Review of Angiotensin-Converting Enzyme Inhibitor Induced Angioedema and Current Pharmacologic Treatment Options
Authors: Angela Chu, Pharm.D.; Truman Medical Centers PGY-1 Pharmacy Resident
Kerra A. Cissne, Pharm.D.; Truman Medical Centers PGY-2 Critical Care Pharmacy Resident
Program Number: 2017-11-01
Approval Dates: 12/06/17 – 03/06/2018
Approved Contact Hours: One (1) CE(s) per LIVE session.
Submit Answers to CE Questions to Jim Andrews at: firstname.lastname@example.org
MeSH terms: angiotensin-converting enzyme inhibitors, angioedema, hereditary angioedema, bradykinin, icatibant, C1-esterase inhibitor, kallikrein, emergency department
1. Review the incidence and severity of ACE-i induced angioedema.
2. Discuss the proposed mechanism of ACE-i induced angioedema.
3. Review standard treatment options for acute complications of ACE-i induced angioedema.
4. Evaluate literature regarding novel treatment options.
5. Assess clinical recommendations of treatment options and future directions for therapy.
Angiotensin-converting enzyme inhibitors (ACE-i) are some of the most commonly prescribed drugs in the United States owing to their utility across multiple disease states. Examples of these are captopril, enalapril and lisinopril. A rare, but potentially life-threatening, side effect of this drug class is angioedema. Angioedema is swelling of the soft tissues involving the deep dermal, subcutaneous and/or mucosal layers.1,2 It can affect any area of the body but is most commonly seen in the lips and face. If involvement of the larynx or pharynx is present, the risk of airway compromise increases drastically. This complication of ACE-i therapy is relatively rare, consistently reported as an incidence of 0.1 to 0.7%.1 Certain risk factors such as African-American race, concomitant non-steroidal anti-inflammatory drug use and C1-esterase inhibitor abnormalities have been suggested, but are difficult to link directly.1,3
The leading hypothesis behind the mechanism of ACE-i induced angioedema involves a pathological buildup of a naturally occurring substance, bradykinin. ACE-i work by inhibiting angiotensin-converting enzyme in the lung that blocks the conversion of angiotensin I to angiotensin II, thereby producing a vasodilatory effect. However, angiotensin-converting enzyme is responsible for the inactivation of bradykinin, an endogenous substance which vasodilates and increases capillary permeability, subsequently leading to vascular fluid leak and edema.4 It is hypothesized that in the setting of ACE inhibition, bradykinin metabolism is shifted to a host of other metabolic processes, some of which are potential drug targets. C1-esterase inhibitors (C1-INH) cleave factor XIIa to kallikrein, an enzyme that cleaves kininogen to its active form of bradykinin.5 Novel pharmacologic agents have been developed to target these enzymes and will be discussed further in this article.
Standard of Care Treatments
In contrast to other related disease states such as hereditary angioedema (HAE), treatment for ACE-i induced angioedema is based on less robust data and management is often comprised of supportive care. While ACE-i induced angioedema is frequently transient, self-limiting and self-resolving, a certain subset of patients will experience a more severe reaction. These patients may require airway intervention (intubation, cricothyrotomy, etc.) secondary to severe edema which may obstruct the patient’s airway.6 Management strategies have included a range of treatments from observation to administration of antihistamines, corticosteroids and intramuscular epinephrine. Based on the proposed mechanism of ACE-i induced angioedema, these pharmacologic interventions rarely have a full therapeutic effect in severe cases.
Novel Pharmacologic Agents
Although the exact mechanism of ACE-i angioedema has not been proven, the proposed link to bradykinin receptor activation – similar to hereditary angioedema – may help guide treatment. In 2013, the American Academy of Emergency Medicine (AAEM) conducted a systematic review to develop a clinical practice statement regarding the evaluation and treatment of ACE-i angioedema.6 A total of 27 studies were included for review. However, there was a lack of strong evidence to support any particular pharmacologic treatment and the AAEM could not make a formal recommendation regarding treatment. The following sections summarize off-label uses of novel agents that could potentially treat ACE-i angioedema emergently.
