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Coxibs,
the Cardiologist’s Advice
John Ducas
Associate Professor of Medicine
University of Manitoba
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Disclosure
Have received honoraria for: – lectures
Have received payment for– Clinical trial participation
From: Pfizer, AstraZeneca, Merck/Schering Plough,
SanofiAventis, Servier, Boehringer-Ingelheim, Novartis
From: Pfizer, AstraZeneca, CSL Ltd, Servier,
Schering-Plough, GSK, Roche
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Conflict of Interest
• I am paid to give this talk
• Content has been determine by me, not sponsor
• Comments & content reflects my views, not the
University of Manitoba Faculty of Medicine
• My intent is to provide a fair & balanced
discussion of current science & treatment options
For feedback or questions:
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Agenda
At the end of this lecture you should
understand:
1. The mechanism of action of NSAIDs
2. The GI affects of NSAIDs
3. The CV effects of NSAIDs
4. The interaction between low dose ASA & NSAIDs
5. Some common misconceptions about NSAIDs
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The problem
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The problem
1. 1:4 adults have musc-skel pains
– nsNSAID & sNSAID are commonly Rx’ed
– nsNSAID are now OTC
2. nsNSAID & sNSAID have serious AE
– GI
– CV– Renal
– Hepatic
– Allergic
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The problem
3. Musc-skel pain pts have other problems &
risks:
Chronic inflammatory state
Immobility
- smoking
- hypertension
- dyslipidemia
- alcoholism
High GI risk
-previous GI bleed
-H pylori infection
-anticoagulants
-oral steroids
High CV risk
-elderly
-CV disease present
-multiple RF
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The problem
4. The Nomenclature
NSAID, nsNSAID, sNSAID, COX-2 inhibitors, COXIBS,
COX-2 selective
Generic Vs Brand
celecoxib (Celebrex®)
rofecoxib (Vioxx®), valdecoxib (Bextra®), lumiracoxib (Prexige®)
etoricoxib (Arcoxia®)
Older Drugs (some OTC)
Ibuprofen, diclofenac, aspirin, naproxen, indomethacin, sulindac,
ketorolac
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4. The Nomenclature simplified
All NSAID:
nsNSAID, = Mostly Older Drugs (aspirin, naproxen, etc)
sNSAID = celecoxib (Celebrex®)
The problem
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Salix sepulcralis - weeping willow
abundant watery sap, bark which is
heavily charged with salicylic acid
1700’s bark extract used for
effects on fever, pain and inflammation
1829, German chemists isolated
salicin from willow bark
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Charles Frederic Gerhardt
1853 ASA synthesized in an unstable and impure form
1897, scientists at the drug
and dye firm Bayer began
investigating acetylsalicylic
acid as a less-irritating
replacement for standard
common salicylate medicine
66 years later…
Indomethacin was discovered in 1963 and it was first approved
for use in the U.S. by the Food and Drug Administration in 1965
Efficacy unquestioned
Mechanism of action entirely unknown
Today there is no way this drug would have been approved
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Sir John Robert Vane (1927 – November 19, 2004)
won a Nobel Prize in Medicine in 1982
for his work 1971 on aspirin in which he discovered
it inhibited prostaglandin biosynthesis
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Prostaglandins
• found in virtually all tissues and organs
• lipid mediators or hormones
• potent
• short half-life inactivated rapidly after excretion
• paracrine (locally active)
• autocrine (acting on the same cells synthesizing it)
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Circulation 2005;112;759
BronchoconstrictionBronchoconstriction
Uteroconstriction
Multiple effectsBronchocodilation
Vasodilatation
Platelet inhibition
Platelet activation
Prostaglandins
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nsNSAID
Large Dose
Three different types of blockade
1
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Low dose
ASA
•Platelet irreversible
•Other sites intermittent
Three different types of blockade
2
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sNSAID
(coxib)
3
Three different types of blockade
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They have different T1/2
/ ASA
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A brief word on the GI effects…
Annals of Internal Medicine 85:299-303, 1976
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A brief word on the GI effects…
nsNSAIDS cause:
– 100,000 hospital stays USA per year
– 16,500 deaths per year
J Rheumatol 1999:26(Suppl 56):18
Incidence in Pts over 2 months:
2:3………….dyspepsia
1:5………….endoscopically demonstrable ulcer
1:40………...symptomatic ulcer
1:145……….bleeding ulcer
1:1,220…….dies from nsNSAID
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A brief word on the GI effects…
PUB
J Rheumatol 1999:26(Suppl 56):18
~1%
nsNSAIDS cause:Perforation
Ulcer
Bleeding
Annual
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A brief word on the GI effects…
10 X
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BMC Musculoskeletal Disorders 2007, 8:73
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N Engl J Med 2000;343:1520
VIGOR n=8076 with RA, rofecoxib 50 Vs naprosen 1000
overall & CV mortality rate were similar
(%)(%)
MI 12 (0.4) 4 (0.1)
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RofecoxibPoint Estimates and Summary Relative Risks for CV event With Rofecoxib
