

Side Effects of AntithromboticSide Effects of AntithromboticTherapyTherapy

You are seeing a 56 y/o maleYou are seeing a 56 y/o malefollowing total knee following total knee arthroplastyarthroplasty

Enoxaparin Enoxaparin 40 mg SQ QD started on POD #140 mg SQ QD started on POD #1

Pre-operative platelet count was 200,000Pre-operative platelet count was 200,000

Post-operative day #1 platelets were 160,000Post-operative day #1 platelets were 160,000

Post-operative day #2 platelets are 110,000Post-operative day #2 platelets are 110,000

Should you suspect heparin inducedShould you suspect heparin inducedthrombocytopenia?thrombocytopenia?

Heparin InducedHeparin InducedThrombocytopeniaThrombocytopenia

Antibodies bind platelet factor 4 and heparinAntibodies bind platelet factor 4 and heparin

Induces pro-thrombotic stateInduces pro-thrombotic state–– ThrombocytopeniaThrombocytopenia

–– ThrombosisThrombosis

Thrombosis develops in 30-50% of casesThrombosis develops in 30-50% of cases

Yplatelet IgGHeparin

YSplenic Platelet

Destruction

Thrombocytopenia

PF4

PlateletActivation

Thrombosis

HITHIT

Platelets drop >50% or less than 150,000Platelets drop >50% or less than 150,000

Heparin exposure usually precedes Heparin exposure usually precedes plt plt drop bydrop by5-10 days5-10 days

Diagnosis difficult in situations whereDiagnosis difficult in situations wherethrombocytopenia is caused by other mechanismsthrombocytopenia is caused by other mechanisms

–– TraumaTrauma

–– Post-operativePost-operativeParticularly CABGParticularly CABG

Definite other causeDefinite other causePossible alternatePossible alternatecausecause

No other causeNo other causeevidentevident

OOtther cause?her cause?

NoneNoneProgressive/recurrentProgressive/recurrentthrombus or suspectedthrombus or suspectedthrombusthrombus

New thrombusNew thrombusTThrombosishrombosis

Fall too earlyFall too earlyOnset > day 10 orOnset > day 10 orunclear timeunclear time

Clear onset day 5-10Clear onset day 5-10TTiming of falliming of fall

<30% fall or<30% fall orPltPlt nadernader <10 <10

30-50% fall or30-50% fall orPltPlt nadernader 10-20 10-20

>50% fall and>50% fall andPltPlt nadernader >> 20 20

TThrombocytopeniahrombocytopenia

001122

6-8 = High Risk4-5 = Intermediate Risk<3 = Low Risk

“4 T” Score

PearlsPearls

Low risk score (<3) has low probability of HITLow risk score (<3) has low probability of HITand testing not neededand testing not needed

Intermediate and High risk scores (>3) meritIntermediate and High risk scores (>3) merittestingtesting

Pre-operative platelet count was 200,000Pre-operative platelet count was 200,000Post-operative day #1 platelets were 160,000Post-operative day #1 platelets were 160,000Post-operative day #2 platelets are 110,000Post-operative day #2 platelets are 110,000

Definite other causeDefinite other causePossible alternatePossible alternatecausecause

No other causeNo other causeevidentevident

OOtther cause?her cause?

NoneNoneProgressive/recurrentProgressive/recurrentthrombus or suspectedthrombus or suspectedthrombusthrombus

New thrombusNew thrombusTThrombosishrombosis

Fall too earlyFall too earlyOnset > day 10 orOnset > day 10 orunclear timeunclear time

Clear onset day 5-10Clear onset day 5-10TTiming of falliming of fall

<30% fall or<30% fall or

PltPlt nadernader <10 <10

30-50% fall or30-50% fall or

PltPlt nadernader 10-20 10-20

>50% fall and>50% fall and

PltPlt nadernader >> 20 20

TThrombocytopeniahrombocytopenia

001122

Score of 1 = low riskNo Testing Needed

But why is the potassium elevated?But why is the potassium elevated?

Unfractionated Heparin inhibits aldosteroneUnfractionated Heparin inhibits aldosteroneproductionproduction–– Acts only at Acts only at glomerulosa glomerulosa so other steroids are sparedso other steroids are spared

Heparin-Induced Hyperkalemia. Diabetes Research and Clinical Practice 2008;80:e7-8

Aldosterone suppression impairs K+ excretion by kidneys

End result can be hyperkalemia

How often does this happenHow often does this happen

Heparin, even in prophylactic doses, leads toHeparin, even in prophylactic doses, leads tohyperkalemiahyperkalemia in about 7% of patients in the first in about 7% of patients in the first2 wks2 wks

LMWH also causes LMWH also causes hyperkalemiahyperkalemia–– K K++ >5.0 in 9% of patients on LMWH by day#3 >5.0 in 9% of patients on LMWH by day#3

Early Onset of Hyperkalemia in Patients Treated with Low Molecular Weight Heparin: A prospective study. Pharmacoepidemiology and Drug Safety 2004;13:299-302

Switch to Switch to SCDsSCDs–– Not as effective DVT prevention as chemoprophylaxisNot as effective DVT prevention as chemoprophylaxis

–– SCDsSCDs used far more in US (22%) compared to other countries used far more in US (22%) compared to other countries(0.2%)(0.2%)

–– Unlike the surgical literature, Unlike the surgical literature, SCDsSCDs not as proven in medical pts not as proven in medical pts

Substitution of LMWH for UFHSubstitution of LMWH for UFH–– Both cause Both cause hyperkalemiahyperkalemia via via aldosteronealdosterone inhibition inhibition

FondaparinuxFondaparinux–– Synthetic Synthetic pentasacharidepentasacharide binds to binds to antithrombinantithrombin

–– Indirectly inhibits factor XIndirectly inhibits factor X

–– Will not cause Will not cause hyperkalemiahyperkalemia

Heparin-Induced Hyperkalemia. Diabetes Research and Clinical Practice 2008;80:e7-8Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients.Chest 2007;132:936-45

Take Home PointsTake Home Points

Upper Extremity DVT should be treated for Upper Extremity DVT should be treated for >> Months Months–– Catheter removal not required if still functioningCatheter removal not required if still functioning

LMWH preferred over LMWH preferred over warfarin warfarin for VTE in cancer patientsfor VTE in cancer patients

Weigh individual risk/benefit of bridging anticoagulation Weigh individual risk/benefit of bridging anticoagulation periperi--operativelyoperatively–– Low risk patients do not require bridgingLow risk patients do not require bridging

““4 Ts4 Ts”” can identify patients in whom HIT should be can identify patients in whom HIT should besuspectedsuspected

Hyperkalemia Hyperkalemia is a rare but under-recognized side effect ofis a rare but under-recognized side effect ofheparin and LMWHheparin and LMWH