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Pucker Up! The Pharmacologic Treatment of Angioedema
John Trnka, PharmD
Pharmacy Grand Rounds 2018 February 27, 2018
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Objectives
1. Identify the etiology and pathophysiology of ACE inhibitor-induced and hereditary angioedema
2. Develop a pharmacologic plan for a patient experiencing acute angioedema and for prophylaxis
3. List medications that are safe and those that should be avoided in a patient with a history of angioedema
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Abbreviations • ACEI: Angiotensin Converting
Enzyme inhibitor
• ACEI-A: ACEI induced angioedema
• ARB: angiotensin receptor blocker
• B2: type 2 bradykinin receptor
• C1INH: C1 inhibitor
• DPP-IV: dipeptidyl peptidase-IV
• ED: Emergency Department
• FFP: fresh frozen plasma
• GI: gastrointestinal
• HAE: hereditary angioedema
• ICU: intensive care unit
• MOA: mechanism of action
• NSAID: non-steroidal anti-inflammatory drug
• OR: operating room
• PMH: past medical history
• O2 Sat: oxygen saturation
• SC: subcutaneous
• SERM: selective estrogen receptor modulator
• TXA: tranexamic acid
• U: unit
• WNL: within normal limits
• Y/O: year-old
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Patient Case • 61 y/o male presents to the ED with shortness of breath
and tongue swelling • Reports no new medications • Denies any family history of allergic reactions or
anaphylaxis • Did try a new protein shake ~4 hours prior to
symptom onset
• PMH: hypertension, depression, hyperlipidemia • No known allergies
• Objective: • No urticaria noted, obvious oral mucosa swelling
• Medications: lisinopril, bupropion, atorvastatin
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What is the most likely cause of this patients symptoms? • A. Elevated bradykinin levels • B. Elevated C1 inhibitor levels • C. Elevated histamine levels • D. Elevated C1 inhibitor function
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What is the most likely cause of this patients symptoms? • A. Elevated bradykinin levels • B. Elevated C1 inhibitor levels • C. Elevated histamine levels • D. Elevated C1 inhibitor function
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Introduction to Angioedema • Localized, transient, episode of subcutaneous
or submucosal swelling • Increased vascular permeability leads to
interstitial edema • May affect the face, airway, GI tract, hands,
feet, and genitalia • Generally due to histamine release or excess
bradykinin production • Angioedema may occur in isolation,
accompanied by urticaria, or as a component of anaphylaxis.
Bernstein et al. Allergy Asthma Proc 2011; 32:408-12
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Pathophysiology XII XIIa
XI XIa
Coagulation Cascade
Fibrin Fibrin degradation
Complement Activation
Prekallikrein
Kallikrein
HMWK
Bradykinin
Vasodilation
Vascular permeability
Increased pain
Plasminogen
Plasmin
C1 Inhibitor
ACE
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Classifications of Angioedema • Hereditary
• Type 1: ~85% of patients, low C1INH levels • Type 2: ~15% of patients, normal C1INH levels, but
poor function • Type 3: very rare, normal C1INH
• ACE inhibitor induced
• Acquired
• Immunologic/allergic
• Physically induced
• Idiopathic Wilkerson RG. Emergency Medicine Practice. 2012;14(11):1-21
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Epidemiology
HAE
• 1:50,000 people, regardless of sex or age
• Attacks generally affect the skin, mucosal membranes, upper airway, and GI tract
• Triggers include hormonal changes, physical or emotional stress, and medications
ACEI-A
• 0.1 to 0.7 percent of recipients
• 5x more likely in African American patients
• Over 50% of cases occur within first week of therapy
• Attacks may occur at any time
Zanichelli et al. Orphanet J Rare Dis. 2015;10:11. Zotter et al. Orphanet J Rare Dis 9(1):44
Brown et al. Clin Pharmacol Ther. 1996;60(1):8.
