What’s New in the World of Anticoagulation Angela Lambing, MSN, ANP-c, GNP-c Hemophilia & Thrombosis Treatment Center Henry Ford Health System Detroit, MI

Objectives  Understand the coagulation cascade and risks of VTE  Identify the variety of current anticoagulants available  2012 CHEST guidelines  To bridge or not to bridge

Disclosures  Speaker’s Bureau:  GSK Pharmaceuticals  Novartis  Nursing Advisory Boards  Pfizer  Baxter  Bayer Health Care  CSL Behring  Octapharma  I have no current affiliation or financial arrangement with any grantor or commercial interests that might have direct interest in the subject matter of this CE program

Pathophysiology of a Thrombosis  Abnormalities of vessel wall  atherosclerosis (arterial)  trauma, erosion  deficient fibrinolysis, venous hypotonia (pregnancy)  Abnormalities of blood flow  hypertension, turbulence  hyper-viscosity  stasis, deficient clearance of coagulation factors  Abnormalities of blood  quantitative platelet abnormalities  thrombocytosis  decrease of inhibitors, activation of coagulation hypercoagulability  Protein C Def, Protein S Def, Antithrombin III Def Virchow’s Triad Vessel wall Blood flow blood

Statistics Statistics  Incidence of Venous Thromboembolism exceeds 1 per 1000 cases  Over 200,000 cases reported annually in the USA  30% pts die within 30 days of diagnosis  1/5th pts sudden death due to PE  30% survive to develop recurrent VTE within 10 yrs - greatest risk in 1st yr (5-15%) then 1%/yr  28% of cases develop venous stasis syndrome within 20 yrs Heit et al, 2001  Incidence increases with age from 1:1,000 people/year to 1%/year in old age Rosendal,1999

Padua Prediction Score Risk  8 fold risk of VTE  50-75% of VTE events in hospitalized medical pts Hi Risk > 4 Heit et al. Arch In Med, 2000 Heit et al. Arch Int Med, 2002 Spyropoulos et al. Chest 2011

Why Anticoagulate?  Thrombosis  Arterial  Venous  Stroke  Ineffective management with antiplatelet medications  Atrial Fibrillation  Cardiomyopathy  Prosthetic valves  Prophylaxis during cancer therapy

Reproduced with permission from: Rao. Am J Med Sci 1998;316:69.

How Does Blood Clot - Overview

History of Anticoagulants

Coumadin© (Warfarin) Advantages:  Inhibits production of Vit K needed for production of thrombin, factors II, VII, IX, X, protein C & S  No ceiling to dosing  Monitored by INR; (normal range )  Dosing amount can decrease with age  Inexpensive- 5 mg tabs, #30 = $22.00  Easy to reverse;  vitamin K Disadvantages:  Requires regular blood test monitoring  Interactions with multiple medications  Can be affected by oral vitamin K food intake  Bleeding risk 1%/year long term use  Can be difficult to regulate  Can cause tissue necrosis if used without concomitant heparin initially after thrombosis

Botanicals with Potential Anticoagulant & Interactive Effects with Coumadin © * AlfalfaDong QuaiAniseed ArnicaASA Bogbean BoldoBuchoCapsicum CassiaCeleryChamomile DandelionFenugreekHorse Chestnut HorseradishLicoriceMeadowsweet NettleParsleyPassion Flower Prickly AshQuassiaRed Clover WoodruffTonka Beans Bladder Wrack Wild CarrotWild LettuceFoetida Sweet CloverSweet * Non-exhaustive list ALWAYS check formulary

Botanicals than contain Salicylates or Antiplatelet Properties AgrimonyAloe GelAspen Black CohoshBlack HawBogbean CassiaCloveDandelion FeverfewGarlicGinger Gingo BilobaGinsengLicorice MeadowsweetPolicosanolOnion PoplarSenegaTamarind WillowWintergreen German Sarsaparilla

Botanicals with Coagulant Properties  Agrimony  Goldenseal  Mistletoe  Yarrow

Affected by warfarin

Injectable Anticoagulants  Enoxaparin (Lovenox©) - LMWH  1 mg/kg Q12,  1.5 mg/kg/day  Dalteparin (Fragmin©) - LMWH  200 IU/kg daily  Tinzaparin (Innohep©) - LMWH  175 units/kg/day  Fondaparinux (Arixtra©) - Direct Anti Xa inhibitor  7.5 mg, sq daily  5.0 mg for < 50 kg  10 mg > 100 kg  Renal Dosing

