4//0 Objectives Reducing the Use of Reversal Agents in a Community Hospital Maria Paulina Duarte, PharmD PGY- Pharmacy Resident Mercy Hospital, A Campus of Plantation General Hospital Review the appropriate use of reversal agents Identify opportunities for reduction strategies of reversal agents Understand pharmacist s role in impacting the use of reversal agents Background Drug overdoses, whether accidental or intentional, constitute a significant source of increasing morbidity, mortality, and healthcare expenditure worldwide, Hospitalized patients are susceptible to accidental drug overdoses, and immediate reversal may be warranted to decrease harm 3 However, in some clinical settings, it has become common practice to use reversal agents and in some occasions the use of reversal agents might not be of value for a drug overdose 3,4 Reversal Agents Reversal of opioids Examples: Morphine, hydromorphone, and fentanyl Side effects: Cardiac complications Flumazenil Reversal of benzodiazepines Examples: Lorazepam, clonazepam, and diazepam Side effects: May result in seizures Reversal of vitamin K antagonist Example: Warfarin Side effects: May cause warfarin resistance Reversal Agents Reversal of heparin Example: Unfractionated heparin and low molecular weight heparin Side effects: cardiac and pulmonary complications Prothrombin Complex Concentrate (PCC) Reversal of warfarin and direct oral anticoagulants Example: Warfarin, dabigatran, rivaroxaban, and apixaban Side effects: Thromboembolic complication Study s Objective To assess the utilization of reversal agents and identify areas to potentially streamline their use
4//0 Methods A pre and post study 4Q0 Intervention Retrospective Assess outcomes Q0 Prospective Assess outcomes Methods The electronic medical record system was used to identify patients The use of reversal agents was evaluated for appropriateness, efficacy, and safety 4Q: Evaluated data to identify areas for potential streamlining reversal agent use Q: Will evaluate data to assess the results of the intervention Methods: Exclusion Criteria If patient presented to the Emergency Department in need of a reversal agent If reversal agents were provided within one hour after admission If they received a reversal agent without having received an implicated drug Infants less than or equal to one week of age Outpatients Procedural/surgical patients Methods: Study Indications for Administration Patients on an opioid plus one or more of the following: Respiratory rate less than breaths per minute Oxygen saturation less than 90% Miosis Stupor Flumazenil 7 Patients on benzodiazepines with signs and symptoms of CNS depression Decreased breathing Decreased heart rate Loss of consciousness No history or risk of seizures Methods: Study Indications for Administration 8 Patients taking warfarin INR > 0 (no evidence of bleeding) Evidence of a bleed Preoperative patients with an INR >. 9 Patient on heparin with evidence of a bleed Study Population Eligible patients N=79 Patients included in the study N = 9 Study indications for administration Patients Excluded N = 90 PCC 0 Patient taking a direct oral anticoagulant and with evidence of an active bleed Naloxone Flumazenil Vitamin K Protamine PCC N = 0 N = N = 7 N = 3 N = *Two patients received both naloxone and flumazenil *One patient received both naloxone and PCC
4//0 Results for 4 th Quarter 0 Baseline Characteristics Naloxone (N = 0) Flumazenil (N = ) Vitamin K (N = 7) Protamine (N = 3) PCC (N = ) Age, years 73 ± 77 ± 77 ± 73 ±9 Female sex, no. 7 3 Weight, mean (kg) 7 ± 73 ±7 78 ± 7 ±8 74 Creatinine Clearance, no. Above 0 ml/min Below or equal to 0 ml/min Hemodialysis Risk Factors, no. Sleep apnea Preexisting pulmonary disease Code Sepsis Risk of seizures Results for 4 th Quarter 0: Baseline Characteristics Naloxone (N = 0) Flumazenil (N = ) Vitamin K (N = 7) Protamine (N = 3) PCC (N = ) Signs of CNS depression, no. INR greater than 3., no. PTT above target range (089), no. Hemoglobin, mean (g/dl) 9. ±.8 8 ±0.8 Platelet, mean (0 3 /microl) 97 ± 70 ± Home Medications, no. Opioids Benzodiazepines Anticoagulants 3 ADR Documented on emar, no. 4 Results: Study Indications (N = 9) Percent (%) 00 90 80 70 0 0 40 30 0 0 0 90% (9/0) 7% (8/) 7% (/7) 7% (/3) Naloxone Flumazenil Vitamin K Protamine 00% (/) PCC (N = 0) (N = ) (N = 7) (N = 3) (N = ) Results: Respiratory Rate After Naloxone Use Breaths/min 0 0 0 3 4 7 8 9 0 Before 8 8 4 8 7 3 0 After 8 9 9 4 4 7 p= 0.3 breaths per minute Before After Results: Oxygen Saturation After Naloxone Use 00 90 80 70 0 0 40 30 0 0 0 3 4 7 8 9 0 Before 8 9 8 93 98 98 9 9 90 89 After 99 9 89 00 98 98 00 00 94 9 Percent (%) 9% Before After Results: Naloxone One patient was hypotensive on a bupivacaine No signs of improvement after naloxone Four patients received opioids after 0:00 p = 0.004 3
