Management of Orolingual Angioedema Post-Alteplase Treatment in Stroke Patients Oumaima Sahbani, PharmD PGY1 Pharmacy Resident John Dempsey Hospital at UCONN Health May 8th, 2018

Conflicts of Interest I have no conflicts of interest to report I intend to reference unlabeled/unapproved uses of drugs or products in my presentation

Objectives Describe the mechanism of action behind post-alteplase angioedema Understand the difference between allergic and non-allergic angioedema Describe the treatment and medical management of angioedema post-alteplase Orolingual angioedema post-alteplase therapy is a rare occurrence that is not frequently encountered by a majority of pharmacists

Alteplase (Activase ) Fibrinolytic effect: activates plasmin, which cleaves thrombus-bound fibrin Used in treatment of acute ischemic stroke, pulmonary embolism, and ST-elevation myocardial infarction Contraindication: hypersensitivity ADRs Bleeding Orolingual angioedema Cerebral edema Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; September, 2017

Orolingual Angioedema Post-Alteplase Rarely occurs ~1.3-5% in patients treated for ischemic stroke 0.02% in patients treated for myocardial infarction Most patients respond well to medical management Potentially life threatening if not recognized immediately and treated accordingly Only well-known risk factor is prior use of an ACE inhibitor O’Carroll, C. B., & Aguilar, M. I. (2015). Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. The Neurohospitalist, 5(3), 133-141.

Mechanisms of Orolingual Angioedema Allergic Type I hypersensitivity Antigen cross links with immunoglobulin E antibody bound on the surface of mast cells Results in release of histamine Non-allergic Mediated by bradykinin Three types: Hereditary Acquired Drug-induced Antigen cross links with immunoglobulin E antibody bound on the surface of mast cells – results in release of histamine Important to understand the mechanisms between both because they differ in their mediator, clinical presentations, and their management Non-allergic: Onset is more progressive – symptoms may subside in 3-5 days Symptoms are resistant to antihistamine and corticosteroid treatment, symptoms resolve only after drug discontinuation Kalambay J, Ghazanfar H, Martes pena K A, et al. (August 23, 2017) Pathogenesis of Drug Induced NonAllergic Angioedema: A Review of Unusual Etiologies. Cureus 9(8): e1598.

Mechanism of Allergic Orolingual Angioedema Angioedema results as a consequence of the underlying mechanism of alteplase Hill, M.D., Barber, P.A., et. al. Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke. CMAJ. 2000;162(9):1281-4.

Mechanism of Allergic Orolingual Angioedema Alteplase activates plasmin, which can activate complement cascade and kinin pathway Hill, M.D., Barber, P.A., et. al. Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke. CMAJ. 2000;162(9):1281-4.

Mechanism of Allergic Orolingual Angioedema Results in activation of mast-cell degranulation and histamine release Which leads to anaphylactoid reactions Hill, M.D., Barber, P.A., et. al. Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke. CMAJ. 2000;162(9):1281-4.

Mechanism of Non-Allergic Orolingual Angioedema KKS is a cascade of proteolytic enzymes that release vasoactive peptides Plasma kallikrein cleaves human high molecular weight kininogen and releases bradykinin Bradykinin stimulates beta-2 adrenergic receptors, which results in the release of nitric oxide and prostacyclin Nitric oxide and prostacyclin Drugs can target three different sites of actions in the KKS to cause bradykinin mediated angioedema: Synthesis of bradykinin with C1 INH suppression Response to bradykinin: Bradykinin Metabolism of bradykinin and substance P with ACE and DPP-IV suppression Icatibant: Bradykinin 2 (B2) receptor antagonist FDA approved for treatment of hereditary angioedema Used off-label for ACE-I induced angioedema Studies show that resolution of angioedema occurs significantly sooner with Icatibant than with conventional therapy Kalambay J, Ghazanfar H, Martes pena K A, et al. (August 23, 2017) Pathogenesis of Drug Induced NonAllergic Angioedema: A Review of Unusual Etiologies. Cureus 9(8): e1598.

Fresh frozen plasma (FFP) – provides the patient with kinase II which acts as an ACE thus allowing for the break down of bradykinin C1 esterase inhibitor – inhibit kallikrein conversion of kininogen thus preventing the production of bradykinin Scalese MJ, Reinaker TS. Pharmacologic management of angioedema induced by angiotensin-converting enzyme inhibitors. Am J Health-System Pharm 2016; 73(12): 873-879. Scalese MJ, Reinaker TS. Pharmacologic management of angioedema induced by angiotensin-converting enzyme inhibitors. Am J Health-System Pharm 2016; 73(12): 873-879.

C1 Inhibitors Blood product derivatives Berinert® Cinryze® Play a role in regulating the complement and intrinsic coagulation pathway As well as the fibrinolytic and kinin pathways Inactivate plasma kallikrein and factor XIIa, thus preventing bradykinin production Make sure to know ADRs for these drugs as well as price HAE = hereditary angioedema Unregulated bradykinin production is thought to contribute to the increased vascular permeability and angioedema observed in HAE Berinert® Cinryze® Main role: hereditary angioedema (HAE) Case reports have shown that C1 inhibitors are a safe and effective addition to standard of therapy, and further exploration is encouraged

Clinical Presentation: Allergic Important to quickly recognize symptoms and have treatment algorithm in place Transient, self-limiting swelling of the tongue and lips Caused by increased vasodilation and vascular permeability Can potentially cause airway obstruction and respiratory compromise requiring emergent intubation Localized, nonpitting edema involving the mucosa of the upper respiratory tract Caused by increased vasodilation and vascular permeability Drug induced allergic – rapid onset of swelling of mucosa and submucosa tissues, urticarial rash – responds to antihistamine, epinephrine, and corticosteroid treatment O’Carroll, C. B., & Aguilar, M. I. (2015). Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. The Neurohospitalist, 5(3), 133-141.