Bradykinin (B2) Receptor Antagonist
The most studied novel agent to treat ACE-i angioedema is icatibant. Icatibant is a synthetic, competitive bradykinin (B2) receptor antagonist that is not susceptible to bradykinin degrading enzymes, such as carboxypeptidase N or angiotensin-converting enzyme.7,8 Icatibant is a subcutaneous injection dosed at 30 milligrams (mg) and may be re-administered every 6 hours for 3 doses should symptoms worsen7 In a small case series conducted by Bas et al, 30 mg of icatibant was administered to eight patients diagnosed with ACE-i angioedema in the emergency department (ED).8 When icatibant was compared to a historical group of 47 patients treated with methylprednisolone and clemastine, icatibant had a mean time to first symptom improvement of 50.6 minutes, reduced mean time to complete resolution (4.4 hours vs. 33 hours, respectively), did not require tracheostomy or intubation (0 respiratory interventions vs. 5 respiratory interventions, respectively) nor redosing (0 second doses vs. 12 second doses of methylprednisolone). The only adverse effect patients experienced was injection site reaction.
In a second case series conducted by Bova et al, thirteen patients with ACE-i angioedema were treated with standard therapy (epinephrine, corticosteroids and/or antihistamines) without relief of symptoms in the ED.9 The patients then received 30 mg of icatibant and saw a median time to symptom relief of 30 minutes, median time to complete resolution of 5 hours, did not have to receive tracheostomy or intubation, did not have to be redosed and only experienced injection site reactions. Of these 13 patients, 10 had a history of ACE-i angioedema and were compared to their icatibant treatment. Compared to previously received standard therapy alone, these patients had a significantly worse median time to complete resolution of 54 hours (p=0.002).
Bas et al conducted a multicenter, double-blind, double-dummy, randomized phase two study comparing 30 mg of icatibant (n=13) versus standard therapy of intravenous prednisolone and clemastine (n=14) in ACE-i angioedema patients in the ED.10 Icatibant versus standard therapy resulted in a reduced median time to onset of symptom relief (2 hours vs. 11.7 hours, respectively, p=0.03) and a reduced median time to complete resolution (8 hours vs. 27.1 hours, respectively, p=0.002). Similarly to previously reported studies, icatibant was only associated with injection site reactions whereas one patient in the standard therapy group received a tracheostomy.
Sinert et al conducted the first phase three, randomized, double-blind clinical trial comparing icatibant 30 mg (n=61) versus placebo (n=60) injection in moderately severe or worse ACE-i angioedema.11 All participants were administered standard of care treatment, then study drug if not improved. Unlike previously published studies, they did not find a clinically significant difference in median time to discharge (4 hours for both groups, p=0.63) nor median time to onset of symptom relief (2 hours for icatibant vs. 1.6 hours for placebo, p=0.57). Both groups had a similar overall rate of adverse effects with injection site reaction occurring more frequently in the icatibant group. Only one patient in the icatibant group required endotracheal intubation. The authors cited potential reasons for study result differences including delay in study drug administration as compared to other studies, possible non-bradykinin mediated angioedema, increased African-American patients who may be more susceptible to bradykinin-mediated angioedema and the predominant use of lisinopril which has a short half-life compared to other ACE-i. More studies to validate these results are needed to develop a strong recommendation for or against icatibant use.
C1-esterase Inhibitor (C1-INH) Concentrates
C1-INH concentrates have only been trialed in HAE patients and the couple of case reports done in ACE-i angioedema patients have shown symptom relief, but randomized, controlled trials are still needed to confirm this off-label use in ACE-i angioedema.12,13 Patients with HAE types I or II have a deficiency in either the quantity or function of C1-INH, respectively.14 Human plasma derived C1-INH concentrates have been developed to restore this enzyme in these patients to decrease the activation of bradykinin.5 Three human derived products – Berinert®, Cinryze® and Haegarda® – and one recombinant product – Ruconest® – have been FDA approved to treat hereditary angioedema. These agents are dosed by body weight and administered through intravenous injection.
Craig et al performed a randomized, double-blind, placebo-controlled phase II/III study to compare Berinert®, a C1-INH concentrate, 10 international units per kilogram (IU/kg, n=39) versus 20 IU/kg (n=43) versus placebo (n=42) in the acute treatment of abdominal and facial angioedema in HAE patients.14 Berinert® dosed at 20 IU/kg was significantly reduced the median time to onset of symptom relief compared to placebo (0.5 hours vs. 1.5 hours, respectively, p=0.0025) and median time to complete resolution (4.92 hours vs. 7.79 hours, p=0.0237). Berinert® dosed at 10 IU/kg, however, did not yield statistically significant median time to onset of symptom relief compared to placebo (1.17 hours vs. 1.5 hours, respectively, p=0.2731). Berinert® patients experienced fewer adverse effects compared to placebo with headache, abdominal pain and nausea being the most commonly reported events.
