PRACTICAL MANAGEMENT OF ANTICOAGULATION

Transcription

1 PRACTICAL MANAGEMENT OF ANTICOAGULATION THE BLOOD THINS AND THE PLOT THICKENS Juliann Horne, PharmD PGY2 Pharmacy Resident in Ambulatory Care UNM College of Pharmacy

2 Disclosure No conflicts of interest to disclose Thanks to Allison Burnett, PharmD, CACP, PhC and the UNMH Inpatient Anticoagulation Service for much of the material and resources in this presentation.

3 Learning Objectives Compare and contrast available parental anticoagulants. Compare and contrast available oral anticoagulants. Design an appropriate anticoagulant bridging plan. Describe payment challenges and offer solutions for direct oral anticoagulants. Given an individual patient, recommend an appropriate anticoagulant therapy.

4 Outline Review of coagulation cascade Review of parenteral anticoagulants Review of oral anticoagulants Direct oral anticoagulants (DOACs) Bridging and switching between agents

5 Coagulation Cascade X TF/VIIa VIIIa IXa IX VitK VitK VitK VitK Warfarin Initiation Apixaban Edoxaban Rivaroxaban II Xa Va AT AT Amplification Fondaparinux AT Heparin LMWH Dabigatran IIa Propagation Fibrinogen Fibrin Adapted from Weitz JI, Bates SM. J Thromb Haemost 2005; 3:

6 Parenteral Anticoagulants Agent Heparin LMWH Fondaparinux DTIs Target Xa/IIa Xa>IIa Xa IIa Routes IV/SQ IV/SQ IV/SQ IV Peak effect h 3-4 h 1-3 h 1-2 h Half-life 1 h 4 h 17 h 0.5 h Renal elim. No Yes Yes Some Reversal with protamine Complete Partial None None Lab measure aptt, anti-xa Anti-Xa Anti-Xa aptt When to avoid HIT CrCl < 30 HIT CrCl < 50 Ppx if < 50 kg High bleed risk Ppx = DVT prophylaxis

7 Monitoring LMWH Consider monitoring anti-xa levels: Weight under 50 kg or BMI over 40 CrCl ml/min Pregnant women No better alternative anticoagulant Draw level 4 hours after dose (peak effect) After at least 2-3 doses to achieve steady state Caution: Not correlated with outcomes! Dosing Target Anti-Xa (IU/mL) 1 mg/kg BID mg/kg QD mg/kg QD renal dosing UNMH Adult Parenteral Anticoagulant Dosing Guideline.

8 Oral Anticoagulants Target Agent Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban IIa, VIIa, IXa, Xa IIa Xa Xa Xa Peak effect 4-5 days h 2-4 h 1-3 h 1-2 h Half-life 40 h h 5-9 h 9-14 h 9-11 h Renal elim. None 80% 33% 25% 35-50% Dialyzable No Yes No No No Interactions Many P-gp 3A4, P-gp 3A4, P-gp P-gp Monitoring Yes No No No No Antidote Vitamin K No No No No Cove CL, Hylek EM. J Am Heart Assoc. 2013;2:e P-gp = P-glycoprotein 3A4 = Cytochrome P450 3A4

9 Outline Review of coagulation cascade Review of parenteral anticoagulants Review of oral anticoagulants Direct oral anticoagulants (DOACs) Bridging and switching between agents

10

11 DOACs Approved indications & dosing Efficacy & safety in NVAF & VTE Lab measurement Patient selection Payment challenges and solutions

12 DOACs Approved indications & dosing Efficacy & safety in NVAF & VTE Lab measurement Patient selection Payment challenges and solutions

13 DOACs: FDA-Approved Indications VTE Prophylaxis VTE Treatment Non-valvular AF Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Dabigatran is approved for VTEP in EU and Canada Edoxaban is approved for VTEP in Japan Rivaroxaban is approved for use in ACS in the EU

14 DOACs: Changing the Treatment of VTE UFH LMWH Fondaparinux Initial treatment 0 to 7 days Warfarin Long term-treatment Warfarin Extended treatment 3 to 6 months 1 year to indefinite Dabigatran, Edoxaban Rivaroxaban, Apixaban Chest. 2012;141(2Suppl):7S-47S.

