Pit Vipers, Fat Lips and

Personalized MedicineNancy J. Brown, MD

Funding: HL079184, HL065193

Consulting: Merck, Novartis, Forest, Via

Investigation drug: icatibant

Drugs that interrupt the renin-angiotensin-aldosterone system save lives

DRI X

ARB X

X MR antag

X

Risk of ACE inhibitor-associated angioedema is increased in black Americans

Events (n) Rate/103 Risk Ratio P

Race Black White

5329

3.890.76

4.5 (2.9-6.8)1

<0.0001

Brown Clin Pharmacol Ther 1996

Utilized Tennessee Medicaid databaseConfirmed cases by chart reviewCompared rates of angioedema blacks and whites taking ACE inhibitors Normalized to rates in patients taking a calcium channel blocker

Mechanism(s) of ACE inhibitor-associated angioedema

BK

Substance P

ACEDPPIVAPNNEP

ACENEPAPP

Inactivemetabolites

B2

Increased vascular permeability

CPN Des-Arg9-BK

B1

NK1

Negative surface

KKC1INH

Activation of the intrinsic coagulation

pathway

KHPM

KHPM

pKK

KK

FXII

FXIIa

KHPM

FXI

- - -

FXIa

Bradykinin Arg1 Pro7Ser6Phe5Gly4Pro3Pro2 Phe8 CArg9

Arg1 Pro7Ser6Phe5Gly4Pro3Pro2 Phe8 CDes Arg9-BK

Arg1 Phe7Gln6Gln5Pro4Lys3Pro2 Phe8 CGly9Leu10Met11

Substance P

APP ACE CPNNEPDPPIV

DPPIV deficiency increases susceptibility to ACE inhibitor-induced peritracheal edema

0 10 20 30 40 50 60

-25

0

25

50

75

100

125

DPPIV deficent+ captopril

DPPIV intact+ captopril

DPPIV deficient+ captopril + NK1 inh

Time (min)

Ed

ema

(vo

xels

)

Byrd et al J Allergy Clin Immunol 2008

DPPIV inhibitor use is associated with increased risk of ACEi angioedema

Brown et al Hypertension 2009

A Healthy Tension

“Personalized Medicine”

“Evidenced-based

Medicine”

“Comparative Efficacy”

“Blockbuster Drugs”from Monty Python

Thank you

Libby Stone, RN Alencia Woodard-Grice, PhD

Brian Byrd, MD Annis Marney, MD

Albert Adam, PhDUniversity of Montreal

Marie Griffin, MDWayne Ray, PhDDivision of Pharmacoepidemiology