NSAIDs: Friend or Foe

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

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

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

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

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)

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

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

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)

Meta-analysisDrug 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?

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 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

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

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