What’s New What’s New in the World ofin the World ofAnticoagulationAnticoagulation

Angela Lambing, MSN, ANP-c, GNP-cAngela Lambing, MSN, ANP-c, GNP-cHemophilia & Thrombosis Treatment CenterHemophilia & Thrombosis Treatment CenterHenry Ford Health SystemHenry Ford Health SystemDetroit, MIDetroit, MI

ObjectivesObjectives

Understand the coagulation cascade and Understand the coagulation cascade and risks of VTErisks of VTE

Identify the variety of current Identify the variety of current anticoagulants availableanticoagulants available 2012 CHEST guidelines2012 CHEST guidelines

To bridge or not to bridgeTo bridge or not to bridge

DisclosuresDisclosures Speaker’s Bureau:Speaker’s Bureau:

GSK PharmaceuticalsGSK Pharmaceuticals NovartisNovartis

Nursing Advisory BoardsNursing Advisory Boards Pfizer Pfizer Baxter Baxter Bayer Health CareBayer Health Care CSL BehringCSL Behring OctapharmaOctapharma

I have no current affiliation or financial arrangement with any I have no current affiliation or financial arrangement with any grantor or commercial interests that might have direct interest grantor or commercial interests that might have direct interest in the subject matter of this CE programin the subject matter of this CE program

Pathophysiology of a ThrombosisPathophysiology of a Thrombosis

AbnormalitiesAbnormalities of vessel wall of vessel wall atherosclerosis (arterial)atherosclerosis (arterial) trauma, erosiontrauma, erosion deficient fibrinolysis, venous hypotonia deficient fibrinolysis, venous hypotonia

(pregnancy)(pregnancy)

Abnormalities of blood flowAbnormalities of blood flow hypertension, turbulencehypertension, turbulence hyper-viscosityhyper-viscosity stasis, deficient clearance of coagulation stasis, deficient clearance of coagulation

factorsfactors Abnormalities of bloodAbnormalities of blood

quantitative platelet abnormalities quantitative platelet abnormalities thrombocytosisthrombocytosis

decrease of inhibitors, activation of decrease of inhibitors, activation of coagulation hypercoagulabilitycoagulation hypercoagulability

Protein C Def, Protein S Def, Antithrombin III Protein C Def, Protein S Def, Antithrombin III DefDef

Virchow’s Triad

Vessel wall

Bloo

d flow blood

StatisticsStatistics

Incidence of Venous Thromboembolism exceeds 1 Incidence of Venous Thromboembolism exceeds 1 per 1000 casesper 1000 cases

Over 200,000 cases reported annually in the USAOver 200,000 cases reported annually in the USA 30% pts die within 30 days of diagnosis30% pts die within 30 days of diagnosis 1/5th pts sudden death due to PE1/5th pts sudden death due to PE 30% survive to develop recurrent VTE within 10 yrs 30% survive to develop recurrent VTE within 10 yrs

- greatest risk in 1st yr (5-15%) then 1%/yr- greatest risk in 1st yr (5-15%) then 1%/yr 28% of cases develop venous stasis syndrome 28% of cases develop venous stasis syndrome

within 20 yrswithin 20 yrs Heit et al, 2001Heit et al, 2001

Incidence increases with age from 1:1,000 Incidence increases with age from 1:1,000 people/year to 1%/year in old age people/year to 1%/year in old age Rosendal,1999Rosendal,1999

Padua Prediction Score RiskPadua Prediction Score Risk

8 fold risk of VTE8 fold risk of VTE 50-75% of VTE 50-75% of VTE

events in hospitalized events in hospitalized medical ptsmedical pts

Hi Risk > 4Heit et al. Arch In Med, 2000

Heit et al. Arch Int Med, 2002Spyropoulos et al. Chest 2011

Why Anticoagulate?Why Anticoagulate?

ThrombosisThrombosis ArterialArterial VenousVenous

StrokeStroke Ineffective management with antiplatelet medicationsIneffective management with antiplatelet medications

Atrial FibrillationAtrial Fibrillation CardiomyopathyCardiomyopathy Prosthetic valvesProsthetic valves Prophylaxis during cancer therapyProphylaxis during cancer therapy

Reproduced with permission from: Rao. Reproduced with permission from: Rao. Am J Med SciAm J Med Sci

1998;316:69.1998;316:69.

