NSAIDs: Friend or Foe
Non-Steroidal AntiInflammatory Drugs
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Acetylsalicylic acid first produced
by Charles Frederic Gerhardt in
1853
Not until1897 that Bayer, a drug
and dye firm, began investigating
its use as a less irritating version
of standard salicylate medicines.
By 1899, Bayer was distributing
their Aspirin around the world
Ibuprofen launched in 1969
COX-2 enzyme discovered in
1988
Celecoxib launched in 1999
How do they work?
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Cyclo-oxygenase (COX) enzyme used by
cells in the synthesis of prostaglandins
Exists in 2 forms – COX-1 and COX-2
Analgesic and anti-inflammatory effect mainly
dependent on COX-2
Unwanted GI side effects due to inhibition of
COX-1
GI Effects
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Traditional NSAIDs (tNSAIDs) associated
with 4-fold increase in incidence of severe
upper GI ulcer complications (e.g. bleeding or
perforation)
No clear consistent evidence that any nonaspirin tNSAID is any better than another
COX-2 selective NSAIDs (coxibs) result in
significant decrease in upper GI
complications
Renal Effects
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NSAIDs inhibit prostaglandininduced vasodilation
Potentially causes reduced renal
blood flow and can precipitate
renal failure
Likelihood highest if existing
renal impairment, CCF, liver
cirrhosis and those on ACE
inhibitors, ARBs or diuretics
No difference between tNSAIDs
or coxibs
What about CV effects?
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Natural balance between:
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Pro-thrombotic Thromboxane A (synthesised by
platelets using COX-1)
Anti-thrombotic Prostacyclin (synthesised in
vascular endothelium by COX-2)
Prostanoid hypothesis
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Aspirin is an irreversible non-selective
inhibitor of COX-1 and COX-2.
Platelets have no nucleus so blockade from
aspirin lasts for their entire lifespan
Prostacyclin can be synthesised de novo by
endothelial cells so aspirin tips balance to
anti-thrombotic side
Hence aspirins use in secondary prevention
of CV disease
Does this explain NSAID CV
risk?
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Other NSAIDs not irreversible blockers so
may tip things into prothrombotic balance
(especially coxibs) – or so the theory goes
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Thought to be oversimplistic, however…
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No alternative full and credible mechanism
for CV s/e of NSAID’s yet been demonstrated
Vioxx (Rofecoxib)
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Large RCT by Bombardier et al (2000)
found higher rate of MI in patients
taking Vioxx compared to naproxen
Subsequent studies found Vioxx to be
associated with significant increase in
thrombotic events
Worldwide withdrawal of Vioxx in 2004
Sparked numerous further trials looking
into CV safety of coxibs and tNSAIDs
(e.g. ADAPT, CLASS, MEDAL,
TARGET)
Meta-analysis
Drug
RR of CV events (95%CI)
Rofecoxib <25mg/d
1.33 (1.00-1.79)
Rofecoxib >25mg/d
2.19 (1.64-2.91)
Celecoxib (all doses)
1.06 (0.91-1.23)
Meloxicam
1.25 (1.00-1.55)
Diclofenac
1.40 (1.16-1.70)
Naproxen
0.97 (0.87-1.07)
Ibuprofen
1.07 (0.97-1.18)
McGettigan P, Henry D. JAMA 2006;296(13);1633-44
So what does this mean for
us?
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BOTH tNSAIDs and coxibs are associated to
varying degrees with increased CV risk
We must consider co-morbidities and
concurrent medications that may sway risk
Older patients are at increased risk of CV, GI
and renal side effects – weigh up risk/benefit
Both tNSAIDs and coxibs are viable and
effective options to treat pain and have
manageable side effect profiles
Practical Advice
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In terms of CV effects, naproxen is associated with lowest risk
and diclofenac the highest
All NSAIDs contraindicated in active peptic ulceration but coxib
may be used in those with a history of ulceration
Always consider prescribing gastric protection in form of PPI for
those requiring long-term tNSAIDs OR coxibs
NICE judged that it is cost-effective to add generic PPI to
tNSAIDs or coxibs used as treatment for rheumatoid or
osteoarthritis
NICE advises against use of any NSAID in those taking low-dose
aspirin
Avoid tNSAIDs and coxibs in those with history of heart failure
Avoid tNSAID or coxib in those with GFR <30, use with caution
when GFR 30<60
Practical Advice – Bottom Line
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Prescribe lowest effective dose for the
shortest period of time
In chronic pain consider as required dosing
and review regularly
Advise patient regarding potential side effects
and do what you can to minimise risks
Monitor BP, renal function and liver function
in those on long term
The Future
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Await results of trials such as PRECISION
(Prospective Randomised Evaluation of
Celecoxib Integrated Safety versus Ibuprofen
or Naproxen)