In 2011, Craig et al conducted a follow-up study to assess long-term safety and efficacy of Berinert® 20 IU/kg (n=57) in treating any type of HAE angioedema in all patients who had previously been enrolled in their study.15 Median time to onset of symptom relief remained similar to their previous study at 0.46 hours. There were more adverse events noted in more patients but a relatively low incidence amongst total attacks (n=1085), with headache and abdominal pain still being the most common.
Zuraw et al conducted a double-blind, placebo-controlled randomized trial comparing C1-INH concentrate dosed at 1000 IU/kg (n=35) versus placebo (n=33).16 Median time to onset of relief was significantly reduced in patients who received the C1-INH concentrate versus placebo at 2 hours versus over 4 hours, respectively (p=0.02). Twenty-three patients in the treatment group and 28 patients in the placebo group received a second dose after one hour if symptoms still existed or worsened. Median time to complete resolution remained significantly better in the treatment group at 12.3 hours versus 25 hours, respectively (p=0.004). A larger, open-label study echo similar results.17
Although ACE-i angioedema patients have functional C1-INH, these agents may still be useful to further decrease bradykinin activation to hasten symptom resolution.
As discussed previously, kallikrein is responsible for cleaving bradykinin from its inactive precursor. As bradykinin is the most likely culprit for angioedema complications, a drug to target kallikrein would in theory prevent its production.
Ecallantide (trade name Kalbitor) is a recombinant plasma kallikrein inhibitor. It was approved by the Food and Drug administration (FDA) in 2009 for HAE. In order to evaluate its use in ACE-i induced angioedema, a phase 2, triple blind, randomized controlled study was conducted. Study patients included those in the ED in which corticosteroids and antihistamines failed.18 Groups included treatment with ecallantide versus placebo with the option for open label ecallantide. The primary efficacy endpoint was defined as meeting predetermined criteria for ED discharge within four hours of treatment. Fifty patients were randomized, 26 to ecallantide and 24 to placebo. Thirty-one percent of patients in the treatment arm met the primary outcome criteria, while 21% of the placebo group did the same (95% CI, -14% to 34%). These results are not statistically significant but the study was likely underpowered with a small number of randomized patients. No adverse events were attributed to study drug administration.
Lewis and colleagues carried out a phase 2, double blind, placebo controlled trial comparing three different strengths of ecallantide (10mg, 30 mg and 60 mg) versus placebo.19 The primary endpoint included discharge within six hours. At an interim analysis, the study was halted due to an overwhelming response rate in all arms. Of note, the treatment group experienced new or worsening angioedema, affecting 20 ecallantide-treated patients as opposed to 4 patients in the placebo group.
Of import, ecallantide has not yet been compared to other target-specific therapies in the setting of ACE-I induced angioedema. Therefore, it is difficult to place it in a certain order while considering other treatment options.
Reactions associated with ecallantide are generally mild and include headache, nausea, fatigue and diarrhea.20 However, with a boxed warning for anaphylaxis of 4% within one hour, it is difficult to recommend this drug even in the emergent setting.21
Fresh Frozen Plasma
Owing to its proposed mechanism, angioedema has intermittently been treated using fresh frozen plasma or FFP. While levels of bradykinin theoretically climb, administration of FFP can inhibit this process to some degree by providing kininase II – identical to angiotensin converting enzyme.22
In a case series by Hassen et al, seven patients were identified as having “refractory” angioedema.23 They were treated with corticosteroids, antihistamines and epinephrine before FFP was administered. While their swelling had progressed with previous treatments, it either stopped or seemed to resolve within 2 to 4 hours of FFP administration. Dosing was variable based on provider’s preference and ranged from 1 to 3 units per patient. The authors note that this was a retrospective review, limiting the conclusions that may be drawn from the events.
