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MECHANISM BASED ADVERSE CARDIOVASCULAR EVENTS AND SPECIFIC INHIBITORS OF COX-2

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MECHANISM BASED ADVERSE CARDIOVASCULAR EVENTS AND SPECIFIC INHIBITORS OF COX-2. Garret A. FitzGerald M.D. Robinette Professor of Cardiovascular Medicine ... – PowerPoint PPT presentation

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Title: MECHANISM BASED ADVERSE CARDIOVASCULAR EVENTS AND SPECIFIC INHIBITORS OF COX-2


1
MECHANISM BASED ADVERSE CARDIOVASCULAR EVENTS AND
SPECIFIC INHIBITORS OF COX-2
  • Garret A. FitzGerald M.D.
  • Robinette Professor of Cardiovascular Medicine
  • Elmer Bobst Professor of Pharmacology
  • University of Pennsylvania

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3
Coxibs are not platelet inhibitors
Plt0.01 vs placebo
100
90
80
70
60
Inhibition of platelet aggregation ( control)
50
40
30
20
10
0
100
400
800
Placebo
Ibuprofen
Celecoxib (mg)
20 ?M arachdonic acid as agonist.
McAdam et al. Proc Natl Acad Sci USA. 199996272.
4
COX in Human Platelets Western Blot Analysis
AnitbodiesCOX-1 monoclonalantibody raised
againstpurified ram COXCOX-2
monoclonalantibody raised against theCOOH
peptide of humanCOX-2
EC PMA
Platelets
COX-2(max exposure)
COX-2
COX-1
COX-1
COX-2
COX-2
117
97
COX-1
COX-1
66
45
Protein (µg)
10 50 100
30 30
10 50 100
10 50 100
Habib A 2000
5
Inhibition of prostacyclin synthesis by celecoxib
and rofecoxib
200
200
160
160
Mean urinary PGI-M SE (pg/mg creatinine)
120
120
80
80




40
40

0
0
Placebo (n7)
Celecoxib 400 mg (n7)
Ibuprofen 800 mg (n7)
Placebo (n12)
Rofecoxib50 mg qd(n12)
Indomethacin50 mg tid(n10)
Celecoxib 800 mg (n7)
PGI-M 2,3-dinor-6-keto-PGF1? Plt0.01 vs
Placebo Plt0.05 vs Placebo.
McAdam et al. Proc Natl Acad Sci USA.
199996272
Catella-Lawson et
al. J Pharmacol Exp Ther. 1999289735.
6
REGULATED EXPRESSION OF COX-2 IN ENDOTHELIUM BY
LAMINAR SHEAR
Control
LSS 1 hr
LSS 6 hr
Control
TSS 1 hr
TSS 6 hr
Control
IL-1 1 hr
IL-1 6 hr
COX-2
COX-1
Topper et al. Proc Natl Acad Sci USA. 1996
7
PGI2 modulates the cardiovascular response to
TxA2 in vivo
Cheng et al Science. 296 539 541, 2002.
8
Endothelial COX-2 dependent PGI2 modulates
thrombosis induced in vivo by photochemical
injury to the vasculature
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DELETION OR 98 KNOCK DOWN OF COX-1 PROTECTS
AGAINST THROMBOSIS
Yu et al JCI (in press) 2005
11
Parecoxib/valdecoxib and combined coronary and
cerebrovascular events
  • Study Valde Plcb Valde Plcb RR
    95CI
  • Ott 311 151 14 2
    3.40 0.82-13.98
  • 2nd CABG 1088 548 17 3 2.85
    0.81-10.02
  • Meta-analytic RR
    3.08 1.20-7.87
  • p-value
    0.019
  • p-value heterogeneity
    0.86