15 DOAC: Dosing Varies by: DOAC Indication Country May require adjustment for: Renal impairment Age Weight Drug interactions A combination of the above

16 DOACs: Dosing (FDA Labeling) Non-valvular atrial fibrillation Apixaban Dabigatran Rivaroxaban Edoxaban 5 mg PO BID 2.5 mg PO BID* 150 mg PO BID 75 mg PO BID* Avoid: CrCl < mg PO daily 15 mg PO daily* Avoid: CrCl < mg PO daily 30 mg PO daily* Avoid: CrCl > 95 VTE prophylaxis (orthopedic) 2.5 mg PO BID Not approved in US 10 mg PO daily Avoid: CrCl < 30 Not approved in US VTE tx & prevention of recurrence 10 mg PO BID x 7 days, then 5 mg BID 150 mg PO BID after parenteral 15 mg PO BID x 21 days, then 20 mg PO daily 60 mg PO daily 30 mg PO daily* after parenteral 2.5 mg BID after 6 months Avoid: CrCl < 30 Avoid: CrCl < 30 Avoid: CrCl < 15 * Adjusted for renal impairment, drug interactions, age, low weight or a combination of these factors Treatment doses of rivaroxaban should be taken with largest meal of the day

17 DOACs Approved indications & dosing Efficacy & safety in NVAF & VTE Lab measurement Patient selection Payment challenges and solutions

18 NON-VALVULAR ATRIAL FIBRILLATION (NVAF)

19 Meta-Analysis: Efficacy & Safety of DOACs in NVAF Lancet. 2014;383:

20 Meta-Analysis: Efficacy & Safety of DOACs in NVAF Lancet. 2014;383:

21 VENOUS THROMBOEMBOLISM (VTE) TREATMENT

22 Meta-Analysis: Efficacy in VTE Prevention of Recurrent VTE DVT PE Non-Fatal PE Eur J Vasc Endovasc Surg. 2014;48(5): NOAC VKA

23 Meta-Analysis: Safety in VTE Major Bleeding Fatal Bleeding All-Cause Mortality Net Clinical Benefit Eur J Vasc Endovasc Surg. 2014;48(5): NOAC VKA

24 DOACs Approved indications & dosing Efficacy & safety in NVAF & VTE Lab measurement Patient selection Payment challenges and solutions

25 Measurement of DOACs Increased specificity for target inhibition Predictable pharmacokinetics and pharmacodynamics Minimal dietary effect Less intrasubject and intersubject variability Wide therapeutic index Do not require routine monitoring Dose is not adjusted based on laboratory measurements No quantitative therapeutic ranges established

26 Potential indications for DOAC measurement Detection of clinically relevant levels Urgent or emergent invasive procedure Neuraxial anesthesia Major trauma Potential thrombolysis in acute thromboembolism Detection of expected on-therapy levels Assessing adherence Breakthrough thrombosis Detection of excessive levels Hemorrhagic episode Overdose Accumulation? - Renal insufficiency - Hepatic impairment - Drug interactions - Elderly Cuker A, et al. J Am Coll Card. 2014; 64(11):

27 Measurement of DOACs J Am Coll Cardiol. 2014;64:

28 Measurement of DOACs Routine coagulation assays aptt, PT, anti-xa Helpful in determining presence of drug (qualitative only) Readily available in most reference labs Specialty coagulation assays Calibrated anti-xa, TT, dtt, ECT, drug concentration Not readily available nor standardized Research or investigational use only at this point Do not use warfarin-based INR J Am Coll Cardiol. 2014;64:

29 DOACs Approved indications & dosing Efficacy & safety in NVAF & VTE Lab measurement Patient selection Payment challenges and solutions