How Does Blood Clot - OverviewHow Does Blood Clot - Overview

History of AnticoagulantsHistory of Anticoagulants

CoumadinCoumadin©© (Warfarin) (Warfarin)

Advantages:Advantages:

Inhibits production of Vit K Inhibits production of Vit K needed for production of needed for production of thrombin, factors II, VII, IX, X, thrombin, factors II, VII, IX, X, protein C & Sprotein C & S

No ceiling to dosingNo ceiling to dosing Monitored by INR; 2-3.0 (normal Monitored by INR; 2-3.0 (normal

range 0.8-1.2)range 0.8-1.2) Dosing amount can decrease Dosing amount can decrease

with age with age Inexpensive- 5 mg tabs, #30 = Inexpensive- 5 mg tabs, #30 =

$22.00$22.00 Easy to reverse; Easy to reverse;

vitamin Kvitamin K

Disadvantages:Disadvantages:

Requires regular blood test Requires regular blood test monitoringmonitoring

Interactions with multiple Interactions with multiple medicationsmedications

Can be affected by oral vitamin K Can be affected by oral vitamin K food intakefood intake

Bleeding risk 1%/year long term Bleeding risk 1%/year long term useuse

Can be difficult to regulateCan be difficult to regulate Can cause tissue necrosis if Can cause tissue necrosis if

used without concomitant used without concomitant heparin initially after heparin initially after thrombosisthrombosis

Botanicals with Potential Anticoagulant & Botanicals with Potential Anticoagulant & Interactive Effects with CoumadinInteractive Effects with Coumadin©©**

AlfalfaAlfalfa Dong QuaiDong Quai AniseedAniseedArnicaArnica ASA ASA BogbeanBogbeanBoldoBoldo BuchoBucho CapsicumCapsicumCassiaCassia CeleryCelery ChamomileChamomileDandelionDandelion FenugreekFenugreek Horse ChestnutHorse ChestnutHorseradishHorseradish LicoriceLicorice MeadowsweetMeadowsweetNettleNettle ParsleyParsley Passion FlowerPassion FlowerPrickly AshPrickly Ash QuassiaQuassia Red CloverRed CloverWoodruffWoodruff Tonka Beans Tonka Beans Bladder WrackBladder WrackWild CarrotWild Carrot Wild LettuceWild Lettuce FoetidaFoetida Sweet CloverSweet Clover SweetSweet

**Non-exhaustive listNon-exhaustive list

ALWAYS check formularyALWAYS check formulary

Botanicals than contain Salicylates or Botanicals than contain Salicylates or

Antiplatelet PropertiesAntiplatelet Properties

AgrimonyAgrimony Aloe GelAloe Gel AspenAspenBlack CohoshBlack Cohosh Black HawBlack Haw BogbeanBogbeanCassiaCassia CloveClove DandelionDandelionFeverfewFeverfew GarlicGarlic GingerGingerGingo BilobaGingo Biloba GinsengGinseng LicoriceLicoriceMeadowsweetMeadowsweet PolicosanolPolicosanol OnionOnionPoplarPoplar SenegaSenega TamarindTamarindWillowWillow WintergreenWintergreenGerman SarsaparillaGerman Sarsaparilla

Botanicals with Coagulant Botanicals with Coagulant PropertiesProperties

AgrimonyAgrimony GoldensealGoldenseal MistletoeMistletoe YarrowYarrow

Affected by warfarin

Injectable AnticoagulantsInjectable Anticoagulants

Enoxaparin (LovenoxEnoxaparin (Lovenox©©) - LMWH) - LMWH 1 mg/kg Q12,1 mg/kg Q12, 1.5 mg/kg/day1.5 mg/kg/day

Dalteparin (FragminDalteparin (Fragmin©©) - LMWH) - LMWH 200 IU/kg daily200 IU/kg daily

Tinzaparin (InnohepTinzaparin (Innohep©©) - LMWH) - LMWH 175 units/kg/day175 units/kg/day

