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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