30 Patient Case Which of the following patients would be considered a good candidate for DOAC therapy? A. 68 year-old obese male on aspirin and clopidogrel for a drug-eluting stent placed 1 month ago B. 65 year-old female with diabetes & hypertension, both well-controlled on medication, normal kidney function and new onset atrial fibrillation C. 37 year-old female with end-stage renal disease, on hemodialysis, who has thrombosed her dialysis fistula D. 54-year-old male with a history of recurrent VTE and labile INR due to non-compliance with warfarin therapy

31 Preference for Warfarin: Patient has 1 of the following: Non-adherence to current medications Mechanical cardiac valve Requires dual antiplatelets (e.g., ASA, clopidogrel) Severe renal dysfunction (Estimated CRCl <30 ml/min) Severe liver dysfunction Patient s weight is 50 kg or 120 kg Major drug-drug interactions with DOAC (CYP 3A4, P-gp) Able to comply with warfarin monitoring (no physical, geographic barriers) and no preference for DOAC Good TTR ( 65%) with warfarin compliance Financial barriers to ongoing DOAC access

32 Preference for LMWH Active cancer Pregnant Patient has 1 of the following:

33 DOAC Selection Patient characteristic History of GI bleed Prefer once a day dosing Moderate renal insufficiency (CrCl 30-49) History of MI History of stroke Dyspepsia Preferred Agent Apixaban Edoxaban (dose adjust) Rivaroxaban Edoxaban Apixaban Rivaroxaban Apixaban Rivaroxaban Apixaban Rivaroxaban/apixaban/edoxaban

34 Patient Case Which of the following patients would be considered a good candidate for DOAC therapy? A. 68 year-old obese male on aspirin and clopidogrel for a drug-eluting stent placed 1 month ago B. 65 year-old female with diabetes & hypertension, both well-controlled on medication, normal kidney function and new onset atrial fibrillation C. 37 year-old female with end-stage renal disease, on hemodialysis, who has thrombosed her dialysis fistula D. 54-year-old male with a history of recurrent VTE and labile INR due to non-compliance with warfarin therapy

35 DOACs Approved indications & dosing Efficacy & safety in NVAF & VTE Lab measurement Patient selection Payment challenges and solutions

36 Insurance Coverage NM Medicaid Medicare Part D Dabigatran (Pradaxa) US: 100% (87%) Rivaroxaban (Xarelto) BCBS Molina (PA) Pres (10 mg only) UHC (PA) Apixaban (Eliquis) Pres (PA) UHC (PA) Edoxaban (Savaysa) NM: 78% (59%) US: 93% TBD Commercial US: 96% (80%) NM: 85% (61%) US: 87% (73%) TBD (% available at lowest branded copay in parentheses)

37 Patient Assistance Programs Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) NM Medicaid N/A N/A N/A N/A Medicare Part D Free 30-day supply card Free 30-day supply card Free 30-day supply card N/A Commercial $10 copay card Free 30-day + $5 copay card for 15 mg and 20 mg Free 30-day + $10 copay card $4 copay card Non-insured BIpatient assistance.com JJpaf.org: free for those who qualify (income) BMSpaf.org: free for those who qualify (income)?

38 DOACs: Advantages Improved pharmacokinetic/pharmacodynamic profile Rapid onset/offset of action Fewer dietary and drug interactions Wide therapeutic window allows fixed dosing No need for routine monitoring Greater convenience and patient satisfaction Improved safety profile compared to warfarin 20-40% relative risk reduction in major bleeding 40-50% relative risk reduction in fatal bleeding 60-70% relative risk reduction in intracranial hemorrhage Potentially more cost-effective Chai-Adisaksopha, et al. Blood 2014; 124(15): Bauer KA. ASH Education Book 2013; 1: Ruff CT, et al. Lancet 2013; 383 (9921): Van Der Hulle T, et al. J Thromb Haemost 2014; 12:

39 DOACs: Disadvantages Dose reduction or avoidance in kidney impairment Lack of flexibility in dosing Limited availability of lab assays to measure anticoagulant effect Short half-life mandates strict adherence Lack of antidote Higher drug acquisition costs and prior authorizations Fewer studied/approved indications (e.g. valves, cancer, pregnancy) Bauer KA. ASH Education Book. 2013;1: Majeed A, et al. Circulation 2013;128(21):

