Cross-reactivity of A ngioedema - PowerPoint Presentation

Slide1

Cross-reactivity of Angioedema Between ACEIs and ARBs

Jimmy Gonzalez,

Pharm.D

.

PGY-2 Drug Information Resident

Robert Wood Johnson University Hospital

May 2016

Slide2

Financial Disclosures

Neither the presenter nor the planning committee has received any commercial support in the development of this educational activity.

2

Slide3

Learning Objectives

Explain proposed mechanisms for cross-reactivity between ACEIs and ARBsDescribe the risk of angioedema with ARBs following ACEI-induced angioedema

3

Slide4

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?

4

Slide5

What is Angioedema?

Localized, nonpitting and nonpruritic swellingExtravasation of plasma into subcutaneous tissueCommon locations:FaceLips Rarely: intestinal tractTongueRespiratory tractInduced by increased formation or reduced clearance of vasoactive peptides

5

Hoover

T.

Clin

Exp

Allergy

. 2010;40(1):50-61

.

Slide6

Risk Factors for Angioedema

African American raceHeart failureFemale genderSmokingIncreased age

6

Hoover T.

Clin

Exp

Allergy

. 2010;40(1):50-61

.

Slide7

Drug-induced Angioedema

Common classes which cause angioedema:ACEIsARBsNSAIDsFibrinolyticsDPP-IV inhibitorsVasoactive mediatorsBradykininSubstance P

7

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

Microsoft Clipart

Slide8

Bradykinin Formation

8

Kaplan AP. J Allergy Clin Immunol. 2002;109(2):195-209.

LMWK

Bradykinin

Tissue

Kallikrein

HMWK

Plasma

Kallikrein

FXIIa

Prekallikrein

Slide9

Bradykinin/Substance P Degradation

9

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

Bradykinin

Substance P

ACE

NEP

APP

DPP-IV

Slide10

Mechanism of ACEI/ARB Angioedema

High levels of vasoactive peptidesEnhanced production vs reduced clearanceACEI-induced angioedemaAccumulation of bradykinin and substance PSlow clearance via alternative mechanismsARB-induced angioedemaARBs increase circulating bradykininUpregulation of AT2 receptors and kinin-NO-cGMP pathwayNegative tonic effect on ACE?

10

Campbell DJ.

Circulation

. 2005;111(3):315-20.

Hiyoshi

H.

Hypertension

. 2004;43(6):1258-63.

Slide11

ACEI-induced Angioedema

11

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

Bradykinin

Substance P

ACE

NEP

APP

DPP-IV

Slide12

ARB-induced Angioedema

12

Campbell DJ. Circulation. 2005;111(3):315-20.Hiyoshi H. Hypertension. 2004;43(6):1258-63.Wadelius M. Clin Pharmacol Ther. 2002;109:195-209.

Bradykinin

AT I

AT II

ACE

AT

1

Receptor

B

2

Receptor

ARB

NEP

AT

2

Receptor

Slide13

Native Incidence of Angioedema

13

Makani

H.

Am J

Cardiol

.

2012;110(3):383-91

.

Slide14

Likelihood of Cross-reactivity

14

Warner

KK. Ann Pharmacother. 2000;34(4):526-8.Cicardi M. Arch Intern Med. 2004;164(8):910-3.Haymore BR. Ann Allergy Asthma Immunol. 2009;103(1):83-4.

Possible cases: 2.5% [95% CI: 0-6.6%]Confirmed cases: 1.5% [95% CI: 0-5.1%]

Slide15

DPP-IV: Interactions as well?

15

Slide16

DPP-IV Functions

Cell-surface endopeptidaseFound throughout the bodyNumerous substratesIncretins (e.g., GLP-1)Substance PDes-Arg9–bradykininImportance may grow with ACE, angiotensin receptor, or neprilysin co-inhibition

16

Mentlein

R.

Regul

Pept

. 1999;85(1):9-24

.

Slide17

DPP-IV Angioedema

Decreased DPP-IV activity noted during acute angioedema attacksCompared to normotensive, remote angioedema, untreated hypertensive patientsLow contribution on bradykinin metabolismAngioedema likely Substance P-mediatedRisk enhanced by:Concomitant ACEIsAcquired or genetic DPP-IV deficiency

17

Byrd JB.

Hypertension

. 2008; 51:141–7.

Lefebvre J.

Hypertension

. 2002;39[part 2]:460-4

.

Slide18

Case Reports with DPP-IV Inhibitors

ReferenceCase InformationMedication(s)AftermathSkalli 201079 y/o woman presented with swelling of lips, tongue, and mouth 14 days after starting tx; recurred with rechallengeIrbesartan + sitagliptinResolved within days after d/c and recurred with dyspnea 2 days after rechallengeMillot 201267 y/o male presented x5 with laryngeal angioedema; discovered to have 30% APP function in setting of DPP-IV and ACE inhibitionPerindopril + sitagliptinResolved within 30-60 minutes with PCC (containing C1-esterase inhibitor), C1-inh, or icatibant.Gosmanov 201246 y/o AA female who had flank pruritus and edema of lipsLosartan + sitagliptinResolved after self-d/c, did not resume with other antidiabeticsSaisho 201369 y/o Japanese male presented with lip angioedema 1 day after starting DPP-IV inhibitorVildagliptinResolved 1 day after switching to alogliptinHamasaki 201360 y/o Japanese male presented with edema of hands and face 1 month after starting DPP-IV inhibitorAnagliptinResolved within 2 weeks after d/c

18

Slide19

DPP-IV Inhibitor-induced Angioedema

19

Bradykinin

Substance P

ACE

NEP

APP

DPP-IV

Slide20

Conclusions

The relative incidence of angioedema withACEIs: 0.3%ARBs: 0.11%Both: 1.5-2.5% (cross-reactivity)Likelihood of cross-reactivity: <10% chanceAngioedema risk with DPP-IV inhibitors may be higher with ACEI/ARBs

20

Slide21

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.

21

Slide22

Assessment Question 1

What is the likelihood of BB developing angioedema from telmisartan given a history of angioedema with ramipril?0%<10%20-30%40-60%>60%

22

Slide23

Assessment Question 1

What is the likelihood of BB developing angioedema from telmisartan given a history of angioedema with ramipril?0%<10%20-30%40-60%>60%

23

Slide24

Assessment Question 2

Which of the following statements is correct regarding ACE/ARB/DPP-IV induced angioedema?Bradykinin levels are elevated in both ACEI and ARB-angioedemaSubstance P levels may be elevated with DPP-IV inhibitorsARBs may indirectly inhibit ACE and NEP activityDPP-IV primarily inactivates Substance PAll of the above

24

Slide25

Assessment Question 2

Which of the following statements is correct regarding ACE/ARB/DPP-IV induced angioedema?Bradykinin levels are elevated in both ACEI and ARB-angioedemaSubstance P levels are elevated with DPP-IV inhibitor useARBs may indirectly inhibit ACE and NEP activityDPP-IV primarily inactivates Substance PAll of the above

25

Slide26

Questions?

Thank you!

26

Slide27

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.

27