4/21/2016

Objectives

• Review the appropriate use of reversal agents Reducing the Use of Reversal Agents in a Community Hospital • Identify opportunities for reduction strategies of reversal agents Maria Paulina Duarte, PharmD PGY-1 Pharmacy Resident • Understand pharmacist’s role in impacting the Mercy Hospital, A Campus of use of reversal agents Plantation General Hospital

Background Reversal Agents • Drug overdoses, whether accidental or intentional, • Naloxone constitute a significant source of increasing ▫ Reversal of opioids morbidity, mortality, and healthcare expenditure  Examples: Morphine, hydromorphone, and fentanyl worldwide1,2 ▫ Side effects: Cardiac complications • Flumazenil • Hospitalized patients are susceptible to accidental ▫ Reversal of benzodiazepines drug overdoses, and immediate reversal may be 3  Examples: Lorazepam, clonazepam, and diazepam warranted to decrease harm ▫ Side effects: May result in seizures • Vitamin K • However, in some clinical settings, it has become ▫ Reversal of vitamin K antagonist common practice to use reversal agents and in some  Example: Warfarin occasions the use of reversal agents might not be of ▫ Side effects: May cause warfarin resistance value for a drug overdose3,4

Reversal Agents Study’s Objective

• Protamine ▫ Reversal of heparin  Example: Unfractionated heparin and low molecular To assess the utilization of reversal agents weight heparin ▫ Side effects: cardiac and pulmonary complications and identify areas to potentially streamline their use • Prothrombin Complex Concentrate (PCC) ▫ Reversal of warfarin and direct oral anticoagulants  Example: Warfarin, dabigatran, rivaroxaban, and apixaban ▫ Side effects: Thromboembolic complication

1 4/21/2016

Methods Methods

• A pre and post study • The electronic medical record system was used to identify patients • The use of reversal agents was evaluated for 4Q2015 2Q2016 appropriateness, efficacy, and safety Intervention • 4Q15: Evaluated data to identify areas for Retrospective Prospective potential streamlining reversal agent use • 2Q16: Will evaluate data to assess the results of the intervention Assess outcomes Assess outcomes

Methods: Study Indications for Methods: Exclusion Criteria Administration • If patient presented to the Emergency • Naloxone6 Department in need of a reversal agent ▫ Patients on an opioid plus one or more of the following:  Respiratory rate less than 12 breaths per minute • If reversal agents were provided within one hour  Oxygen saturation less than 90% after admission  Miosis • If they received a reversal agent without having  Stupor 7 received an implicated drug • Flumazenil ▫ Patients on benzodiazepines with signs and symptoms • Infants less than or equal to one week of age of CNS depression • Outpatients  Decreased breathing  Decreased heart rate • Procedural/surgical patients  Loss of consciousness ▫ No history or risk of seizures

Methods: Study Indications for Study Population Administration

8 Eligible patients • Vitamin K N=719 ▫ Patients taking warfarin Patients Excluded  INR > 10 (no evidence of bleeding) N = 690  Evidence of a bleed Patients included  Preoperative patients with an INR >1.5 in the study N = 29

• Protamine9 Study indications ▫ Patient on heparin with evidence of a bleed for administration • PCC10 ▫ Patient taking a direct oral anticoagulant and with Naloxone Flumazenil Vitamin K Protamine PCC evidence of an active bleed N = 10 N = 11 N = 7 N = 3 N = 1 *Two patients received both naloxone and flumazenil *One patient received both naloxone and PCC

2 4/21/2016

Results for 4th Quarter 2015 Results for 4th Quarter 2015:

Baseline Characteristics Naloxone Flumazenil Vitamin K Protamine PCC Baseline Characteristics Naloxone Flumazenil Vitamin K Protamine PCC (N = 10) (N = 11) (N = 7) (N = 3) (N = 1) (N = 10) (N = 11) (N = 7) (N = 3) (N = 1) Age, years 73 ±15 77 ±11 77 ±15 73 ±19 66 Signs of CNS depression, no. 6 11 Female sex, no. 67311 INR greater than 3.5, no. ‐‐ 1 ‐‐ Weight, mean (kg) 75 ±16 73 ±17 78 ±21 75 ±8 74 PTT above target range (50‐89), no. ‐‐ ‐‐ ‐ Creatinine Clearance, no. Hemoglobin, mean (g/dL) ‐‐ 9.5 ± 1.8 8 ±0.85 12 Above 50 mL/min 5 5 1 2 ‐ Below or equal to 50 mL/min 5 6 6 1 1 Platelet, mean (103/microL) 197 ±66 170 ± 51 155 Hemodialysis 1 2 2 ‐ ‐ Home Medications, no. Risk Factors, no. Opioids 5 3 ‐ ‐ ‐ Sleep apnea 1 1 ‐ ‐ ‐ Benzodiazepines 5 6 ‐ ‐ ‐ Pre‐existing pulmonary disease 6 ‐ ‐ ‐ ‐ Anticoagulants ‐ ‐ 4 ‐ ‐ Code Sepsis 1 ‐ ‐ ‐ ‐ ADR Documented on eMAR, no. ‐ 1 ‐‐ ‐ Risk of seizures ‐ 2 ‐ ‐ ‐