Furberg, Psaty and FitzGerald Circ 111249,2005
12
VALDECOXIB AND ENVIRONMENTAL PREDISPOSTION TO
THROMBOSIS
Fig. 1 Ventilation-Perfusion Scan (VQ Scan).
A. After inhalation of 20.1mCi of Xenon-133 gas,
scintigraphic images were obtained in the
posterior projection showing uniform ventilation
to lungs. B. After IV injection of 4.1mCi of
Tc-99m-labeled MAA, scintigraphic images were
obtained in the posterior projection showing
decreased activity in the following regions
apical segment of right upper lobe, anterior
segment of right upper lobe, superior segment of
right lower lobe, posterior basal segment of
right lower lobe, anteromedial basal segment of
left lower lobe, and lateral basal segment of
left lower lobe.
13
MECHANISM BASED CARDIOVASCULAR HAZARD - 1
  • HEMODYNAMIC INDUCTION OF ENDOTHELIAL COX-2
    DERIVED PROSTACYCLIN
  • PROSTACYCLIN CONSTRAINS PLATELET ACTIVATION AND
    THROMBOGENESIS IN VIVO
  • SUPPRESSION OF PROSTACYCLIN DOES NOT CAUSE
    SPONTANEOUS THROMBOSIS , BUT AUGMENTS THE
    RESPONSE TO THROMBOGENIC STIMULI IN VIVO
  • HAZARD FROM COXIBS PARTICULARLY IN THOSE
    OTHERWISE PREDSIPOSED TO THROMBOSIS
  • HAZARD ATTENUATED BY gt98 INHIBITION OF COX-1

14
Breyer and colleagues 2002
15
SALT SENSITIVE HYPERTENSION IN IPKOs
170

160
150

SBP (mmHg)
140

130

120
110
100
Normal salt
Low salt
High Salt
Francois et al 2004
16
MECHANISM BASED CARDIOVASCULAR HAZARD -2
  • SUPPRESSION OF COX-2 DERIVED PGI2 AND PGE2
    INCREASES BP AND AUGMENTS THE RESPONSE TO
    HYPERTENSIVE STIMULI
  • DELETION OR INHIBITION OF COX-1 DEPRESSES THE
    RESPONSE TO VASOSCONSTRICTORS IN VIVO
  • HYPERTENSION ON NSAIDS RELATES TO INHIBITION OF
    COX-2 AND THE SELECTIVITY WITH WHICH IT IS
    ATTAINED

17
TxA2 and PGI2 have opposing effects on the
initiation of Atherosclerosis
Narumiya, JCI 2004.
18
DELETION OF THE IP REDUCES MARKEDLY THE
ANTIATHEROSCLEROTIC EFFECT OF ESTROGEN IN VIVO
Egan et al Science 306 1954- 1957, 2004
19
MECHANISM BASED CARDIOVASCULAR HAZARD -3
  • INITIATION AND ACCELERATION OF EARLY
    ATHEROGENESIS BY DELETION OF THE IP
  • FOSTERS PLATELET AND NEUTROOPHIL ACTIVATION AND
    VASCULAR INTERATIONS
  • REMOVES CONSTRAINT ON ATTENDANT OXIDANT STRESS.
  • HYPERTENSION ALSO ACCELERATES ATHEROGENESIS
  • PREDISPOSITION TO ATHEROSCLEROSIS AND
    HYPERTENSION ATTENUATED BY COINCIDENT INHIBITION
    OF COX-1

20
Confirmed Thrombotic Endpoint





Kaplan-Meier Estimates (95 CI)
RR(95 CI) 1.96 (1.20, 3.19)
Patients at RiskPlaceboRofecoxib 25 mg
1299 1192 1148 1079 1039 1002
4701287 1123 1050 986 935
898 411
plt0.05
21
COX-2
COX-1
COX-1
PGI2
BP
Cardiac Fibrosis
TXA2
COX-2
COX-2
COX-1
22
Detection of a Cardiovascular Signal
HIGH
CABG
LOW
Intrinsic CV Risk
Drug Exposure and Selectivity in vivo
INTER
? RA
INTER
OA / ? Polyps
LOW
HIGH
NNT /or Trial Duration
23
VARIATION WITHIN A CLASS EFFECT
  • Underlying substrate of cardiovascular risk
  • Dose, duration of dosing
  • Duration of drug action
  • Volume of distribution?
  • Concomitant therapy eg ASA

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WHAT ABOUT
  • TRADITIONAL NSAIDs?

