9 years since Vioxx: NSAIDs still a concern

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Practice points | NSAIDs – balancing pain relief against CV risk | COX-1 vs COX-2 what's the difference? | NSAIDs: What factors should you consider in a risk assessment? | Are all NSAIDs equally harmful? | References


NSAIDs are an important part of treatment for many people with painful conditions. However, there is a growing body of evidence that most NSAIDs are associated with an increased risk of cardiovascular events, some more than others.

Practice points

  • Use lowest effective dose

Higher daily doses of NSAIDs are associated with increased risk of MI, stroke and death from CV disorders.

  • Use for the shortest time possible

Even short term use of NSAIDs is associated with increased risk, but this should be balanced against the need for pain relief.

  • Choose an NSAID with the lowest risk profile

There is now substantial evidence that the NSAIDs that inhibit COX-2 without complete inhibition of COX-1 incur the greatest risk.

  • Exercise particular caution when prescribing diclofenac

Evidence suggests that diclofenac has a significant CV risk profile.

  • Consider CV risk factors before prescribing

Patients with other risk factors for the development of CV disorders may be at an increased risk with NSAID medicines.

NSAIDs – balancing pain relief against CV risk

A recent study of NSAIDs use in middle- and low-income countries1 has once again highlighted the potential risks associated with the use of these medicines. NSAIDs are a mainstay for the treatment of painful conditions and many patients rely on them to maintain daily activities.2 NSAIDs have been shown to reduce pain significantly in patients with arthritis, low-back pain and soft tissue pain.2 However, there is a comprehensive body of evidence to suggest that, in spite of their popularity and availability over-the-counter, the clinical efficacy of NSAIDs does not come without a potential risk of significant cardiovascular harm.3-8 In fact, one large meta-analysis has suggested that for all NSAIDs except naproxen the increased risk of CV events exceeds 30%.7 As a comparison, smoking increases the risk of developing coronary artery disease by around 50–100%.9

Recently, several studies have investigated the effect of NSAIDs on cardiovascular risk in patients with a history of cardiovascular disease and in presumed healthy people with no comorbidities showing an increase in risk of:

  • cardiovascular death
  • fatal and non-fatal myocardial infarction 
  • stroke.2,3,5-8,10

The benefits of treating painful conditions with NSAIDs may, in general, outweigh the harms,8 but consider the harms before making treatment decisions.

COX-1 vs COX-2 what's the difference?

The cyclooxygenase isozymes (COX-1 and COX-2) are essential proteins in the arachidonic acid pathway. NSAIDs inhibit COX-1 and COX-2 activity and achieve relief from pain and inflammation by reducing production of prostaglandins.11

COX-2 also has an important protective role in thrombogenesis, hypertension and atherogenesis.11 Inhibition of COX-2 in the absence of inhibition of platelet aggregation through NSAID-mediated complete COX-1 inhibition may lead to the development of a thrombogenic environment.10,12 In fact the extent to which an NSAID inhibits the respective cyclooxygenase isoforms may be related to risk.10 Diclofenac completely inhibits COX-2, but only provides partial inhibition of COX-1 and has one of the worst CV risk profiles.10 This is compared to naproxen which completely inhibits both isoenzymes and has been shown to have a neutral risk profile.10

NSAIDs: What factors should you consider in a risk assessment?

Long-term use?

Although studies have suggested that risk increases with increasing exposure,10 a recent observational study performed in over 1 million Danish residents found that even short exposure to NSAIDs is associated with cardiovascular harms such as MI, stroke and CV/coronary death.3

Higher doses?

Most studies in this area have found that increasing dose also increases risk.8 However, even at lower doses, NSAIDs are associated with increased risk that may be significant for some people. For example, in a study of healthy individuals taking diclofenac, the relative risk of experiencing coronary death or non-fatal MI was lower in those taking a daily dose of < 100 mg than in those taking a dose >100 mg, however, the risk was still elevated over those reporting no NSAID use. 3

Other CV risk factors?

The risk of CV events associated with NSAID use is higher in people with risk factors for coronary artery disease, and previous CV events.6,10 However, increases in risk are also seen in healthy people with no comorbidities.3 This may indicate the need for caution when prescribing NSAIDs in otherwise healthy low-risk patients.

Other risk factors to consider

NSAIDs have other important adverse effects that should also be taken into account when considering medicine for a particular patient. These adverse effects include gastrointestinal bleeding, peptic ulcer disease and renal disease.2 The incidence of mortality due to complications related to NSAID use is estimated to be around 6 per 100 000 in the US.2 Risks may be mitigated by using topical agents in place of oral agents or by using proton pump inhibitors concomitantly.2

Are all NSAIDs equally harmful?

The message emerging from a comprehensive body of literature is that, while all NSAIDs regardless of their COX isoenzyme specificity carry a risk of cardiovascular harm, some medicines may be more harmful than others.1-3,5-8,10

Regulatory bodies are concerned

Since the voluntary withdrawal of rofecoxib (Vioxx) from the market in 2004 there has been a great deal of interest in the safety of NSAIDs.8 The European Medicines Agency (EMA) launched safety reviews in 2005 and 2006 concluding that, as a class of medicine NSAIDs increase the risk of CV events including MI and stroke.8 In its latest review, the EMA concluded NSAIDs increase the risk of thrombotic complications — in particular diclofenac was identified as having a similar or worse risk profile than COX-2 inhibitors.8

Diclofenac: a cause for concern?

Across the literature, diclofenac has consistently been associated with CV risk equal to or greater than the COX-2 specific inhibitors.3,6-8,10 Diclofenac, completely inhibits COX-2, but only has around a 70% inhibition of COX-1 at therapeutic concentrations.10 The greatest risk appears to be in patients taking diclofenac for long periods and at doses greater than 100 mg/day.6,8,10 By comparison, naproxen consistently demonstrates a lower CV risk profile.3-7 Because of this risk profile the EMA is currently reviewing diclofenac-containing medicines.13 In the light of these concerns and as a precaution consider cardiovascular risk factors when prescribing or recommending diclofenac, especially when other factors such as age, weight, hypertension and hypercholesterolaemia put your patients at higher risk.

Making the best choice for patients taking NSAIDs

NSAIDs represent an important part of treatment for people experiencing a range of painful conditions. Stopping pain relief medicine may not be an option for many patients for whom NSAIDs allow them to continue their daily activities. Recent assessments of comparative efficacy have shown that all NSAIDs are comparable in terms of efficacy with none showing a significant benefit over others.2 The EMA’s advice is that, while the benefits of NSAIDs for the treatment of pain outweigh their risks, they should be used at the lowest effective dose for the shortest possible time.8

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  13. European Medicines Agency. Review of diclofenac-containing medicines started (announcement) 31 October 2012. 2012. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Diclofenac-containing_medicines/human_referral_prac_000009.jsp&mid=WC0b01ac05805c516f (accessed 22 April 2013).