A single case study by Chayaa et al re-demonstrated a similar scenario in which a patient with refractory ACE-i induced angioedema was successfully treated with FFP.24 In the emergency department, he received the familiar cocktail including corticosteroids, antihistamines and epinephrine but still required intubation. A fiberoptic nasal intubation was unsuccessful due to the amount of swelling so a cricothyroidotomy was performed, after which the patient desaturated and eventually required emergent tracheostomy. Two units of FFP were administered postoperatively and his symptoms resolved completely within four hours.
FFP is not a benign product and has numerous potential adverse effects including delay from preparation to administration, potential for viral transmission and volume overload with particular concern in patients with heart failure. Of particular note, FFP does contain bradykinin so this may exacerbate symptoms, particularly in a patient with HAE.22 These characteristics should be considered when developing a patient’s treatment algorithm.
Clinical Recommendation and Future Directions
The exact mechanism of ACE-i angioedema still needs to be further elucidated in order to develop targeted treatment options. Novel therapies are aimed at proposed mechanisms based on what is known about hereditary angioedema. Reducing bradykinin concentration either through C1-esterase or kallikrein inhibition and directly antagonizing bradykinin receptors are the underlying concepts to novel therapy options. While limited studies and case reports suggest successful treatment with bradykinin inhibitors, C1-esterase inhibitor concentrates, kallikrein inhibitors and fresh frozen plasma, their routine use cannot be recommended at this time. Additional large, placebo or standard therapy controlled, randomized trials are needed to validate published literature regarding potential treatment options. However, standard therapy with epinephrine, corticosteroids and antihistamines have yielded poor results in treatment efficacy and the novel agents detailed in this article should be considered during treatment failure or severe exacerbation.
1. Which part of the body may be affected by ACE-i induced angioedema?
d. All of the above
2. Which of the following drug regimens are considered standard therapy for ACE-i induced angioedema?
a. Fresh frozen plasma + antihistamines=
b. Corticosteroids alone
c. Antihistamines + corticosteroids + epinephrine
d. None of the above
3. Which of the following molecules is most often attributed to the pathophysiologic dysfunction in ACE-i induced angioedema?
a. Angiotensin converting enzyme
4. What is the most clinically relevant adverse effect associated with ecallantide therapy?
d. Gastrointestinal hemorrhage
5. Based on published case reports, what is the most common dosing range of FFP in refractory ACE-i induced angioedema?
a. One to three units
b. Three to five units
c. Five to seven units
d. Seven to ten units
6. What is the recommended dose of icatibant for ACE-i induced angioedema?
a. 10 mg
b. 20 mg
c. 30 mg
d. 60 mg
7. What is the most common adverse drug reaction to icatibant?
b. Injection site reaction
8. What is the mechanism of C1-esterase inhibitors?
a. Cleaves factor XII to kallikrein
b. Antagonizes bradykinin receptors
c. Breaks down kininogen
d. Breaks down bradykinin
9. Berinert® is FDA approved for which indication?
a. ACE-i induced angioedema
b. IgE mediated allergic reaction
c. Hereditary angioedema
10. The American Academy of Emergency Medicine recommends what therapy for ACE-i induced angioedema?
d. No therapy can be recommended at this time
Submit your answers for CE Credit
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17. Riedl MA, Hurewitz DS, Levy R, et al. Nanofiltered C1 esterase inhibitor (human) for the treatment of acute attacks of hereditary angioedema: an open-label trial. Ann Allergy Asthma Immunol. 2012 Jan; 108(1):49-53.
18. Bernstein JA, Moellman JJ, Collins SP. Effectiveness of ecallantide in treating angiotensin converting enzyme inhibitor-induced angioedema in the emergency department. Ann Allergy Asthma Immunol. 2015; 114:245-249.
19. Lewis LM, Graffeo C, Crosley P, et al. Ecallantide for the acute treatment of angiotensin-converting enzyme inhibitor-induced angioedema: a multicenter, randomized, controlled study. Ann Emerg Med. 2015; 65(2):204-213.
20. Levy RJ, Lumry WR, McNeil DL, et al. EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol. 2010; 104(6):523.
21. Lexicomp [Internet]. Hudson (OH): Lexicomp Inc. c.1978-2017. Ecallantide, Mechanism of action, Warnings; [cited 2017 Sep 24]; [2 screens]. Available from: http://lexicomp.com.
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24. Chaaya G, Afridi A, Faiz A. When nothing else works: fresh frozen plasma in the treatment of progressive, refractory angiotensin converting enzyme inhibitor-induced angioedema. Cureus. 9(1):e972.