Order Verification for High Risk Medications Review

1. Order Verification for High Risk MedicationsReview August 17th, 2017 Ashley Thompson, PharmD

2. Unfractionated Heparin Infusions • Contraindications and cautions • Allergy to heparin or hypersensitivity to pork products • History of Heparin Induced Thrombocytopenia (HIT) • Active bleeding, where the risk of bleeding outweighs the benefit from thrombosis treatment or prevention • Use caution • IM injections and arterial punctures during anticoagulant therapy • Concurrent medications that affect platelet function (i.e. NSAIDs, Aspirin, Dipyridamole, Clopidogrel, etc.) • Use caution in patients with platelets <60

3. Heparin Infusion Background • Therapeutic aPTT within 24 hours associated with reduced thromboembolism recurrence • Weight based heparin dosing associated with quicker time to therapeutic aPTT range • Limited data in obese patients • No consensus on dosing strategy • Data suggests using 100kg dose cap or adjusted weight Therapeutic aPTT 50-70.9sec Hull RD, et al. N Engl J Med 1986;15:1109–1114 Raschke R et al. Ann Intern Med 1993; 119:874-81.

4. Summary of Recent Heparin Order-set updates • All heparin infusions in a single order set • Exc: EKOS • Weight based titration algorithm • Example: Increase/decrease by 1 unit/kg/hour instead of 100 units/hour • Weight cap of 100kg for obese patients • Pre-checked bolus, as appropriate • VAD protocol & Fixed dose added • Widespread effort to update Alaris infusion pumps more efficiently

5. Recent Heparin Build Updates

6. Why were these updates made?

7. Compliance to Heparin Infusion Guideline dosing2014 MUE (N= 168 orders (114 patients)) NO BOLUS CI: 15 units/kg/hr Bolus: 60 units/kg CI: 12 units/kg/hr Bolus: 80 units/kg CI: 18 units/kg/hr

8. Compliance to Heparin Infusion Guideline dosing2014 MUE (N= 168 orders (114 patients))

9. Time to Therapeutic Goal (TTG)* 2014 MUE (N= 168 orders (114 patients) Olson J, Arkin C, Brandt J, Cunningham M.  Arch Pathol Lab Med. 1998;122:782-798.

10. Heparin Quality Assurance Audit Results

11. Post Heparin Implementation Updates • Use “drug dosing weight (admit weight)” for all patients  ≤100kg • Use “order-specific weight” in the heparin order for all patients > 100kg and enter 100kg Pharmacist Facing BPA Implemented Monday June 26th, 2017

12. Unfractionated Heparin Monitoring with Anti-Xa Levels

13. aPTT Monitoring for Systemic HeparinBackground • Activated partial thromboplastin time • Measures global activity of intrinsic coagulation factors targeted by heparin • Most widely used method for therapeutic monitoring of heparin • Therapeutic range for systemic heparin: 1.5 - 2.5x the control value Targets of heparin-antithrombin complex Eikelboom J. 2006. Francis et al. 2004

14. aPTT Monitoring for Systemic HeparinConcerns • Preanalytic sampling issues: different aPTT reagents produce different reference ranges (1.6 - 2.7x to 3.7 - 6.2x control) • Patient-specific variables affect ability to achieve appropriate heparin dose and monitoring of aPTT Olson et al. 1998.

15. Anti-Xa Monitoring for Systemic HeparinBackground • Measures ability of heparin-antithrombin complex to inhibit activated Factor X • Direct measure of heparin’s intrinsic activity on a single enzyme • Reference range: 0.3 - 0.7 anti-Xa units/mL • Not affected by patient-specific issues related to aPTT monitoring • Factor VIII or fibrinogen elevations associated with acute phase reactions • Other factor deficiencies associated with liver disease • Presence of antiphospholipid antibodies • No need for lab to create a reagent-specific reference range Lehman et al. 2009. Guervil et al. 2011. CHEST Antithrombotic Therapy and Prevention of Thrombosis, 9th ED: ACCP Guidelines, Parenteral Anticoagulants. 2012

16. Brief Overview of Anti Xa Literature In summary, studies show similar efficacy with an improved safety profile

17. Anti-Xa Availability at Other InstitutionsNational Survey Pharmacist list serve – 2016 (n=87) Available at ~75% of hospitals; Nursing-driven protocol – 31%

18. Anti-Xa Availability at UCSF • Anti-Xa assay is available at UCSF • Test run 7 days per week, 0800 - 2300 • Turn-around time ~2 hours

19. Current Anti-Xa Algorithm at UCSFMCExcludes ECLS/VAD Anti-Xa level to be checked q6hours until 2 consecutive therapeutic levels, then qAM

20. Background Continuous Flow Left Ventricle Assist Devices • High rate of discordance between anti-factor Xa heparin assays & aPTT – 74.7% [supra therapeutic aPTTs, therapeutic anti Xa] • 96% Observed aPTT above expected range • Higher rates of discordance in patients with: • Higher INR values • Low levels of factor XII, V • Hemolysis (LDH) • 97% patients with elevated VIII • Patients at risk for thrombosis and gastrointestinal bleeding Adatya S et a. J Heart Lung Transplant 2016; 35: 1311-1320

