Cardiovascular safety of Cox-2 inhibitors and non-selective NSAIDs

Anti-inflammatory drugs are widely used important medicines in the treatment of arthritis and many other painful conditions. Cox-2 selective inhibitors (‘coxibs’) are a relatively new type of anti-inflammatory medicine which are thought to produce fewer gastrointestinal side effects than older non-selective ‘non-steroidal anti-inflammatory drugs’ (NSAIDs). Available coxibs include celecoxib (Celebrex), etoricoxib (Arcoxia), and parecoxib (Dynastat – which is given by injection for short-term use in hospitals). Available non-selective NSAIDS include ibuprofen (Brufen, Nurofen), naproxen (Naprosyn), diclofenac (Voltarol), etodolac (Lodine), and meloxicam (Mobic).

Doctor and patient with electrodes on his chest


Cardiovascular safety of Cox-2 inhibitors

As with all medicines, the safety of Cox-2 selective inhibitors is continuously monitored by the MHRA, with expert advice from the Commission on Human Medicines (CHM), which has replaced the Committee on Safety of Medicines (CSM).

Whilst Cox-2 selective anti-inflammatory medicines may be useful for some patients, recent evidence indicates that patients treated with selective Cox-2 inhibitors may be at a slightly increased risk of cardiovascular problems such as heart attacks and strokes.  Rofecoxib (Vioxx, Vioxxacute) was withdrawn in September 2004 because evidence of increased risk after long-term treatment:

Immediate withdrawal of Rofecoxib (Vioxx, Vioxxacute) - 30 September 2004

Other evidence has related to celecoxib, and valdecoxib/parecoxib:
MHRA statement on new data on cardiovascular risk with celecoxib (Celebrex) - 17 December 2004
Advice on the use of celecoxib and other selective Cox-2 inhibitors in light of concerns about cardiovascular safety - 21 December 2004

It is not possible to measure the increased risk precisely from the available evidence, but Cox-2 inhibitors may be associated with about three additional thrombotic events per 1000 patients per year in the general population (see British Medical Journal article, external link).

The former Committee on Safety of Medicines (CSM) reviewed the evidence relating to cardiovascular safety selective Cox-2 inhibitors as part of a Europe-wide review, and has provided advice to healthcare professionals and patients, most recently on 17 February 2005:

MHRA/ CSM advice to healthcare professionals on the safety of selective Cox-2 inhibitors -17 February 2005
The European review has subsequently been finalised. Information relating to the European review of the safety of coxibs can be found at the European Medicines Agency (EMA) website (external link).

The cardiovascular safety of non-selective NSAIDs
The cardiovascular safety of non-selective NSAIDs has been reviewed within the UK by CSM (2005)PDF file (opens in new window) (30Kb) and by Commission on Human Medicines (2006, 2012 and 2013) as part of European-wide reviews.

The 2006 European review concluded that some non-selective NSAIDS may be associated with a small increased risk of thrombotic events such as heart attack or stroke. The lowest effective dose of non-selective NSAID should be prescribed for the shortest possible time.

The 2013 European review considered the balance of benefits of risks of the non-selective NSAID diclofenac. The review concluded that diclofenac has a thrombotic risk profile similar to that of the coxibs. The review recommended that the precautions already in place to minimise the risks of arterial thromboembolic events (blood clots in the arteries) with selective COX-2 inhibitors should also be applied to diclofenac. 

MHRA responds to European Medicines Agency recommendation on diclofenac

There is some evidence that naproxen may have a lower risk of heart attacks or strokes than selective Cox-2 inhibitors.

Ibuprofen is a non-selective NSAID that has been available in low doses for many years as an over-the-counter medicine for short-term use.  Current evidence does not suggest an increased thrombotic risk for short-term, low dose treatment with ibuprofen; however, high-dose ibuprofen (which is not available over the counter) may be associated with a small increased thrombotic risk.

Less evidence is available for other NSAIDs, but it is possible that they may be associated with a small risk of thrombotic events, especially with long duration of treatment and high doses.

Previous communications sent to healthcare professionals (in October 2006) and a question and answer document are available here:
NSAIDs: Letter to healthcare professionalsPDF file (opens in new window) (39Kb)
NSAIDs: Question and answer documentPDF file (opens in new window) (31Kb)


Studies on cardiac safety of NSAIDs since 2006
Since 2006 a number of further studies have been published which examine the risk of cardiovascular events (such as heart attacks) with NSAID use in the general population.

This includes two important studies that both found that all NSAID users may be at an increased risk of cardiovascular events, not only those with baseline cardiovascular risk factors. These findings are in line with the conclusions of the 2006 review.

The following Public Assessment Report (published January 2010) presents a summary of the results from these two studies, and the conclusions based on the data.

Non-steroidal anti-inflammatory drugs and cardiovascular risks in the general populationPDF file (opens in new window) (391Kb)

The MHRA will continue to monitor closely the safety of all non-selective NSAIDs and coxibs.

Other issues with selective Cox-2 inhibitors

Withdrawal of valdecoxib (April 2005)

In April 2005, valdecoxib (Bextra) was withdrawn voluntarily by the manufacturer because of concerns that this medicine may be associated with more frequent serious skin reactions than other selective Cox-2 inhibitors:
Voluntary suspension of valdecoxib - 7 April 2005

Suspension of lumiracoxib (Nov 2007)
In November 2007, the marketing authorisations (licences) for the osteoarthritis drug, lumiracoxib (Prexige), were suspended in the UK. This followed a review of the latest worldwide data on spontaneously-reported cases of serious hepatotoxicity associated with use of lumiracoxib 100mg daily (the licensed dose in the EU). Following this, the Committee for Medicinal Products for Human Use (CHMP) recommended at its December 2007 meeting that the licenses for these medicines should be withdrawn in all EU Member States where they are approved:
EMEA recommends withdrawal of the licences for lumiracoxib-containing medicines - 13 December 2007 (external link)


Further reading
Many studies of NSAIDs have been published in the scientific literature, some of which are listed below.

Non-selective NSAIDs and coxibs

  1. Coxib and traditional NSAID Trialists’ (CNT) Collaboration (external link). Lancet published online May 20, 2013
  2. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials (external link). BMJ 2006; 332: 1302–05.
  3. Hernandez-Diaz S, Varas-Lorenzo, Garcia Rodriguez LA. Non-steroidal anti-inflammatory drugs and the risk of acute myocardial infarction (external link). Basic Clin Pharmacol Toxicol 2006; 98: 266–74.
  4. McGettigan P, Henry D. A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2 (external link). JAMA 2006; 296: 1633–44.

Coxibs
Rofecoxib (Vioxx)

  1. Bresalier RS, Sandler RS, Quan H, et al, for the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial. Cardiovascular events associated with rofecoxib in a colorectal adenoma prevention trial (external link). N Engl J Med 2005; 352: 1092–102.
  2. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis (external link). VIGOR Study Group. N Engl J Med 2000; 343: 1520–28

Celecoxib (Celebrex)

  1. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial (external link). Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284: 1247–55.

Lumiracoxib

  1. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial (external link). Lancet 2004; 364: 665–74.


Page last modified: 26 July 2013