Cross-reactivity of

Angioedema Between ACEIs

and ARBs

Jimmy Gonzalez, Pharm.D.

PGY-2 Drug Information Resident
Robert Wood Johnson University Hospital
May 2016
Financial Disclosures

Neither the presenter nor the planning

committee has received any commercial
support in the development of this
educational activity.

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Learning Objectives
• Explain proposed mechanisms for cross-reactivity
between ACEIs and ARBs

• Describe the risk of angioedema with ARBs following

ACEI-induced angioedema

3
Case Vignette
BB is a 56-year old white male with a prior medical
history significant for hypertension, chronic kidney
disease, diabetes, and coronary artery disease. He
currently takes atorvastatin, metformin, sitagliptin,
sevelamer, and telmisartan.

He experienced multiple minor episodes of lip and

tongue swelling while taking ramipril in the past.

How likely is he to develop angioedema secondary to

any of his current medications?

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What is Angioedema?
• Localized, nonpitting and nonpruritic swelling
• Extravasation of plasma into subcutaneous tissue

• Common locations:
– Face
– Lips Rarely: intestinal tract
– Tongue
– Respiratory tract

• Induced by increased formation or reduced

clearance of vasoactive peptides

Hoover T. Clin Exp Allergy. 2010;40(1):50-61.

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Risk Factors for Angioedema
• African American race
• Heart failure
• Female gender
• Smoking
• Increased age

Hoover T. Clin Exp Allergy. 2010;40(1):50-61.

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Drug-induced Angioedema
• Common classes which cause angioedema:
– ACEIs
– ARBs
– NSAIDs
– Fibrinolytics
– DPP-IV inhibitors

• Vasoactive mediators
– Bradykinin
– Substance P

Microsoft Clipart

Agostoni A. Drug Saf. 2001;24(8):599-606.

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Bradykinin Formation

LMWK HMWK

Tissue Plasma
Kallikrein Kallikrein

FXIIa

Bradykinin
Prekallikrein
Kaplan AP. J Allergy Clin Immunol. 2002;109(2):195-209.
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Bradykinin/Substance P Degradation
DPP-IV

Substance P
Bradykinin

ACE

NEP

APP

Preferential degradation of bradykinin: ACE>APP>>>NEP/DPP-IV 9

Mechanism of ACEI/ARB
Angioedema
• High levels of vasoactive peptides
– Enhanced production vs reduced clearance

• ACEI-induced angioedema
– Accumulation of bradykinin and substance P
– Slow clearance via alternative mechanisms

• ARB-induced angioedema
– ARBs increase circulating bradykinin
– Upregulation of AT2 receptors and kinin-NO-cGMP pathway
• Negative tonic effect on ACE?

Campbell DJ. Circulation. 2005;111(3):315-20. 10

Hiyoshi H. Hypertension. 2004;43(6):1258-63.
ACEI-induced Angioedema
DPP-IV

Substance P
Bradykinin

ACE

NEP

APP

Duan QL. Am J Hum Genet. 2005;77(4):617-26.

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ARB-induced Angioedema

Bradykinin AT I
NEP

ACE

AT II ARB

AT2 AT1
B2 Receptor
Receptor Receptor
Campbell DJ. Circulation. 2005;111(3):315-20.
Hiyoshi H. Hypertension. 2004;43(6):1258-63.
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Wadelius M. Clin Pharmacol Ther. 2002;109:195-209.
Native Incidence of Angioedema

ACEI-induced
0.3% [0.28-0.32%] ARB-induced
0.11% [0.09-0.13%]

Makani H. Am J Cardiol. 2012;110(3):383-91.

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Likelihood of Cross-reactivity

1.5-2.5%
Meta-analysis
8% Haymore 2009
Retrospective
chart review
Cicardi 2004
32% Possible cases: 2.5%
[95% CI: 0-6.6%]
Retrospective
chart review Confirmed cases: 1.5%
[95% CI: 0-5.1%]
Warner 2000

Warner KK. Ann Pharmacother. 2000;34(4):526-8.