Fondaparinux (ArixtraFondaparinux (Arixtra©©) - Direct Anti Xa inhibitor) - Direct Anti Xa inhibitor 7.5 mg, sq daily 7.5 mg, sq daily 5.0 mg for < 50 kg5.0 mg for < 50 kg 10 mg > 100 kg10 mg > 100 kg

Renal DosingRenal Dosing

Injectable Anticoagulant PropertiesInjectable Anticoagulant Properties

Advantages:Advantages:

PredictablePredictable pharmacokinetic pharmacokinetic properties and drug interactionsproperties and drug interactions

Can be effective in recurrent VTE Can be effective in recurrent VTE while on warfarinwhile on warfarin

Poor GI absorption not a concernPoor GI absorption not a concern Therapeutic dosage based on Therapeutic dosage based on

patient’s weightpatient’s weight Lab monitoring not routinely Lab monitoring not routinely

neededneeded Rapid onset of action and Rapid onset of action and

predictable clearancepredictable clearance convenient for frequent convenient for frequent

interruptions due to proceduresinterruptions due to procedures

Disadvantages:Disadvantages: CostCost Must perform sq injectionMust perform sq injection Difficult to use for patients with Difficult to use for patients with

decreased GFRdecreased GFR Many medical personnel do not Many medical personnel do not

understand pharmacokineticsunderstand pharmacokinetics

Injectable anticoagulantsInjectable anticoagulants

AnticoagulantAnticoagulant ½ life ½ life MeasurementMeasurement

Lovenox (EnoxaparinLovenox (Enoxaparin©©)) 12 hours12 hours Heparin x assay – 4 hours post Heparin x assay – 4 hours post injectioninjection

Fragmin (DalteparinFragmin (Dalteparin©©)) 19 hours19 hours Heparin x assay– 4 hours post Heparin x assay– 4 hours post injectioninjection

Innohep (TinzaparinInnohep (Tinzaparin©©)) 19 hours19 hours Heparin x assay– 4 hours post Heparin x assay– 4 hours post injectioninjection

Arixtra (FondaparinuxArixtra (Fondaparinux©©)) 19 hours19 hours Arixtra drug trough levels – just Arixtra drug trough levels – just prior to next doseprior to next dose

**All injectables are cleared through the renal system

Affected by UFH

Low molecular weight heparins

Direct Factor Xa Inhibitor (Arixtra)

New Oral AnticoagulantsNew Oral Anticoagulants

Rivaroxaban --- XareltoRivaroxaban --- Xarelto©© Affects XaAffects Xa

Hip and knee prophylaxis of DVTHip and knee prophylaxis of DVT Stroke in NVAFStroke in NVAF November 2, 2012 treatment of DVT/PENovember 2, 2012 treatment of DVT/PE

Apixaban --- EliquisApixaban --- Eliquis©© Affects XaAffects Xa

FDA December 2012 to decrease the number of stokes and FDA December 2012 to decrease the number of stokes and dangerous blood clots in NVAFdangerous blood clots in NVAF

Dabigatran --- PradaxaDabigatran --- Pradaxa©© Direct Thrombin inhibitor: affects IIaDirect Thrombin inhibitor: affects IIa

FDA October 10, 2010 approvalFDA October 10, 2010 approval Stroke prevention in NVAFStroke prevention in NVAF

PharmacologyPharmacology

CharacteristicCharacteristic WarfarinWarfarin©© Rivaroxaban Rivaroxaban ©© Apixaban Apixaban ©© Dabigatran Dabigatran ©©

TargetTarget Vitamin K Vitamin K factorsfactors

Factor XaFactor Xa Factor XaFactor Xa ThrombinThrombin

BioavailabilityBioavailability 100%100% 60-80%60-80% 60%60% 6%6%

DosingDosing ODOD OD (BID)OD (BID) BIDBID BID (OD)BID (OD)

Time to peak Time to peak effecteffect

4-5 day4-5 day 2-4 hours2-4 hours 1-2 hours1-2 hours 1-3 hours1-3 hours

Half lifeHalf life 40 hours40 hours 7-11 hours7-11 hours 12 hours12 hours 8-15 hours8-15 hours

Renal Renal clearanceclearance

NoneNone 33%33% 25%25% 80%80%

MonitoringMonitoring YesYes NoNo NoNo NoNo

InteractionsInteractions MultipleMultiple 3A4/P-gp3A4/P-gp 3A4/P-gp3A4/P-gp P-gpP-gp