21. Anti-Xa at Other InstitutionsNational Survey Pharmacist list serve – 2017 (n=41)

22. Anti-Xa at Other Institutions for MCS PatientsNational Survey Pharmacist list serve – 2017 (n=41) ECLS • Four institutions use ACT for monitoring ECLS • ECLS Goals (most have one range): • 0.3-0.5 (4) • 0.2-0.5 (2) • 0.3-0.7 (2) VAD PROTOCOLS • Low Intensity Targets • 0.2-0.4 (low) or 0.15-0.25 (ultra low) • 0.1-0.3 • 0.2-0.5 • Standard • 0.3-0.7 (3) • 0.2-0.5 (1) • High • 0.3-0.7 (2)

23. Proposed LVAD Algorithm Adatya S et a. J Heart Lung Transplant 2016; 35: 1311-1320 Adatya S et a.. J Am CollCardiol HF 2015; 3:314-22

24. Proposed Titration Algorithm • Recommended Provider Driven Titration Algorithm for LVAD patients • > 0.2 units/mL BELOW the target therapeutic range, INCREASE heparin infusion by 3 units/kg/hour • 0.1-0.19 units/mL BELOW the target therapeutic range, INCREASE heparin infusion by 2 units/kg/hour • 0.01 - 0.09 units/mL BELOW the target therapeutic range, INCREASE heparin infusion by 1 units/kg/hour • If within target therapeutic range, no adjustment needed • 0.01 - 0.09 units/mL above the target therapeutic range, DECREASE heparin infusion by 1 units/kg/hour • 0.1-0.19 units/mL ABOVE the target therapeutic range, DECREASE heparin infusion by 2 units/kg/hour • 0.2-0.29 units/mL ABOVE the target therapeutic range, DECREASE heparin infusion by 3 units/kg/hour • > 0.3 units/mL ABOVE the target therapeutic range, HOLD heparin for 60 minutes and DECREASE heparin infusion by 4 units/kg/hour Presentation Title and/or Sub Brand Name Here

25. Helpful Anticoagulation References https://carelinks.ucsfmedicalcenter.org/ Presentation Title and/or Sub Brand Name Here

26. What is wrong with this heparin order? • San Francisco, Sandy MRN: 58052647 • Orders, Teri MRN: MRN 58043141 • Clindoc Mekhala MR: 58047783 • Test William MRN: 58042641 • Wanttheflu, Donna MRN: 58050091 • Anticoagulation and Epidurals

27. Parenteral Direct Thrombin Inhibitors • Patients with suspected/confirmed HIT are typically anticoagulated with a parenteral direct thrombin inhibitor, such as bivalirudin or argatroban. • Argatroban • hepatically eliminated • Bivalirudin • cleared by blood proteases (80%) and renal elimination (20%). • A copy of Stepwise Approach for Suspected Heparin-Induced Thrombocytopenia may be found on the pharmacy website

28. Argatroban • Indications • treatment or prophylaxis of thrombosis with heparin-induced thrombocytopenia • Monitoring: • aPTT should be obtained q 2 hours after initiating drip until therapeutic, then q 4 hours until two consecutive values • Known to increase PT/INR lab values, use caution when bridging to Warfarin LinkinsLA, Dans AL, Moores LK, et al. Chest. 2012;141:e495S–530S Alquwaizani, Mohammed, et al. Current emergency and hospital medicine reports 1.2 (2013): p90 January, Craig T., et al.Circulation (2014)

29. Argatroban • Starting dose depends on comorbid conditions: • Standard • 2mcg/kg/min • Critically Ill (Heart failure, MODS, severe anasarca, post cardiac surgery) • 1mcg/kg/min • Moderate to severe liver dysfunction (Child-Pugh Class B/C) • 0.5mcg/kg/min Presentation Title and/or Sub Brand Name Here

30. Argatroban to WarfarinBridging to Warfarin • ≤2 mcg/kg/minute: • Stop Argatroban when INR >4 on combined warfarin + argatroban • Repeat INR in 4 to 6 hours; if INR < goal, restart argatroban • Repeat daily until desired INR on warfarin alone is obtained. • >2 mcg/kg/minute: • Decrease argatrobanto 2 mcg/kg/minute and check INR 4 to 6 hours after dose reduction; • Stop argatroban when the INR on warfarin + argatroban >4. • Repeat INR in 4 to 6 hours; if INR < goal, restart argatroban • Repeat procedure daily until desired INR on warfarin alone is obtained. Presentation Title and/or Sub Brand Name Here

31. Bivalirudin Dosing 1. Kearon, Clive, et al. CHEST Journal 149.2 (2016): 315-352. 2. 2014 AHA/ACC 3. Robson, Richard, et al. ClinicalPharmacology & Therapeutics 71.6 (2002): 433-439.

32. Bivalirudin Conversion to Warfarin: • Once the platelet count has recovered to at least 150 x109/L and with an overlap of at least five days. • All direct thrombin inhibitors can prolong the INR. • The mean prolongation in the INR from bivalirudin in one study was 0.4.2 • When a patient is believed to be therapeutic on warfarin (5 days), hold bivalirudin and recheck an INR once bivalirudin is cleared (generally 2-6 hours or 3-5 half-lives Presentation Title and/or Sub Brand Name Here

33. Antithrombotic Agents in the setting of Neuraxial Procedures • Systemic Heparin • Systemic Direct Thrombin Inhibitors (Argatroban, Bivalirudin) • GBIIb/IIIa inhibitors • Thrombolytics [10 day waiting period] http://medctrpharm.ucsf.edu/system/files/documents/UCSF%20Antithrombotics%20%20Neuraxial%20Intervention%20July%202015.pdf Presentation Title and/or Sub Brand Name Here

34. IP Adult Anticoagulation Reversal Orders (KCentra, Praxbind)

36. Questions?