Injectable Anticoagulant Properties Advantages:  Predictable pharmacokinetic properties and drug interactions  Can be effective in recurrent VTE while on warfarin  Poor GI absorption not a concern  Therapeutic dosage based on patient’s weight  Lab monitoring not routinely needed  Rapid onset of action and predictable clearance  convenient for frequent interruptions due to procedures Disadvantages:  Cost  Must perform sq injection  Difficult to use for patients with decreased GFR  Many medical personnel do not understand pharmacokinetics

Injectable anticoagulants Anticoagulant ½ life Measurement Lovenox (Enoxaparin © ) 12 hours Heparin x assay – 4 hours post injection Fragmin (Dalteparin © ) 19 hours Heparin x assay– 4 hours post injection Innohep (Tinzaparin © ) 19 hours Heparin x assay– 4 hours post injection Arixtra (Fondaparinux © ) 19 hours Arixtra drug trough levels – just prior 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 Anticoagulants  Rivaroxaban --- Xarelto ©  Affects Xa  Hip and knee prophylaxis of DVT  Stroke in NVAF  November 2, 2012 treatment of DVT/PE  Apixaban --- Eliquis ©  Affects Xa  FDA December 2012 to decrease the number of stokes and dangerous blood clots in NVAF  Dabigatran --- Pradaxa ©  Direct Thrombin inhibitor: affects IIa  FDA October 10, 2010 approval  Stroke prevention in NVAF

Pharmacology Characteristic Warfarin © Rivaroxaban © Apixaban © Dabigatran © Target Vitamin K factors Factor Xa Thrombin Bioavailability100%60-80%60%6% DosingOD OD (BID) BID BID (OD) Time to peak effect 4-5 day 2-4 hours 1-2 hours 1-3 hours Half life 40 hours 7-11 hours 12 hours 8-15 hours Renal clearance None33%25%80% MonitoringYesNoNoNo InteractionsMultiple3A4/P-gp3A4/P-gpP-gp

Oral direct thrombin inhibitors Advantages  ½ life of 19 hours  Oral medication  No need for blood testing Disadvantages  Side effects: GI upset, diarrhea,  Renal clearance of the drug  monitor renal/liver function  Drug-drug interactions  No reversal drug  Prothrombin complex concentrates (PCC)  Feiba ©; Bebulin ©, Profilnine ©; FFP, Factor VIIa;  Dialysis  Lack of understanding mechanism

Direct thrombin inhibitors: Arixtra (sq) Dabigatran(PO) Direct Factor Xa Inhibitor: Apixaban Rivaroxaban

CHEST Guidelines 2012

ACCP Guidelines: Chest 2012  Patients on vitamin K antagonists (warfarin) undergoing minor dental procedures:  Continuation of warfarin around the time of procedure  Co-administration of oral pro-hemostatic agents [Grade 1C]

ACCP Guidelines: 2012  Patients who require a temporary interruption of a warfarin before surgery and require a normal INR for surgery:  Stop warfarin 5 days before procedure (1B)  Use of LMWH with last dose 24 hr before surgery at ½ recommended dose (1C)  Resume warfarin 12 – 24 hours after surgery (1C)  Resume LMWH 24 hr after procedure (1C)

ACCP Guidelines: 2012  Mechanical heart valve or atrial fibrillation or current VTE  High risk for recurrent VTE;  Bridging with therapeutic LMWH of IV UFH  Low risk for recurrent VTE:  Low dose LMWH or no bridging with LMWH/UFH [Grade 2C]

ACCP Guidelines: 2012  Bare metal coronary stent who require surgery within 6 weeks of stent placement:  Continuation of ASA and clopidogrel in the peri- operative period  Drug-eluting coronary stent who require surgery within 12 months of stent placement:  Continuation of ASA and clopidogrel in the peri- operative period [ Grade 2C]

ACCP Guidelines: 2012  Patients who require temporary interruption of ASA or clopidogrel before surgery:  Stop 7-10 days before procedure  Resume agents 24 hours after procedure (2C)

CHADS score  Indication: Assess risk of stroke with AFib  Criteria  A. Congestive Heat Failure (1point)  B. Hypertension (1 point)  C. Age > 75 years (1 point)  D. Diabetes (1 point)  E. Stroke or TIA history (2 points)  Recommendations:  CHADS score > 2, consider bridging if on warfarin Gage. Circulation 2004