Results: Study Indications (N = 29) Results: Respiratory Rate After Naloxone Use 25 100% (1/1) 100 20 90% (9/10) 90 15 80 72% (8/11) 71% (5/7) 67% (2/3) 12 breaths 70 10 per minute (%)

60 Breaths/min 50 5 40 Percent 0 Before 30 12345678910 20 Before 16 18 16 18 14 18 17 12 23 10 After 10 After 16 18 19 19 14 16 14 17 22 16 0 Naloxone Flumazenil Vitamin KProtamine PCC p= 0.36 (N = 10) (N = 11) (N = 7) (N = 3) (N = 1)

Results: Oxygen Saturation After Naloxone Use Results: Naloxone 100 90 92% 80 • One patient was hypotensive on a bupivacaine 70 ▫ No signs of improvement after naloxone 60 50 40 • Four patients received opioids after 20:00

Percent (%) Percent 30 20 10 Before 0 12345678910 After Before 86 92 82 93 98 98 95 95 90 89 After 99 96 89 100 98 98 100 100 94 91

p = 0.004

3 4/21/2016

Results: Flumazenil Results: Vitamin K

• Two patients with risk of seizures • Two patients not matching study indications for administration • Eight patient improved after flumazenil ▫ One patient with INR 3.5 with no signs of bleeding ▫ One patient with INR 2.1 received vitamin K due • Three patients did not improve after flumazenil to “blowout of a dialysis catheter vein on first hemodialysis attempt” ▫ Patient remained confused ▫ Minimal improvement

Results: Protamine Results: PCC

• One patient with no evidence of bleeding had a • One patient who was on rivaroxaban 20 mg daily seizure and received protamine to reverse had an episode of bleeding from mouth of about enoxaparin 100cc ▫ DVT prophylaxis ▫ Concomitant medications: Amiodarone ▫ Enoxaparin 40 mg subcutaneously daily

Study’s Conclusion Interventions

• Naloxone ▫ Most of the patients received naloxone based on the study’s indications and had • Naloxone significant improvement in oxygen saturation after administration of naloxone (p ≤ 0.05) ▫ At admission, assess for pre-existing pulmonary ▫ Over half of the patients had preexisting pulmonary disease and renal insufficiency disease and sleep apnea history/risk • Flumazenil  Example: STOPBANG sleep apnea risk assessment ▫ Patients with risk of seizures received flumazenil ▫ About half of the patients had renal insufficiency and were taking benzodiazepines at home • Vitamin K • Vitamin K ▫ Implement an administration criteria ▫ 71 % patients received vitamin K according to study indications • Protamine ▫ Created a pocket reference card ▫ One of three patients who received protamine for the reversal of heparin did not have evidence of bleeding • Protamine • PCC ▫ There may have been a possible interaction between rivaroxaban and ▫ Promote current administration criteria amiodarone, a moderate CYP3A4 inhibitor

4 4/21/2016

Interventions: Vitamin K STOPBANG Adult administration criteria sleep apnea risk • Is the patient on warfarin, AND has a major bleed? Y/N assessment ▫ YES: Use IV Vitamin K • Is the patient on warfarin, AND one of the following? Y/N ▫ YES: Use oral Vitamin K for:  Minor bleed  INR ≥10 and no bleed  Emergent procedure (INR >1.5) ▫ NO: Hold warfarin • Other? Chung F, Subramanyam R, Liao P, Sasaki E, Shapiro C, Sun Y. High STOP-Bang score indicates a high probability of obstructive sleep apnoea. Br J Anaesth. 2012;108(5):768-75.