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Diagnosis
Quantitative C1INH Functional C1INH C4 Level
Normal Range 19-37 mg/dL
>67% (normal) <41% (abnormal)
14-40 mg/dL
HAE Type 1 Decreased Decreased Decreased
HAE Type 2 Normal Decreased Decreased
ACEI-A Normal Normal Normal
Zuraw et al. J Allergy Clin Immunol. 2013;131:1491–1493
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Differences Between Anaphylaxis, HAE, and ACEI-A
Anaphylaxis HAE ACEI-A Symptom Onset Immediate Several hours Several hours
Duration < 24 hr 1-5 days 24-48 hr Angioedema May be present Present Present
Skin Symptoms (urticaria/itching)
Usually present Absent Absent
Main Treatment Epinephrine Corticosteroids Antihistamines
C1INHs Kallikrein inhibitor Bradykinin receptor antagonists
Supportive care
Zuraw et al. J Allergy Clin Immunol. 2013;131:1491–1493
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Treatment Goals • Acute Management
• Reduce airway swelling to avoid asphyxiation and invasive airway support (i.e. intubation or emergent cricothyrotomy)
• Prophylactic Management • Reduce attack frequency and severity
Zuraw et al. J Allergy Clin Immunol. 2013;131:1491–1493
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Pharmacotherapy of Angioedema HAE: Acute HAE: Prophylaxis ACEI-A: Acute
C1INH C1INH C1INH^
• Berinert • Cinryze • Berinert • Ruconest • Haegarda • Ruconest
Icatibant • Ruconest Icatibant^ Ecallantide Androgens Ecallantide^ FFP TXA^ FFP
FFP Avoralstat* Lanadelumab*
*: Novel agents, not FDA approved ^: Off-label use
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Acute Pharmacologic Management of HAE Drug MOA Treatment Dose Onset
(Duration) Adverse Effects
C1INH (Berinert)
C1INH Replacement 20 U/kg IV x 1 1 hr (22 hr)
Headache, Nausea, Anaphylaxis (rare)
Conestat alfa (Ruconest)
C1INH Replacement 50 U/kg IV x 1 (Max of 4200 mg)
1.5 hr (10 hr)
Headache, Abdominal pain, Throat pain, Allergic reactions in rabbit-sensitized patients
Icatibant (Firazyr)
B2 Receptor Antagonist
30 mg SC x 1 (30 mg every 6 hr x 2 within 24 hr)
2 hr (6 hr)
Injection-site reactions, transient erythema
Ecallantide (Kalbitor)
Kallikrein Inhibitor 30 mg SC (three separate 10-mg Injections)
0.5–4 hr (4–10 hr)
Headache, Fatigue, Anaphylaxis, Allergic reactions
FFP Enzyme replacement 1–2 units IV x 1 (May repeat every 2–3 hr)
1 hr (4–6 hr)
Fluid overload Infusion reactions
Zuraw et al. J Allergy Clin Immunol. 2013;131:1491–1493
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Wilkerson RG. Emergency Medicine Practice. 2012;14(11):1-21
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Treatment vs. Watchful Waiting
Face/Neck Elsewhere Abdominal Attack
Laryngeal Attack
Watchful Waiting
- +/- - -
Medication administration
+ +/- + +
Intubation - - - +
Bowen et al. Allergy Asthma Clin Immunol 2010;6:24
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Preferred Treatments for HAE • Currently no head-to-head studies comparing
treatment modalities • One retrospective trial that indirectly compares
agents used for acute laryngeal attacks • Large amounts of bias and confounding
variables • Consensus report does not identify a preferred
agent • Most agent selection revolves around institutional
formulary and insurance coverage
Bork et al. J Emerg Med. 2016 Apr;50(4):567-580 Zuraw et al. J Allergy Clin Immunol. 2013;131:1491–1493
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Prophylactic Pharmacologic Management of HAE Drug MOA Prophylactic Dose Adverse Effects
C1INH (Cinryze)
C1INH Replacement 1000 units IV every 3–4 days
Headache, Nausea, Anaphylaxis (rare)
Conestat alfa (Ruconest)
C1INH Replacement
50 U/kg IV twice weekly (Max of 4200 mg/dose)
Headache, Abdominal pain, Throat pain, Allergic reactions in rabbit-sensitized patients
C1INH (Haegarda)
C1INH Replacement 60 units/kg SC every 3 or 4 days
Headache, Nausea, Anaphylaxis (rare)
Danazol
Stabilization of complement system
200 mg PO BID-TID Headaches, Weight gain, Androgenic effects
Tranexamic Acid Inhibition of plasminogen
25 mg/kg/dose PO TID Nausea, Diarrhea, Vertigo, Enhanced thrombosis risk (<1%)
Aminocaproic acid Inhibition of plasminogen
1 g PO BID Nausea, Diarrhea, Vertigo, Enhanced thrombosis risk (<1%)
Zuraw et al. J Allergy Clin Immunol. 2013;131:1491–1493
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Prophylactic Management Known HAE
Predictable Stressor?
Short-term prophylaxis
Well controlled
symptoms?