4//0 Results: Flumazenil Two patients with risk of seizures Eight patient improved after flumazenil Three patients did not improve after flumazenil Patient remained confused Minimal improvement Results: Vitamin K Two patients not matching study indications for administration One patient with INR 3. with no signs of bleeding One patient with INR. received vitamin K due to blowout of a dialysis catheter vein on first hemodialysis attempt Results: Protamine One patient with no evidence of bleeding had a seizure and received protamine to reverse enoxaparin DVT prophylaxis Enoxaparin 40 mg subcutaneously daily Results: PCC One patient who was on rivaroxaban 0 mg daily had an episode of bleeding from mouth of about 00cc Concomitant medications: Amiodarone Study s Conclusion Most of the patients received naloxone based on the study s indications and had significant improvement in oxygen saturation after administration of naloxone (p 0.0) Over half of the patients had preexisting pulmonary disease and renal insufficiency Flumazenil Patients with risk of seizures received flumazenil About half of the patients had renal insufficiency and were taking benzodiazepines at home 7 % patients received vitamin K according to study indications One of three patients who received protamine for the reversal of heparin did not have evidence of bleeding PCC There may have been a possible interaction between rivaroxaban and amiodarone, a moderate CYP3A4 inhibitor Interventions At admission, assess for pre-existing pulmonary disease and sleep apnea history/risk Example: STOPBANG sleep apnea risk assessment Implement an administration criteria Created a pocket reference card Promote current administration criteria 4
4//0 STOPBANG sleep apnea risk assessment 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. 0;08():78-7. Interventions: Vitamin K Adult administration criteria Is the patient on warfarin, AND has a major bleed? Y/N 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 0 and no bleed Emergent procedure (INR >.) NO: Hold warfarin Other? Pocket Card Front The following Antiplatelet agents should NEVER be given in combination Clopidogrel (Plavix ) Prasugrel (Effient ) Ticagrelor (Brilinta ) The following Anticoagulant agents should NEVER be given in combination Heparin (UFH) Enoxaparin (Lovenox ) Fondaparinux (Arixtra ) Argatroban Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) Edoxaban (Savaysa ) Bridging to Warfarin (Coumadin ) Warfarin may be used in conjunction with heparin and enoxaparin when bridging therapy until a therapeutic INR is reached (3 days). Rev. 3/ Back INR Warfarin Reversal Guidelines > 4. to 9.9 + no significant. Hold warfarin therapy bleed. Resume with an adjusted warfarin dose when INR is therapeutic. Hold warfarin therapy 0 + no significant bleed. Administer oral vitamin K (. mg once). Resume with an adjusted warfarin dose when INR is therapeutic. Hold warfarin therapy Minor bleeding at any INR. Administer oral vitamin K (. mg once) elevation 3. Resume with an adjusted warfarin dose when INR is therapeutic. Hold warfarin therapy Major bleeding at any INR. Administer IV vitamin K 0 mg, FFP, or PCC (if failure with FFP) elevation 3. May repeat vitamin K every h as needed Infuse over 0 minutes Subcutaneous injection is not recommended Vitamin K May cause warfarin resistance if given high doses (e.g. 0 mg) Coagulopathy secondary to liver disease does not respond to vitamin K Chart adapted from 0 Guidelines of American College of Chest Physicians (ACCP) Rev. 3/ Pharmacist s Role Renal adjustment of opioids Avoid administration of opioids close to bedtime Flumazenil Renal adjustment of benzodiazepines Avoid flumazenil in patients with risk of seizures Avoid flumazenil in chronic benzodiazepine users Pharmacist s Role Verify if patient qualifies for the administration criteria Verify if patient qualifies for the administration criteria PCC Verify if patient is taking an oral anticoagulant and there is evidence of bleeding Avoid interactions with direct oral anticoagulants Dual CYP3A4 and pgp-inhibitors Summary Streamlining the use of reversal agents Improving the admission assessment Implementing/promoting an administration criteria Promoting correct use of vitamin K Pharmacist can have an impact at decreasing the use of reversal agents Improving use of implicated drugs Assessing the need of a reversal agent
4//0 References Questions?. Litovitz TL, Klein-schwartz W, Rodgers GC, et al. 00 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 00;0():39-4.. Mowry JB, Spyker DA, Cantilena LR, Mcmillan N, Ford M. 03 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 3st Annual Report. Clin Toxicol (Phila). 04;(0):03-83. 3. Lesar TS, Lomaestro BM, Pohl H. Medication-prescribing errors in a teaching hospital. A 9-year experience. Arch Intern Med. 997;7(4):9-7. 4. Sivilotti ML. Flumazenil, naloxone and the 'coma cocktail'. Br J Clin Pharmacol. 0;8(3):48-3.. Penninga EI, Graudal N, Ladekarl MB, Jürgens G. Adverse Events Associated with Flumazenil Treatment for the Management of Suspected Benzodiazepine Intoxication - A Systematic Review with Meta-Analyses of Randomised Trials. Basic Clin Pharmacol Toxicol. 0;8():37-44.. Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 0;37():4-. 7. Sivilotti ML. Flumazenil, naloxone and the 'coma cocktail'. Br J Clin Pharmacol. 0;8(3):48-3. 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. 0;4( Suppl):eS-84S. 9. Caravati EM. Protamine sulfate. Medical Toxicology. 3rd ed. Dart RC, ed. Philadelphia, PA: Lippincott Williams and Wilkins; 004;43-44. 0. Kcentra (prothrombin complex concentrate human) [prescribing information]. Kankakee, IL: CSL Behring; December 03. Assessment Question # What are the indications for the correct use of naloxone? Assessment Question # True or False Flumazenil can decrease seizure threshold. Assessment Question #3 True or False Vitamin K is indicated for an INR less than 0 and no evidence of bleeding.