40 Outline Review of coagulation cascade Review of parenteral anticoagulants Review of oral anticoagulants Direct oral anticoagulants (DOACs) Bridging and switching between agents

41 Steps to Developing a Bridge Plan Key Question: Does anticoagulation need to be interrupted? 1. Develop plan at least 1 week prior to procedure 2. Evaluate bleeding risk of procedure 3. Evaluate patient s thrombotic risk 4. Timing of cessation and resumption of agent is based on: a. Patient s renal function b. Half-life/onset of agent c. Type of procedure and anesthesia

42 Assessing Bleed Risk Baron TH, et al. N Engl J Med 2013;368:

43 Assessing Thrombotic Risk Blood. 2012;120:

44 Peri-Procedural Management: VKAs Management of Anticoagulation in the Peri-procedural Period (MAP) Tool Two-Page Summary: Management of Anticoagulation in the Peri- Procedural Period at High thromboembolic risk Moderate thromboembolic risk Low thromboembolic risk High Bleed Risk Interrupt VKA, Bridge Interrupt VKA, Consider bridge Interrupt VKA, No bridge Low Bleed Risk Consider interrupting VKA Bridge Consider interrupting VKA, Consider bridge Interrupt VKA, No bridge Minimal Bleed Risk Do not interrupt VKA

45 Peri-Procedural Management: DOACs Management of Anticoagulation in the Peri-procedural Period (MAP) Tool Two-Page Summary: Management of Anticoagulation in the Peri- Procedural Period at Risk Assessment High thromboembolic risk Moderate thromboembolic risk Low thromboembolic risk High Bleed Risk Interrupt DOAC Low Bleed Risk Consider interrupting DOAC Interrupt DOAC Minimal Bleed Risk Do not interrupt DOAC

46 Cessation and Resumption of DOACs Cessation depends on DOAC, renal function, and bleed risk

47 Peri-Procedural Management: DOACs Resumption of DOAC similar to LMWH Rapid onset of anticoagulant effect (~1-4 hours) Caution with resuming too soon or too aggressively May consider step-up approach Lower or prophylactic dose of DOAC for initial hours If tolerated, increase to treatment dose DOAC at hours Spyropolous AC, et al. Blood 2012; 120(15):

48 Switching Between Anticoagulants Reason for switching from parenteral to oral anticoagulant Facilitate longer-term outpatient management Reasons for switching from warfarin to DOAC Drug intolerance Therapeutic failure Patient preference Reasons for switching from DOAC to warfarin Drug intolerance Therapeutic failure Patient preference New comorbidity or contraindication Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37:

49 Switching Between Anticoagulants Can place patients at undue risk for bleeding or thrombosis Requires a carefully constructed and thoughtful approach based on: Pharmacokinetic profile of each anticoagulant Appropriate laboratory assessment of patient s coagulation status Patient s renal function Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37:

50 Switching Between Anticoagulants Unfractionated heparin Short half-life precludes need for lag time until alternative anticoagulant is initiated DOACs and SQ injectables (LMWH, fondaparinux) Longer half-life requires lag time until alternative anticoagulant is initiated Start alternative anticoagulant when the next dose of original anticoagulant would be due Warfarin Extremely long half-life requires confirmed offset via INR Slow onset may require overlap of rapid-acting anticoagulant Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37:

51 Switching Between Anticoagulants Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37:

52 Switching Between Anticoagulants Abo-Salem E, et al. J Thromb Thrombolysis 2014; 37:

53 DOAC Summary DOACs are a viable alternative to traditional anticoagulants in appropriately selected patients Equal or better efficacy for VTE treatment and stroke prevention in NVAF Improved safety profile compared to warfarin Significant reduction in major, fatal, intracranial hemorrhage GIB caution: dabigatran and rivaroxaban Optimal use of DOACs requires familiarity with: Pharmacokinetic/dynamic profiles Dosing strategies Lab measurement Peri-procedural strategies Switching between agents Bleed management Reversal strategies

54 AC Forum- Centers of Excellence

55

56 QUESTIONS? Juliann Horne, PharmD