Oral direct thrombin inhibitorsOral direct thrombin inhibitors

AdvantagesAdvantages

½ life of 19 hours½ life of 19 hours Oral medicationOral medication No need for blood testingNo need for blood testing

DisadvantagesDisadvantages

Side effects: GI upset, diarrhea, Side effects: GI upset, diarrhea, Renal clearance of the drug Renal clearance of the drug

monitor renal/liver functionmonitor renal/liver function Drug-drug interactionsDrug-drug interactions No reversal drugNo reversal drug

Prothrombin complex concentrates Prothrombin complex concentrates (PCC)(PCC) FeibaFeiba©; ©; BebulinBebulin©, ©, Profilnine ©; Profilnine ©;

FFP, Factor VIIa; FFP, Factor VIIa; Dialysis Dialysis

Lack of understanding mechanismLack of understanding mechanism

Direct thrombin inhibitors: Arixtra (sq)

Dabigatran(PO)

Direct Factor Xa Inhibitor: Apixaban

Rivaroxaban

CHEST CHEST GuidelinesGuidelines20122012

ACCP Guidelines: Chest ACCP Guidelines: Chest 20122012

Patients on vitamin K antagonists Patients on vitamin K antagonists (warfarin) undergoing minor dental (warfarin) undergoing minor dental procedures:procedures: Continuation of warfarin around the time of Continuation of warfarin around the time of

procedureprocedure Co-administration of oral pro-hemostatic Co-administration of oral pro-hemostatic

agentsagents

[Grade 1C][Grade 1C]

ACCP Guidelines: 2012ACCP Guidelines: 2012

Patients who require a temporary interruption Patients who require a temporary interruption of a warfarin before surgery and require a of a warfarin before surgery and require a normal INR for surgery:normal INR for surgery:

Stop warfarin 5 days before procedure (1B)Stop warfarin 5 days before procedure (1B) Use of LMWH with last dose 24 hr before Use of LMWH with last dose 24 hr before

surgery at ½ recommended dose (1C)surgery at ½ recommended dose (1C) Resume warfarin 12 – 24 hours after surgery Resume warfarin 12 – 24 hours after surgery

(1C)(1C) Resume LMWH 24 hr after procedure (1C)Resume LMWH 24 hr after procedure (1C)

ACCP Guidelines: 2012ACCP Guidelines: 2012

Mechanical heart valve or atrial fibrillation Mechanical heart valve or atrial fibrillation or current VTE or current VTE High risk for recurrent VTE; High risk for recurrent VTE;

Bridging with therapeutic LMWH of IV UFHBridging with therapeutic LMWH of IV UFH Low risk for recurrent VTE:Low risk for recurrent VTE:

Low dose LMWH or no bridging with LMWH/UFHLow dose LMWH or no bridging with LMWH/UFH

[Grade 2C][Grade 2C]

ACCP Guidelines: 2012ACCP Guidelines: 2012

Bare metal coronary stent who require surgery Bare metal coronary stent who require surgery within 6 weeks of stent placement:within 6 weeks of stent placement: Continuation of ASA and clopidogrel in the peri-Continuation of ASA and clopidogrel in the peri-

operative periodoperative period Drug-eluting coronary stent who require Drug-eluting coronary stent who require

surgery within 12 months of stent placement:surgery within 12 months of stent placement: Continuation of ASA and clopidogrel in the peri-Continuation of ASA and clopidogrel in the peri-

operative periodoperative period

[[Grade 2C]Grade 2C]

ACCP Guidelines: 2012ACCP Guidelines: 2012

Patients who require temporary Patients who require temporary interruption of ASA or clopidogrel before interruption of ASA or clopidogrel before surgery:surgery: Stop 7-10 days before procedureStop 7-10 days before procedure Resume agents 24 hours after procedure Resume agents 24 hours after procedure

(2C)(2C)

CHADS scoreCHADS score

Indication: Assess risk of stroke with AFibIndication: Assess risk of stroke with AFib CriteriaCriteria

