1. Hot Topic Presentation Lars Halford, GP ST3 March 2010
NSAIDs: Friend or Foe
Hot Topic Presentation
Lars Halford, GP ST3
March 2010

2. Non-Steroidal Anti-Inflammatory Drugs
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

3. How do they work?
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

4. GI Effects
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 non-aspirin tNSAID is any better than another
COX-2 selective NSAIDs (coxibs) result in significant decrease in upper GI complications

5. Renal Effects NSAIDs inhibit prostaglandin-induced 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

6. What about CV effects? Natural balance between:
Pro-thrombotic Thromboxane A (synthesised by platelets using COX-1)
Anti-thrombotic Prostacyclin (synthesised in vascular endothelium by COX-2)

7. Prostanoid hypothesis
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

8. Does this explain NSAID CV risk?
Other NSAIDs not irreversible blockers so may tip things into prothrombotic balance (especially coxibs) – or so the theory goes
Thought to be oversimplistic, however…
No alternative full and credible mechanism for CV s/e of NSAID’s yet been demonstrated

9. Vioxx (Rofecoxib)
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)

10. Meta-analysis Drug RR of CV events (95%CI) Rofecoxib <25mg/d
1.33 ( )
Rofecoxib >25mg/d
2.19 ( )
Celecoxib (all doses)
1.06 ( )
Meloxicam
1.25 ( )
Diclofenac
1.40 ( )
Naproxen
0.97 ( )
Ibuprofen
1.07 ( )
McGettigan P, Henry D. JAMA 2006;296(13);

11. So what does this mean for us?
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

12. Practical Advice
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

13. Practical Advice – Bottom Line
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

14. The Future
Await results of trials such as PRECISION (Prospective Randomised Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen)