1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

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

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

10. How Does Blood Clot - Overview

11. History of Anticoagulants

12. 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; 2-3.0 (normal range 0.8-1.2)  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

13. 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

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

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

16. Affected by warfarin

17. 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

18. 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

19. 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

20. Affected by UFH Low molecular weight heparins Direct Factor Xa Inhibitor (Arixtra)

21. 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

22. 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

23. 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

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

25. CHEST Guidelines 2012

26. 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]

27. 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)

28. 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]

29. 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]

30. 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)

31. 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

32. 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)

33. 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)

34. 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 > 2.0 7.Stop LMWH when INR >2.0 8.Expect to be on LMWH for 8-10 days

35. 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 > 2.0 7.Stop injectable anticoagulant when INR >2.0 8.Expect to be on injectable anticoagulant for 8-10 days

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

37. 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

39. Bridging process: oral agents Xarelto ©, Pradaxa ©  Hold 48 hours prior to procedure  Restart 12-24 hours after procedure

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

41. 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

42. 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)

43. 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?

44. 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?

45. 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 12-24 hours after the procedure  NO injectable anticoagulant needed

46. 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?

47. Angela Lambing, MSN, NP-C Hemophilia & Thrombosis Treatment Center Henry Ford Health System alambin1@hfhs.org 313-916-9094