A. Congestive Heat Failure (1point)A. Congestive Heat Failure (1point) B. Hypertension (1 point)B. Hypertension (1 point) C. Age > 75 years (1 point)C. Age > 75 years (1 point) D. Diabetes (1 point)D. Diabetes (1 point) E. Stroke or TIA history (2 points)E. Stroke or TIA history (2 points)

Recommendations:Recommendations: CHADS score > 2, consider bridging if on warfarinCHADS score > 2, consider bridging if on warfarin

Gage. Circulation 2004Gage. Circulation 2004

Bridge TherapyBridge Therapy

““SShift from oral, long-acting anticoagulants hift from oral, long-acting anticoagulants to parenteral, short-acting anticoagulants to parenteral, short-acting anticoagulants during sub-therapeutic levels of oral during sub-therapeutic levels of oral anticoagulant in the perioperative period”anticoagulant in the perioperative period”

Spyropoulos et al. Spyropoulos et al. (2004)(2004)

Bridging TherapyBridging Therapy

AdvantagesAdvantages Provides continued anticoagulationProvides continued anticoagulation Minimal window without anticoagulationMinimal window without anticoagulation Cost savings for hospitalizations: ~ >$13,000Cost savings for hospitalizations: ~ >$13,000

DisadvantagesDisadvantages Use of LMWH for 8-10 days, SQ self injectionUse of LMWH for 8-10 days, SQ self injection Plan aheadPlan ahead Prior insurance authorization may be neededPrior insurance authorization may be needed Requires coordination of careRequires coordination of care Can be costly (approx. cost 10 syringes =$600-Can be costly (approx. cost 10 syringes =$600-

$1,000)$1,000)

Bridging Therapy Process Steps: LovenoxBridging Therapy Process Steps: Lovenox©©

1.1. Hold warfarin 5 days prior to procedureHold warfarin 5 days prior to procedure2.2. Start LMWH q12h, 4 days prior to procedureStart LMWH q12h, 4 days prior to procedure3.3. Check INR/Platelet level day before procedureCheck INR/Platelet level day before procedure4.4. Lovenox dose day before procedure in am ½ the Lovenox dose day before procedure in am ½ the

usual dose; Hold LMWH night before procedureusual dose; Hold LMWH night before procedure5.5. Restart Restart bothboth warfarin and LMWH q12-24 hr warfarin and LMWH q12-24 hr hours after procedure provided there are no signs of hours after procedure provided there are no signs of

bleedingbleeding6.6. Check INR on the 4th day - goal of INR > 2.0Check INR on the 4th day - goal of INR > 2.07.7. Stop LMWH when INR >2.0Stop LMWH when INR >2.08.8. Expect to be on LMWH for 8-10 daysExpect to be on LMWH for 8-10 days

Bridging Therapy Process Steps: Bridging Therapy Process Steps: Using longer ½ life injectables (ArixtraUsing longer ½ life injectables (Arixtra©©))

1.1. Hold coumadin 5 days prior to procedureHold coumadin 5 days prior to procedure2.2. Start injectable daily sq, 4 days prior to procedureStart injectable daily sq, 4 days prior to procedure3.3. Last dose of injectable 2 days prior to event (3 ½ Last dose of injectable 2 days prior to event (3 ½

lives of the drug)lives of the drug)4.4. Check INR/Platelet level day before procedureCheck INR/Platelet level day before procedure5.5. Restart Restart bothboth warfarin and injectable anticoagulant warfarin and injectable anticoagulant

q12-24 hr hours after procedure provided there are q12-24 hr hours after procedure provided there are no signs of bleedingno signs of bleeding

6.6. Check INR on the 4th day - goal of INR > 2.0Check INR on the 4th day - goal of INR > 2.07.7. Stop injectable anticoagulant when INR >2.0Stop injectable anticoagulant when INR >2.08.8. Expect to be on injectable anticoagulant for 8-10 daysExpect to be on injectable anticoagulant for 8-10 days

Normal Coagulation

Anticoagulated

Procedure Date

Warfarin

Injectable anticoagulant

5 days ~4-5 days

Check INRPlatelet ct

CoumadinCoumadin©© induced tissue necrosis induced tissue necrosis

Re-initiation of CoumadinRe-initiation of Coumadin©©

CoumadinCoumadin©© causes decrease of Protein C & S causes decrease of Protein C & S as part of the coagulation system when as part of the coagulation system when initially startedinitially started potentially allows coagulation cascade to go potentially allows coagulation cascade to go

unchecked with increased formulation of thrombinunchecked with increased formulation of thrombin