Onset of Orolingual Angioedema Occurs quickly and unexpectedly after thrombolytic therapy Can occur at any time after starting the infusion of the medication Close monitoring required for the duration of administration of alteplase Typically occurs towards the end of the alteplase infusion The clinical presentation of non-allergic angioedema is very similar – but the symptoms are resistant to antihistamine and corticosteroids, symptoms only resolve after drug discontinuation O’Carroll, C. B., & Aguilar, M. I. (2015). Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. The Neurohospitalist, 5(3), 133-141.

Medical Management: Allergic Guidelines for a specific treatment protocol do not exist Discontinue remaining alteplase infusion if any signs of tongue or lip swelling Promptly administer IV antihistaminergic medications If swelling persists, administer corticosteroids Guidelines for a specific treatment protocol do not exist: Many institutions use the protocol developed by the University of Cincinnati O’Carroll, C. B., & Aguilar, M. I. (2015). Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. The Neurohospitalist, 5(3), 133-141.

Medical Management: Allergic Antihistaminergic: H1 blockade Diphenhydramine 10-50 mg IV per dose every 4-8 hours 100 mg per single dose; max 400 mg/day H2 blockade Famotidine 20 mg IV every 12 hours Ranitidine 50 mg IV every 6 to 8 hours Histamine is the primary mediator of anaphylaxis and can trigger a cascade of inflammatory mediators that modulate its own release, so in order to achieve total histamine blockage we use an h1 blocker like diphen and an h2 blocker like famotidine or ranitidine at their standard doses for anaphylaxis Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; September, 2017

Medical Management: Allergic Glucocorticoids: Methylprednisolone once 125 mg IV (low dose) 250 mg (moderate dose) >500 mg (high dose) Dexamethasone 2 to 6 mg IV every 6 to 12 hours If the histamine blockage was not providing adequate response, glucocorticoids are the next option IV methyl or IV dexa, with the standard doses for anaphylaxis listed here Lexi-Comp, Inc. (Lexi-Drugs® ). Lexi-Comp, Inc.; September, 2017

UCONN Health Clinical Care Guidelines for Stroke Included here is our protocol at uconn health, this is in our guideline for stroke management if the team encounters angioedema during an alteplase infusion This is here to show that it’s a good idea for institution to have a plan in place to know which teams to call such as ENT, in case if patient needs cricothyrotomy UConn John Dempsey Hospital. (2014). Clinical Care Guidelines. Ischemic and Hemorrhagic Stroke. Farmington, CT.

Follow-up Treatment Consider in patients: Required intubation With extensive edema Refractory to initial doses of medications Short course of maintenance corticosteroids Prednisone taper A specific taper is up to what the patient required for management and up to the provider O’Carroll, C. B., & Aguilar, M. I. (2015). Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. The Neurohospitalist, 5(3), 133-141.

Which of the following corticosteroid dosing regimens would you recommend for the treatment of orolingual angioedema during alteplase infusion? A. Methylprednisolone 12.5 mg IV once B. Prednisone 20 mg IV every 4 hours C. Methylprednisolone 125 mg IV once D. Dexamethasone 125 mg IV every 6 hours

Which of the following corticosteroid dosing regimens would you recommend for the treatment of orolingual angioedema during alteplase infusion? A. Methylprednisone 12.5 mg IV once B. Prednisone 20 mg IV every 4 hours C. Methylprednisolone 125 mg IV once D. Dexamethasone 125 mg IV every 6 hours

Patient MTM is brought to the ED for symptoms of stroke and is determined as a candidate for alteplase. Twenty minutes into her alteplase infusion, her lips start to swell and complains of difficulty breathing. What is the mediator of her reaction? A. Bradykinin B. Histamine C. Kininogen D. None of the above

Patient MTM is brought to the ED for symptoms of stroke and is determined as a candidate for alteplase. Twenty minutes into her alteplase infusion, her lips start to swell and complains of difficulty breathing. What is the mediator of her reaction? A. Bradykinin B. Histamine C. Kininogen D. None of the above

Summary Clinical presentation and management of non- allergic vs. allergic angioedema differs Orolingual angioedema post-alteplase therapy rarely occurs Close monitoring of patients required Treatment involves management of symptoms Post-stroke follow up Consider maintenance treatment At the patient’s post-stroke follow up appointment, its important to assess for symptoms and counsel patients to watch out for these symptoms and go to the hospital if they notice OA Consider maintenance in patients with more severe symptoms Clinical presentation and management of non-allergic vs. allergic angioedema differs Orolingual angioedema post-alteplase therapy rarely occurs Requires close monitoring of patients Treatment involves management of symptoms Post-stroke follow up Consider maintenance treatment

Management of Orolingual Angioedema Post-Alteplase Treatment in Stroke Patients Oumaima Sahbani, PharmD PGY1 Pharmacy Resident John Dempsey Hospital at UCONN Health sahbani@uchc.edu