Cicardi M. Arch Intern Med. 2004;164(8):910-3.
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Haymore BR. Ann Allergy Asthma Immunol. 2009;103(1):83-4.
DPP-IV: INTERACTIONS
AS WELL?
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DPP-IV Functions
• Cell-surface endopeptidase
– Found throughout the body

• Numerous substrates
– Incretins (e.g., GLP-1)
– Substance P
– Des-Arg9–bradykinin

• Importance may grow with ACE, angiotensin receptor,

or neprilysin co-inhibition

Mentlein R. Regul Pept. 1999;85(1):9-24.

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DPP-IV Angioedema
• Decreased DPP-IV activity noted during acute
angioedema attacks
– Compared to normotensive, remote angioedema, untreated
hypertensive patients

• Low contribution on bradykinin metabolism

– Angioedema likely Substance P-mediated

• Risk enhanced by:

– Concomitant ACEIs
– Acquired or genetic DPP-IV deficiency

Byrd JB. Hypertension. 2008; 51:141–7. 17

Lefebvre J. Hypertension. 2002;39[part 2]:460-4.
Case Reports with DPP-IV Inhibitors

Reference Case Information Medication(s) Aftermath

Skalli 2010 79 y/o woman presented with Irbesartan + Resolved within days
swelling of lips, tongue, and mouth sitagliptin after d/c and recurred
14 days after starting tx; recurred with dyspnea 2 days
with rechallenge after rechallenge

Millot 2012 67 y/o male presented x5 with Perindopril + Resolved within 30-60
laryngeal angioedema; discovered to sitagliptin minutes with PCC
have 30% APP function in setting of (containing C1-esterase
DPP-IV and ACE inhibition inhibitor), C1-inh, or
icatibant.
Gosmanov 2012 46 y/o AA female who had flank Losartan + Resolved after self-d/c,
pruritus and edema of lips sitagliptin did not resume with
other antidiabetics
Saisho 2013 69 y/o Japanese male presented with Vildagliptin Resolved 1 day after
lip angioedema 1 day after starting switching to alogliptin
DPP-IV inhibitor
Hamasaki 2013 60 y/o Japanese male presented with Anagliptin Resolved within 2 weeks
edema of hands and face 1 month after d/c
after starting DPP-IV inhibitor

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DPP-IV Inhibitor-induced Angioedema

DPP-IV

Substance P
Bradykinin

ACE

NEP

APP

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Conclusions
• The relative incidence of angioedema with
– ACEIs: 0.3%
– ARBs: 0.11%
– Both: 1.5-2.5% (cross-reactivity)

• Likelihood of cross-reactivity: <10% chance

• Angioedema risk with DPP-IV inhibitors may be higher

with ACEI/ARBs

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Case Vignette
BB is a 56-year old white male with a prior medical
history significant for hypertension, chronic kidney
disease, diabetes, and coronary artery disease. He
currently takes atorvastatin, metformin, sitagliptin,
sevelamer, and telmisartan.

He experienced multiple minor episodes of lip and

tongue swelling while taking ramipril in the past.

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Assessment Question 1
• What is the likelihood of BB developing angioedema
from telmisartan given a history of angioedema with
ramipril?
A. 0%
B. <10%
C. 20-30%
D. 40-60%
E. >60%

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Assessment Question 1
• What is the likelihood of BB developing angioedema
from telmisartan given a history of angioedema with
ramipril?
A. 0%
B. <10%
C. 20-30%
D. 40-60%
E. >60%

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Assessment Question 2
• Which of the following statements is correct regarding
ACE/ARB/DPP-IV induced angioedema?
A. Bradykinin levels are elevated in both ACEI and ARB-
angioedema
B. Substance P levels may be elevated with DPP-IV inhibitors
C. ARBs may indirectly inhibit ACE and NEP activity
D. DPP-IV primarily inactivates Substance P
E. All of the above

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Assessment Question 2
• Which of the following statements is correct regarding
ACE/ARB/DPP-IV induced angioedema?
A. Bradykinin levels are elevated in both ACEI and ARB-
angioedema
B. Substance P levels are elevated with DPP-IV inhibitor use
C. ARBs may indirectly inhibit ACE and NEP activity
D. DPP-IV primarily inactivates Substance P
E. All of the above

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Questions?