Onset of thrombosis also causes decreases in Onset of thrombosis also causes decreases in Protein C & SProtein C & S

RESULT: Increases risk of thrombosisRESULT: Increases risk of thrombosis

Bridging process: oral agentsBridging process: oral agentsXareltoXarelto©©, Pradaxa, Pradaxa©©

Hold 48 hours prior to procedureHold 48 hours prior to procedure Restart 12-24 hours after procedureRestart 12-24 hours after procedure

Normal Coagulation

Anticoagulated

Procedure Date

Oral direct thrombin

2 days

1 day

ChallengesChallenges

Injectables are now genericInjectables are now generic Less availability for support programs & educational materialsLess availability for support programs & educational materials Still costlyStill costly

Insurance approvalsInsurance approvals InjectablesInjectables New agentsNew agents

Lack of understandingLack of understanding MedicationsMedications

TestingTesting InteractionsInteractions BridgingBridging

SummarySummary Review risk/benefit of holding any form of Review risk/benefit of holding any form of

anticoagulationanticoagulation Thrombosis vs bleeding riskThrombosis vs bleeding risk

Individualized treatmentIndividualized treatment Co-ordination of care with:Co-ordination of care with:

Patients &/or family caregiversPatients &/or family caregivers Hematology; HTCHematology; HTC Anticoagulation clinicAnticoagulation clinic Primary physicianPrimary physician

Monitor patient during processMonitor patient during process Check INR (as indicated)Check INR (as indicated) Bleeding/bruising Bleeding/bruising Platelet count (as indicated)Platelet count (as indicated)

Question #1Question #1

Patient is on warfarin for atrial fibrillationPatient is on warfarin for atrial fibrillation Need to extract one toothNeed to extract one tooth Should warfarin be held?Should warfarin be held? Questions to ask…..Questions to ask…..

CHADS score; if high, should not stop warfarinCHADS score; if high, should not stop warfarin What is latest INR testing?; must be between 2-3What is latest INR testing?; must be between 2-3 Nature of the procedure…. Increased risks?Nature of the procedure…. Increased risks?

Question #2Question #2

Patient is taking LovenoxPatient is taking Lovenox©© every 12 every 12 hours for history of pulmonary embolushours for history of pulmonary embolus

History of active colon cancer receiving History of active colon cancer receiving chemotherapychemotherapy

Pt requires port placementPt requires port placement Questions to ask….Questions to ask….

Should lovenox be held?Should lovenox be held? How?How?

Question #3Question #3

Patient is on PradaxaPatient is on Pradaxa©© for atrial fibrillation for atrial fibrillation Requires 5 teeth extractedRequires 5 teeth extracted Questions to ask….Questions to ask….

CHADS score? Increased risk of VTE?CHADS score? Increased risk of VTE? Amount of bleeding?Amount of bleeding? ½ life of the medication½ life of the medication Stop PradaxaStop Pradaxa©© 2 days prior to procedure 2 days prior to procedure Restart 12-24 hours after the procedureRestart 12-24 hours after the procedure NO injectable anticoagulant neededNO injectable anticoagulant needed

Question #4Question #4

Pt on long term ArixtraPt on long term Arixtra©© for history of recurrent for history of recurrent VTEVTE

Pt history of recurrent VTE on therapeutic Pt history of recurrent VTE on therapeutic warfarinwarfarin

Allergy to LovenoxAllergy to Lovenox©© itching, rash itching, rash Needs colonoscopy for Hx of polypsNeeds colonoscopy for Hx of polyps Questions to ask?Questions to ask?

Hold ArixtraHold Arixtra©©?? How?How?

Angela Lambing, MSN, NP-CAngela Lambing, MSN, NP-CHemophilia & Thrombosis Hemophilia & Thrombosis Treatment CenterTreatment CenterHenry Ford Health SystemHenry Ford Health Systemalambin1@hfhs.orgalambin1@hfhs.org313-916-9094313-916-9094