29
Effects of Aspirin or Ibuprofen Alone on COX-1
Catella et al NEJM 3451809 -1817,2001
30
RR OF MYOCARDIAL INFARCTION
Garcia Rodriguez 2004
RR1.04 1.00-1.08
NSAIDs
RR0.88 0.8-0.95
NAPROXEN
IBUPROFEN
RR 1.03 .96-1.1
NAPROXEN HALF AS GOOD AS ASPIRIN?
31
The VIGOR Study
Event
Rofecoxib Naproxen Stroke
9 (0.2) 8
(0.2) Myocardial Infarction 20
(0.5) 4 (0.1)

32
Differential Recovery From Steady-State
Inhibition Of Platelet COX-1 By Low-Dose ASA and
Naproxen
Naproxen (N 9)
ASA (N 8)
100
95
90
Platelet
85
COX-1
80

P
lt.01
P
lt.01
P
.074
Inhibition
75
70
65
60
1 3 12 24
Time (hours after last administration)
ASA aspirin COX cyclooxygenase.
Capone et al 2003
33
Human Whole Blood COX1/COX2 Assays
0,01
Updated from FitzGerald Patrono, N Engl J Med
2001 345433-442
34
Diclofenac Celebrex in whole human blood in
vitro
Patrignani et al 2005
35
Aspirin / Ibuprofen vs Aspirin / Diclofenac
36
Diclofenac Celecoxib
  • Same selectivity in whole blood in vitro
  • No pharmacodynamic interaction with asa
  • No clinical asa interaction in MI protection
  • Superimposition of GI and CV events in CLASS
  • EDGE and MEDAL comparisons within the class

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tNSAIDs and CV risk
  • Evidence that naproxen achieves sustained
    platelet inhibition in some individuals. A
    dilute aspirin?
  • Evidence that diclofenac is a COX-2 inhibitor
    like celebrex ( with hepatic AEs )
  • Evidence that ibuprofen might undermine benefit
    from asa
  • No rationale for lumping diclofenac and ibuprofen
    as non-naproxen NSAIDs

40
DEAD DRAGONS
  • Its all naproxen
  • Hypertension is a different mechanism
  • Off target fantasies
  • Its just a matter of reducing the dose
  • Time for a study of coxibs in ACS

41
TP antagonism with COX-2 inhibition results in
plaque destabilization
Vehicle
COX 2
TP
COX 2 / TP
Egan et al Circulation 111334-342,2005
42
THE WAY FORWARD?
  • Exclude patients at high intrinsic risk of
    thrombosis from exposure to selective inhibitors
    of COX-2
  • Dose reduction alone does not protect from
    individual hazard due to variability in dose
    response
  • Subject drugs already approved to the same
    requirements for extended dosing as drugs yet to
    be approved
  • Restrict duration of dosing until the parameters
    of safety for extended dosing are established

43
Interindividual variability in the responses to
coxibs
Fig. 3
ex vivo COX-2 assay
ex vivo COX-1 assay
A
B
5
5
1
1
Inhibition serum PGE2
(post dose / pre dose ratio)
(post dose / pre dose ratio)
Inhibition serumTxB2
0.1
0.1
placebo
rofecoxib
celecoxib
placebo
rofecoxib
celecoxib
urinary 11-dehydro TxB2
urinary 2,3 dinor-6-keto PGF1a
C
D
300
2000
200
1000
100
500
urinary PGI-M
(pg/mg creatinine)
50
urinary TxM
(pg/mg creatinine)
100
50
10
placebo
rofecoxib
celecoxib
placebo
rofecoxib
celecoxib
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PERSONALIZED MEDICINE AND THE FUTURE OF THE COXIBS
  • Restrict to individuals intolerant of tNSAIDs
    plus PPIs
  • Determine whether risk transformation occurs
    during chronic dosing
  • Combine physiologic, biochemical and genomic
    variables in discriminant analysis of evolving
    risk in existing trials APPROVe, APC etc
  • Validate prospectively in studies of extended
    dosing

46
CONCLUSIONS
  • Selective inhibitors of COX-2 depress PGI2
    without concomitant inhibition of TxA2
  • This can result in an augmented response to
    thrombotic and hypertensive stimuli and
    acceleration of atherogenesis in mice
  • An increase in MI and/or stroke has been seen in
    5 placebo controlled trials with 3 structurally
    distinct COX-2 inhibitors
  • Hazard would be expected to relate to drug
    selectivity, dose and duration of exposure and to
    interindividual differences in drug response
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