Pocket Card Pharmacist’s Role Front

The following Antiplatelet agents should NEVER be given in combination • Naloxone Clopidogrel (Plavix®) Prasugrel (Effient®) Back ▫ Renal adjustment of opioids Ticagrelor (Brilinta®) INR Warfarin Reversal Guidelines The following Anticoagulant agents > 4.5 to 9.9 + no significant 1. Hold warfarin therapy ▫ Avoid administration of opioids close to bedtime should NEVER be given in combination bleed 2. Resume with an adjusted warfarin dose when INR is therapeutic Heparin (UFH) 1. Hold warfarin therapy ≥ 10 + no significant bleed 1. Administer oral vitamin K (2.5‐5 mg once) Enoxaparin (Lovenox®) 2. Resume with an adjusted warfarin dose when INR is therapeutic 1. Hold warfarin therapy Fondaparinux (Arixtra®) Minor bleeding at any INR 2. Administer oral vitamin K (2.5‐5 mg once) elevation • Flumazenil Argatroban 3. Resume with an adjusted warfarin dose when INR is therapeutic 1. Hold warfarin therapy Dabigatran (Pradaxa®) Major bleeding at any INR 2. Administer IV vitamin K 5‐10 mg, FFP, or PCC (if failure with FFP) ▫ Renal adjustment of benzodiazepines elevation Rivaroxaban (Xarelto®) 3. May repeat vitamin K every 12 h as needed ‐Infuse over 60 minutes Apixaban (Eliquis®) ‐Subcutaneous injection is not recommended ▫ Avoid flumazenil in patients with risk of seizures Vitamin K Edoxaban (Savaysa®) ‐May cause warfarin resistance if given high doses (e.g. 10‐15 mg) Bridging to Warfarin (Coumadin®) ‐Coagulopathy secondary to liver disease does not respond to vitamin K ▫ Avoid flumazenil in chronic benzodiazepine users Chart adapted from 2012 Guidelines of American College of Chest Physicians (ACCP) Rev. 3/16 Warfarin may be used in conjunction with heparin and enoxaparin when bridging therapy until a therapeutic INR is reached (3‐5 days). Rev. 3/16

Pharmacist’s Role Summary

• Vitamin K • Streamlining the use of reversal agents ▫ Verify if patient qualifies for the administration ▫ Improving the admission assessment criteria • Protamine ▫ Implementing/promoting an administration ▫ Verify if patient qualifies for the administration criteria criteria ▫ Promoting correct use of vitamin K • PCC • Pharmacist can have an impact at decreasing the ▫ Verify if patient is taking an oral anticoagulant and use of reversal agents there is evidence of bleeding ▫ Avoid interactions with direct oral anticoagulants ▫ Improving use of implicated drugs  Dual CYP3A4 and pgp-inhibitors ▫ Assessing the need of a reversal agent

5 4/21/2016

References

1. Litovitz TL, Klein-schwartz W, Rodgers GC, et al. 2001 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2002;20(5):391-452. 2. Mowry JB, Spyker DA, Cantilena LR, Mcmillan N, Ford M. 2013 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st Annual Report. Clin Toxicol (Phila). 2014;52(10):1032-283. 3. Lesar TS, Lomaestro BM, Pohl H. Medication-prescribing errors in a teaching hospital. A 9-year experience. Arch Intern Med. 1997;157(14):1569-76. 4. Sivilotti ML. Flumazenil, naloxone and the 'coma cocktail'. Br J Clin Pharmacol. 2016;81(3):428-36. 5. Penninga EI, Graudal N, Ladekarl MB, Jürgens G. Adverse Events Associated with Flumazenil Questions? Treatment for the Management of Suspected Benzodiazepine Intoxication - A Systematic Review with Meta-Analyses of Randomised Trials. Basic Clin Pharmacol Toxicol. 2016;118(1):37-44. 6. Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012;367(2):146-55. 7. Sivilotti ML. Flumazenil, naloxone and the 'coma cocktail'. Br J Clin Pharmacol. 2016;81(3):428-36. 8. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S-84S. 9. Caravati EM. Protamine sulfate. Medical Toxicology. 3rd ed. Dart RC, ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2004;243-244. 10. Kcentra (prothrombin complex concentrate human) [prescribing information]. Kankakee, IL: CSL Behring; December 2013.

Assessment Question #1 Assessment Question #2

True or False What are the indications for the correct use of naloxone? Flumazenil can decrease seizure threshold.

Assessment Question #3

True or False

Vitamin K is indicated for an INR less than 10 and no evidence of bleeding.

6