pucker up! the pharmacologic treatment of angioedema · • angioedema is a rare, but...

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Pucker Up! The Pharmacologic Treatment of Angioedema

John Trnka, PharmD

Pharmacy Grand Rounds 2018 February 27, 2018


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


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


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


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


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


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


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


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.


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


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



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



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


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



Wilkerson RG. Emergency Medicine Practice. 2012;14(11):1-21


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


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


Prophylactic Pharmacologic Management of HAE Drug MOA Prophylactic Dose Adverse Effects

C1INH (Cinryze)

C1INH Replacement 1000 units IV every 3–4 days


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


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%)



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


No


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



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


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


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.


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


Icatibant Sinert et al3 2017 RCT 121 Icatibant vs placebo


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


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]


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


Which medication would be the best option for an antihypertensive at discharge? • A. Clonidine • B. Valsartan • C. Spironolactone • D. Amlodipine


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


Questions & Discussion


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

pucker up! the pharmacologic treatment of angioedema · • angioedema is a rare, but...

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