MEDIA RELEASE


4th August 2005

European Medicines Agency confirms cardiovascular safety of ibuprofen
Over the counter (OTC) ibuprofen has an excellent safety record and is unlikely to be associated with any measurable increase in the risk of cardiovascular events, the European Medicines Agency (EMEA) has confirmed (ref 2).

The announcement follows a Europe-wide review of evidence regarding the effects of non-selective NSAIDs on the risk of cardiovascular and cardio-renal events. This was prompted by concerns that, like the COX-2 selective coxibs, non-selective NSAIDs may be associated with an increased risk (ref 1).

The review concluded there is insufficient evidence to draw firm conclusions regarding naproxen, diclofenac and ibuprofen but that any cardiovascular risk is likely to be small and associated with long-term continuous use and higher doses. It has now recommended that there should be no change to current prescribing practice for non-selective NSAIDs.

These conclusions were supported by Professor Gordon Duff, Chairman of the UK Committee on Safety of Medicines, in a letter to health professionals (ref 2).
He stated:

At the doses in OTC medicines, ibuprofen has an excellent safety record, particularly in respect of gastrointestinal adverse effects. Whilst evidence relating to any cardiovascular risk associated with prolonged treatment and high doses of ibuprofen is not entirely clear, short-term use at the doses that can be bought over the counter is unlikely to be associated with any measurable increased risk.
- ENDS -

Notes for editors
What are COX-1 and COX-2?
All NSAIDs reduce inflammation by inhibiting the enzyme cyclo-oxygenase (COX). This occurs in two forms in the body. COX-1 is present all the time and plays an important role in protecting the gastrointestinal tract. COX-2 occurs at sites of injury and has an essential role in the generation of inflammation and pain. Newer NSAIDs such as rofecoxib and celecoxib selectively inhibit COX-2 and are claimed to be associated with fewer adverse gastrointestinal effects than older NSAIDs that inhibit both forms of COX.

What was the concern about non-selective NSAIDs?
In 2004, selective COX-2 inhibitors were found to be associated with an increased risk of cardiovascular events such as myocardial infarction and stroke. The mechanism of this effect remains unclear but it is possible that COX-2 selectivity has an unequal effect on the counterbalanced systems that regulate blood clotting. (Specifically, these agents inhibit the formation of prostacyclin, which dilates blood vessels, but have no effect on thromboxane, which promotes platelet aggregation; the net effect would be to increase the risk of clotting.) However, it is important to note that the clinical relevance of this theory has not been confirmed.

Because non-selective NSAIDs inhibit both COX-1 and COX-2, they should have a more balanced effect on these pro- and antithrombotic systems and therefore little overall effect on cardiovascular risk. Nevertheless, clinical trials comparing selective and non-selective NSAIDs suggested that non-selective agents may also be associated with an increased risk of cardiovascular events. Concerns grew following publication of an observational study purporting to show that diclofenac and ibuprofen were associated with an increased risk of myocardial infarction3.

What has the latest review found?
The EMEA's review considered three types of data: clinical trials, observational studies and spontaneously reported adverse reactions4. Although the review included all non-selective NSAIDs, there were sufficient data only for naproxen, diclofenac and ibuprofen.

• Clinical trial data failed to show a clear difference between COX-selective and non-COX selective NSAIDs but are difficult to interpret because the COX-selective agents themselves may have different levels of risk. The EMEA therefore considered evidence from other sources. These data also suggest that naproxen is associated with less thrombotic risk than other NSAIDs and, at high doses, it may even protect against cardiovascular events (though clinical evidence for this is lacking).

• Several observational studies have investigated the risk of myocardial infarction associated with NSAID use. These studies have important limitations: they may not have overcome bias, some considered historical rather than current use of NSAIDs, and there is a lack of data regarding over the counter use. The EMEA also points out that observational data do not provide proof of causality. Bearing these caveats in mind, the tentative conclusions from studies comparing current with no use or past use of NSAIDs are: naproxen may have a protective effect or no effect at all on cardiovascular risk; ibuprofen may have no effect at all or a slightly increased risk; and diclofenac may have an increased risk.

• Spontaneous reports of adverse reactions are not reliable for estimating risk in this case. What evidence there is suggests that older NSAIDs are not associated with increased reporting of thrombotic events.

What does the EMEA conclude?
The situation is less clear for non-selective NSAIDs than it was for COX-2 selective agents and the available evidence is insufficient to allow firm conclusions to be drawn. In summary:

• any risk is likely to be small and associated with long-term treatment and high doses
• there should be no change to current prescribing practice
• treatment decisions should be made on the overall safety profile of NSAIDs and their gastrointestinal safety in particular

What about ibuprofen and aspirin?
The EMEA also examined the data for evidence that, as suggested by laboratory studies, ibuprofen may reduce the cardioprotective effects of low-dose aspirin. The evidence from clinical trials is inadequate to assess a possible risk. Observational studies are, overall, inconclusive but an interaction between ibuprofen and aspirin cannot be ruled out. It does not mention data from spontaneous reports. The EMEA concluded that a clinically important effect has not been clearly demonstrated.

NSAIDs and cardio-renal effects
All NSAIDs have the potential to cause oedema, hypertension and heart failure. This is a dose-related effect and there is no evidence that COX selectivity alters the risk. High doses of ibuprofen (2400 mg/day) may have a 'relatively adverse cardiorenal profile' compared with the coxibs.

The future
More clinical data on the risk of thrombotic events with NSAIDs are expected within the next 12 months4. The EMEA will report on the risk of skin reactions and gastrointestinal safety in September1.


References
1. European Medicines Evaluation Agency. Press Release. London. 2nd August 2005. EMEA/247323/2005 (www.emea.eu.int/pdfs/human/press/pr/24732305en.pdf; accessed 3.8.05)

2. Duff G. Cardiovascular safety of NSAIDs. Review of evidence. (www.mhra.gov.uk/news/nsaidsddlQA020805.pdf; accessed 3.8.05)

3. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. Br Med J 2005;330:1336-42

4. Medicines and Healthcare Products Regulatory Agency. Cardiovascular safety of non-steroidal anti-inflammatory drugs. Overview of key data. (www.mhra.gov.uk/news/nsaidsbriefingdoc020805.pdf; accessed 3.8.05)

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