ACE INHIBITOR-INDUCED ANGIOEDEMA

KENDALL SPICER, PHARM.D.

OBJECTIVES

 Review the different mechanisms of angioedema

 Analyze proposed therapies for ACE inhibitor-induced angioedema

 Relate possible treatment strategies to ICU patients

WHAT IS ANGIOEDEMA?

 Angioedema: the rapid development of severe swelling in

mucous membranes and deep skin tissue layers that can be
extremely painful and may even be life-threatening
 These episodes may be acute or chronic depending on the
etiology
 Certain types may not have a definite trigger
 Swelling can occur in the face/mouth/throat, hands, feet, and
abdomen
 May be accompanied by hives
 Histamine and bradykinin are key players in the different
angioedema types

Image: https://www.tldrpharmacy.com/content/a-primer-on-hereditary-angioedema
TYPES OF ANGIOEDEMA
Histamine-Related
 Allergic angioedema
 Most common
 Related to anaphylaxis
 Allergies to food, environmental
allergens, or medications
 Typically able to isolate specific
cause of symptoms
Bradykinin-Related Idiopathic
 Drug-Induced angioedema  Unknown specific mechanism
 Related to the mechanism of the  May be combination of other two
drug, not allergic reaction categories, but with no notable
 Typical therapies used to treat trigger
histamine-related reactions are less
effective
 Hereditary angioedema
 Genetic disposition to
overproduction of bradykinin
 Patients may experience prodrome
WHY ACE INHIBITORS?

 Angiotensin converting enzyme (ACE) also has

activity in breaking down bradykinin and inactivating it
 In the presence of ACE inhibitors, bradykinin may
accumulate and have enhanced effects
 Effects of bradykinin:
 Vasodilation, vessel leak, inflammation
 Bronchoconstriction
 Nociception
 Risk factors: hx/o angioedema, hx/o ACE inhibitor
cough, seasonal allergies, NSAID use, age >65

Image: https://pubmed.ncbi.nlm.nih.gov/29884969/
MANAGEMENT STRATEGIES

1. Discontinuation of the offending agent

 Generally, symptoms should resolve 24-72 hours after discontinuation

2. Airway management
 Patients with severely impaired airways may need surgical intervention to obtain ventilation

3. May attempt alternative therapies, like those approved for hereditary angioedema, to aid in symptom resolution
 FRESH FROZEN PLASMA (FFP)

 Proposed Mechanism: Plasma contains ACE which can help with degradation and subsequent elimination of
bradykinin, leading to rapid recovery.
 Main point – potentially catalyze bradykinin breakdown to speed recovery
 Dosed as 2 units to start, then dose can be repeated evert 2-4 hours if only minor improvement
 No way to guarantee consistent levels of ACE in each unit
 Plasma may also contain high molecular weight kininogen, a precursor to bradykinin
 May present risk for exacerbation of condition
 Most data exists as case reports and meta-analyses, but the evidence shows favorable efficacy in both acute and
refractory phases
 Pros & Cons
TRANEXAMIC ACID (TXA)

 Proposed Mechanism: TXA is known to inhibit fibrinolysis by displacing plasminogen, thus reducing the
amount of plasmin present. Plasmin can contribute to the production of bradykinin by interacting with high
molecular weight kininogen. TXA can also help sustain the effects of C1-INH which can further inhibit plasmin.
 Main point – potentially reduce the production and accumulation of bradykinin to speed recovery
 No standard dosing known for emergent treatment
 Doses reported in case studies range from 500mg to 4g, with some receiving multiple doses
 Listed oral prophylactic doses may be 1-1.5g two to three times daily, then 500mg one to two times daily
 Case studies and retrospective reviews show that TXA may contribute to reduced recovery time <24 hours,
some report resolution within an hour
 Pros & Cons
C1 INHIBITOR CONCENTRATE (C1-INH)

Complement System
 C1 is an initial component of the classical complement pathway and can be activated by Factor XIIa
 Completion of classical complement cascade results in inflammation and cellular damage
 C1-INH can bind C1 and Factor XIIa to reduce the incidence of inflammation and tissue permeability

Kallikrein-Kinin System
 Factor XIIa converts pre-kallikrein to kallikrein which then cleaves high molecular weight kininogen into bradykinin
 C1-INH can bind Factor XIIa and inhibit kallikrein, decreasing production of bradykinin
C1 INHIBITOR CONCENTRATE (C1-INH)

 C1 inhibitor products have been used off-label to treat ACE inhibitor-induced angioedema due to similarities in
syndrome mechanism to hereditary angioedema
 A February 2021 publication retrospectively analyzed 9 patients who received C1-INH (Berinert) in the ER
 4 patients had resolution of symptoms after median time of 13.5 hours without recurrence
 4 patients had resolution of symptoms after median time of 33.75 hours without recurrence (some required 2 doses)
 1 patient had resolution of symptoms after 14 hours but experienced recurrence
 Correlated concomitant treatment with NSAIDS to a longer time to treatment response
 Additional dose did not improve time to treatment response
 Unable to draw definitive conclusions or recommendations
OTHER POTENTIAL OPTIONS

 Ecallantide (Kalbitor)
 Kallikrein inhibitor – reversibly inhibits kallikrein from converting high molecular weight kininogen into bradykinin
 No statistically significant benefit, but did show some difference in achieving short-term discharge goal versus placebo

 Icatibant (Firazyr)
 Bradykinin receptor antagonist – blocks activity of bradykinin at B2 receptors
 Does not solve issue of overproduced bradykinin unless degradation pathways are still intact, concern for rebound
 Use is not well supported
OUR PATIENTS

Patient A:
 55yo M with PMH of HTN, HLD, COPD, & PCI who presented to the ED on the 13th for swelling of lips/tongue
 Duration was 1 day PTA, gradually worsened, now has hand/feet swelling and difficulty breathing/swallowing. No
itching, hives, N/V/D, or abdominal pain. Has hx/o smoking (quit 2 months ago)
 Was taking lisinopril. Received epinephrine, methylprednisolone, and Benadryl with no improvement. Intubated
 On day 2, no notable improvement, intensivist ordered FFP
 On day 3, angioedema improved, still failed cuff leak and SBT
 On day 4, extubated
 >48 hours to extubate following FFP
OUR PATIENTS

Patient B:
 77yo M with PMH of HTN, HLD, and T2DM presented to the ED on the17th for tongue swelling at dinner
 Duration was 5 hours PTA, worsening, soft palate not visible
 Was taking ramipril. Received epinephrine, methylprednisolone, Benadryl, and famotidine with no improvement.
Intubated
 On day 2, discovered patient received new prostate “vitamin” shortly prior to symptoms, intensivist ordered FFP
 On day 3 & 4, angioedema improved but still present, unable to extubate
 On day 5, extubated
 >72 hours to extubate following FFP
THERAPY CONSIDERATIONS GOING FORWARD

 Can we still use ARBs?

 No absolute contraindications are present in the setting of ACE inhibitor-induced angioedema.
 KDIGO and ACC/AHA recommend using extreme caution if an ARB is used after angioedema
 Based on the high-acuity risks associated with angioedema, it may be in the patient’s best interest to use an alternative agent

 Other things to avoid:

 NSAIDs
 ARNIs
 DPP-4is
 Aliskiren?
ACE INHIBITOR-INDUCED ANGIOEDEMA
KENDALL SPICER, PHARM.D.