Continue on-demand
treatment
Minimize exacerbating
factors
Start long-term
prophylactic
Acute Attack
On-demand treatment
Yes No
Yes
Yes No
Symptoms still uncontrolled
Zuraw et al. J Allergy Clin Immunol. 2013;131:1491–1493
No
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Prophylactic Methods for HAE
Short-term
• No head to head trials comparing treatment modalities
• Decision is made based off individual assessment
• Patient should have dose of on-demand therapy ready for use
Long-term
• Goal is to decrease frequency and severity of attacks
• Patients refractory to androgen or antifibrinolytic therapy are good candidates for C1INH
• Cost is a significant barrier
Zuraw et al. J Allergy Clin Immunol. 2013;131:1491–1493
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Patient Case Continued • Soon after the patient presents to the
emergency department, he begins developing shortness of breath secondary to rapid airway swelling
• O2 Sat: 77% • Decision was made to intubate the patient
• Due to difficult airway, an emergent cricothyrotomy was performed
• ED provider believes this presentation is likely due to ACEI-A
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Which medication could be given to the patient to provide rapid, symptomatic relief? • A. Subcutaneous C1INH • B. Icatibant • C. Epinephrine, diphenhydramine, and
methylprednisolone • D. Tranexamic acid
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Which medication could be given to the patient to provide rapid, symptomatic relief? • A. Subcutaneous C1INH • B. Icatibant • C. Epinephrine, diphenhydramine, and
methylprednisolone • D. Tranexamic acid
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Pharmacotherapy of ACEI-A • No FDA-approved medications for ACEI-A
• Some novel agents used for HAE have been found to be beneficial for ACEI-A through case reports and case series
• Supportive care (airway and breathing) • Add the ACEI to patient’s allergy list and contact
pharmacy to discontinue medication • Up to 50% of patients are not told to
discontinue ACEI
Bluestein et al. Ann Allergy Asthma Immunol 2009;103:502-7.
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Agents to Consider for ACEI-A Medication Author Year Type of Study # of Patients Interventions Results
Ecallantide Bernstein et al1 2015 RCT 50 Ecallantide vs placebo
No difference between treatments
Lewis et al2 2015 RCT 76 Ecallantide vs placebo
No difference between treatments
Icatibant Sinert et al3 2017 RCT 121 Icatibant vs placebo
No difference between treatments
Bas et al4 2015 RCT 27 Icatibant vs standard care
Faster onset of symptom relief with icatibant and C1INH
Javaud et al5 2015 Prospective observational
62 Icatibant vs C1INH vs standard care
Faster onset of symptom relief with icatibant
Fok et al6 2015 Retrospective 13 Icatibant after failed standard care
Improved symptoms after icatibant
C1INH Bouillet et al7 2014 Retrospective 11 C1INH after failed standard care
Faster onset of symptom relief with C1INH
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Medications to Avoid/Limit With History of Angioedema • ACEI
• Repeat attacks may occur for 6 weeks after discontinuation of the medication
• Estrogens • SERMs
• ARBs • Overall risk 0.06-0.1 percent • May switch patient to an ARB 6 weeks after ACEI-A
attack
• NSAIDs, DPP-IV inhibitors, and direct renin inhibitors also implicated as potential causes of angioedema
Cabellero-Fonseca F. Am J Clin Dermatol 2003;3(9): 599-607 Zuraw et al. J Allergy Clin Immunol. 2013;131:1491–1493
Haymore et al. Ann Allergy Asthma Immunol 2008;101:495-9 Whelton PK, et al. Hypertension. 2017 Nov 13.[Epub ahead of print]
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Case Continued • The patient was transferred to the ICU after a
more secure airway was placed in the OR • HAE panel: WNL • Patient did receive C1INH therapy ~4 hours
prior to labs being drawn • Patient discharged home after 6 days in the
hospital
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Which medication would be the best option for an antihypertensive at discharge? • A. Clonidine • B. Valsartan • C. Spironolactone • D. Amlodipine
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Which medication would be the best option for an antihypertensive at discharge? • A. Clonidine • B. Valsartan • C. Spironolactone • D. Amlodipine
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Conclusion • Angioedema is a rare, but life-threatening
condition involving multiple physiological processes
• Pharmacologic management of angioedema depends on the etiology and severity of disease presentation
• While ACE inhibitors are the most common culprit for causing angioedema, many other medications are implicated as causative agents as well
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Questions & Discussion
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Slide #26 References 1. Bernstein et al. Ann Allergy Asthma Immunol. 2015
Mar;114(3):245-9
2. Lewis et al. Ann Emerg Med. 2015 Feb;65(2):204-13
3. Sinert et al. J Allergy Clin Immunol Pract. 2017 Sep - Oct;5(5):1402-1409
4. Bas et al. N Engl J Med 2015; 372:418-425
5. Javaud et al. Medicine (Baltimore). 2015 Nov;94(45):e1939
6. Fok et al. Intern Med J. 2015 Aug;45(8):821-7
7. Bouillet et al. J Allergy Clin Immunol 2014;133:AB37