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

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 recently 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  Rofecoxib (Vioxx, Vioxxacute) was withdrawn in September 2004 because evidence of increased risk after long-term treatment: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 (EMEA) website (external link).

The cardiovascular safety of non-selective NSAIDs
The cardiovascular safety of non-selective has been reviewed by CSM (2005) (30Kb) and by Commission on Human Medicines (2006) as part of European-wide reviews.

Conclusions of the 2006 review of non-selective NSAIDs
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.

Evidence for diclofenac suggests that it has a thrombotic risk profile similar to that of at least one coxib (etoricoxib) and possibly others.

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. The MHRA will continue to monitor closely the safety of all non-selective NSAIDs and coxibs, and will issue updated advice as evidence becomes available.

The communication to healthcare professionals (24 October 2006) and a question and answer document are available on the MHRA website:
› NSAIDs: Letter to healthcare professionals (39Kb)
› NSAIDs: Question and answer document (31Kb)

Further information is also available on the website of the European Medicines Agency
› European Medicines Agency press release (external link)

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. 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.
2. 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.
3. 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.