JAMA. 2006;296:1633-1644
09/2004, Merck announced
a voluntary worldwide
withdrawal of Vioxx
(rofecoxib) because of
increased risk of MI & CVA
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Carol and Robert Ernst
Robert died 2001
ANGLETON, Tex., Aug. 19, 2005
- the first verdict involving Vioxx
- awarded $253.5 m
-10,000 cases & 180 class action suits
pending against Merck
09/2004, Merck announced
a voluntary worldwide
withdrawal of Vioxx
(rofecoxib) because of
increased risk of MI & CVA
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Cardiovascular Effects
• BP
• CHF
– Kidney
• ASA Blockade by NSAID
• Vessel Wall / Platelet
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Cardiovascular Effects
• BP
– rise averages 3 to 6 mmHg
– most prominent in Na & high Na diet
– less effect in pt on CCB
NSAIDs:
1. increase BP
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Cardiovascular Effects
EPIDEMIOLOGY 2003;14:240 –246
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
No NSAID
Current NSAID
Low Dose
High Dose
Rela
tive R
isk C
HF
N=5857
• CHFCohort study / case–control analysis from UK GP Research Database
1ST hospital admission for non-fatal CHF
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Cardiovascular Effects
• CHF
Heart 2006;92:1610
Cohort study / case–control analysis from UK GP Research Database
new hospital admission for non-fatal CHF
0
1
2
3
4
5
6
7
8
9
No CHF Prior CHF
No NSAID
Current NSAID
N=6396
Rela
tive R
isk C
HF
History
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Cardiovascular Effects
• CHF
BMJ 2005;330:1370
Databases of hospital discharge summaries & prescription drug
claims in Quebec
N=2256
NSAIDs:
1. increase BP
2. cause CHF
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Cardiovascular Effects
• Kidney
NSAIDs:
1. increase BP
2. cause CHF
3. cause ARF
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Cardiovascular Effects
• ASA Blockade by NSAID
N Engl J Med 2001;345:1809
nsNSAID
NSAIDs:
1. increase BP
2. cause CHF
3. cause ARF
4. Block LD ASA
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Cardiovascular Effects
• Vessel Wall / Platelet
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COX-1
COX-1
(No COX 2 induced)
Normally, Balance
platelet reactivity
vascular reactivity
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↑COX-1
atherosclerosis,
↑COX-1
↑COX 2 induced
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(Low Dose)
Low dose ASA prevents MI & CVA!
COX-1
↑COX-1
↑COX 2 induced
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sNSAID
sNSAID promotes MI & CVA!
↑COX-1
COX-1
COX 2 induced
NSAIDs:
1.increase BP
2.cause CHF
3.cause ARF
4.cause CV Events
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Myths
1. ASA is the only safe NSAID, use in high dose
2. Naproxen is the only safe NSAID
3. All sNSAID are dangerous
4. Just give a PPI with nsNSAID
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1. ASA is the only safe NSAID, use in high
dose
ACE Trial
n=2849 undergoing CEA, pre op ASA & x 3m
Death, MI, CVA 3m
– ASA 81
– ASA 325
– ASA 650
– ASA 1300
3.7%
8.2%
P=0.002
Lancet 1991;353:2179
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2. Naproxen is the only safe
NSAIDADAPT
>70 y with family history of AD n=2,528
PLoS Clin
Trials 2006;1(7): e33.
•celecoxib 200 b.i.d.
•naproxen sodium 220 b.i.d
•placebo
Cardiovascular Death, MI, Stroke, CHF, or TIA
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3. All sNSAID are dangerousPoint Estimates and Summary Relative Risks for CV With Rofecoxib & Celecoxib
JAMA. 2006;296:1633-1644
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3. All sNSAID are dangerous
Circulation. 2008;117:2104
CV Death, MI , CVA, CHF, or Thromboembolism
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4. Just give a PPI with nsNSAID
image, from: Rheumatol Int (2008) 28:1187, original study :
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3:133
video capsule endoscopy
Normal baseline
No ASA
N=120 celecoxib 200 BID
N=118 naproxen 500 BID + Losec 20 OD
N=118 naproxen 500 BID + placebo
2 weeks
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4. Just give a PPI with nsNSAID
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2007;5:1167
N = 854, OA + CVD
•baseline endoscopy normal
•all ASA 81 or 325
blind randomization
celecoxib 200
naproxen 5002 +lansoprazole 30
•Endoscopy 12 w
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Meta-analysis
99,400 patient years of exposure
Take Home
BMC Musculoskeletal Disorders 2007, 8:73
*
**
*
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Take Home
sNSIAD (+PPI) nsNSAID
(FRS >10%)
Risk Factor Modification / Low Dose ASA / BP / Statin
nsNSAID + PPI
(FRS)
Low Risk (FRS <10%)
nsNSIAD* +PPI or
low dose sNSAID (+PPI)
* ??Naproxen preferred
nsNSIAD*
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Take Home
When starting NSAID Monitor:– BP
– CHF
– Cr
– GI
• Alter NSAID if necessary
• Use plain ASA not ecASA, 2 hours before nsNSAID
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H pylori
H pylori
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Agenda
At the end of this lecture you should
understand:
1. The mechanism of action of NSAIDs
2. The GI affects of NSAIDs
3. The CV effects of NSAIDs
4. The interaction between low dose ASA & NSAIDs
5. Some common misconceptions about NSAIDs
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THANK YOU
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