Thank you!
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References
• Hoover T, Lippmann M, Grouzmann E, et al. Angiotensin converting enzyme inhibitor induced angio-oedema: A review of the pathophysiology
and risk factors. Clin Exp Allergy. 2010;40(1):50-61.
• Agostoni A, Cicardi M. Drug-induced angioedema without urticaria. Drug Saf. 2001;24(8):599-606.
• Kaplan AP, Joseph K, Silverberg M. Pathways for bradykinin formation and inflammatory disease. J Allergy Clin Immunol. 2002;109(2):195-
209.
• Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation. 2005;111(3):315-20.
• Hiyoshi H, Yayama K, Takano M, Okamoto H. Stimulation of cyclic GMP production via AT2 and B2 receptors in the pressure-overloaded aorta
after banding. Hypertension. 2004;43(6):1258-63.
• Duan QL, Nikpoor B, Dube MP, et al. A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme
inhibitors. Am J Hum Genet. 2005;77(4):617-26.
• Wadelius M, Marshall SE, Islander G, et al. Phenotype standardization of angioedema in the head and neck region caused by agents acting on
the angiotensin system. Clin Pharmacol Ther. 2014;96(4):477-81.
• Makani H, Messerli FH, Romero J, et al. Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system
inhibitors. Am J Cardiol. 2012;110(3):383-91.
• Warner KK, Visconti JA, Tschampel MM. Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema. Ann
Pharmacother. 2000;34(4):526-8.
• Haymore BR, DeZee KJ. Use of angiotensin receptor blockers after angioedema with an angiotensin-converting enzyme inhibitor. Ann Allergy
Asthma Immunol. 2009;103(1):83-4.
• Cicardi M, Zingale LC, Bergamaschini L, Agostoni A. Angioedema associated with angiotensin-converting enzyme inhibitor use: outcome after
switching to a different treatment. Arch Intern Med. 2004;164(8):910-3.
• Mentlein R. Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides. Regul Pept. 1999;85(1):9-24.
• Byrd JB, Touzin K, Sile S, et al. Dipeptidyl peptidase IV in angiotensin-converting enzyme inhibitor associated angioedema. Hypertension.
2008;51(1):141-7.
• Lefebvre J, Murphey LJ, Hartert TV, et al. Dipeptidyl peptidase IV activity in patients with ACE-inhibitor-associated angioedema. Hypertension.
2002;39[part 2]:460-4.
• Skalli S, Wion-barbot N, Baudrant M, et al. Angio-oedema induced by dual dipeptidyl peptidase inhibitor and angiotensin II receptor blocker: A
first case report. Diabet Med. 2010;27(4):486-7.
• Millot I, Plancade D, Hosotte M, et al. Treatment of a life-threatening laryngeal bradykinin angio-oedema precipitated by dipeptidylpeptidase-4
inhibitor and angiotensin-I converting enzyme inhibitor with prothrombin complex concentrates. Br J Anaesth. 2012;109(5):827-9.
• Gosmanov AR, Fontenot EC. Sitagliptin-associated angioedema. Diabetes Care. 2012;35(8):e60.
• Saisho Y, Itoh H. Dipeptidyl peptidase-4 inhibitors and angioedema: a class effect?. Diabet Med. 2013;30(4):e149-50.
• Hamasaki H, Yanai H. The development of angioedema in a patient with type 2 diabetes due to a novel dipeptidyl peptidase-IV inhibitor,
anagliptin. Int J Cardiol. 2013;168(3):e106.

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