Bridge Therapy “Shift from oral, long-acting anticoagulants to parenteral, short-acting anticoagulants during sub-therapeutic levels of oral anticoagulant in the perioperative period” Spyropoulos et al. (2004)

Bridging Therapy  Advantages  Provides continued anticoagulation  Minimal window without anticoagulation  Cost savings for hospitalizations: ~ >$13,000  Disadvantages  Use of LMWH for 8-10 days, SQ self injection  Plan ahead  Prior insurance authorization may be needed  Requires coordination of care  Can be costly (approx. cost 10 syringes =$600- $1,000)

Bridging Therapy Process Steps: Lovenox © 1.Hold warfarin 5 days prior to procedure 2.Start LMWH q12h, 4 days prior to procedure 3.Check INR/Platelet level day before procedure 4.Lovenox dose day before procedure in am ½ the usual dose; Hold LMWH night before procedure 5.Restart both warfarin and LMWH q12-24 hr hours after procedure provided there are no signs of bleeding hours after procedure provided there are no signs of bleeding 6.Check INR on the 4th day - goal of INR > Stop LMWH when INR >2.0 8.Expect to be on LMWH for 8-10 days

Bridging Therapy Process Steps: Using longer ½ life injectables (Arixtra © ) 1.Hold coumadin 5 days prior to procedure 2.Start injectable daily sq, 4 days prior to procedure 3.Last dose of injectable 2 days prior to event (3 ½ lives of the drug) 4.Check INR/Platelet level day before procedure 5.Restart both warfarin and injectable anticoagulant q12-24 hr hours after procedure provided there are no signs of bleeding 6.Check INR on the 4th day - goal of INR > Stop injectable anticoagulant when INR >2.0 8.Expect to be on injectable anticoagulant for 8-10 days

Normal Coagulation Anticoagulated Procedure Date Warfarin Injectable anticoagulant 5 days ~4-5 days Check INR Platelet ct

Coumadin © induced tissue necrosis  Re-initiation of Coumadin ©  Coumadin © causes decrease of Protein C & S as part of the coagulation system when initially started  potentially allows coagulation cascade to go unchecked with increased formulation of thrombin  Onset of thrombosis also causes decreases in Protein C & S  RESULT: Increases risk of thrombosis

Bridging process: oral agents Xarelto ©, Pradaxa ©  Hold 48 hours prior to procedure  Restart hours after procedure

Normal Coagulation Anticoagulated Procedure Date Oral direct thrombin 2 days 1 day

Challenges  Injectables are now generic  Less availability for support programs & educational materials  Still costly  Insurance approvals  Injectables  New agents  Lack of understanding  Medications  Testing  Interactions  Bridging

Summary  Review risk/benefit of holding any form of anticoagulation  Thrombosis vs bleeding risk  Individualized treatment  Co-ordination of care with:  Patients &/or family caregivers  Hematology; HTC  Anticoagulation clinic  Primary physician  Monitor patient during process  Check INR (as indicated)  Bleeding/bruising  Platelet count (as indicated)

Question #1  Patient is on warfarin for atrial fibrillation  Need to extract one tooth  Should warfarin be held?  Questions to ask…..  CHADS score; if high, should not stop warfarin  What is latest INR testing?; must be between 2-3  Nature of the procedure…. Increased risks?

Question #2  Patient is taking Lovenox © every 12 hours for history of pulmonary embolus  History of active colon cancer receiving chemotherapy  Pt requires port placement  Questions to ask….  Should lovenox be held?  How?

Question #3  Patient is on Pradaxa © for atrial fibrillation  Requires 5 teeth extracted  Questions to ask….  CHADS score? Increased risk of VTE?  Amount of bleeding?  ½ life of the medication  Stop Pradaxa © 2 days prior to procedure  Restart hours after the procedure  NO injectable anticoagulant needed

Question #4  Pt on long term Arixtra © for history of recurrent VTE  Pt history of recurrent VTE on therapeutic warfarin  Allergy to Lovenox © itching, rash  Needs colonoscopy for Hx of polyps  Questions to ask?  Hold Arixtra © ?  How?

Angela Lambing, MSN, NP-C Hemophilia & Thrombosis Treatment Center Henry Ford Health System