Cox-2 selective inhibitors and non-steroidal anti-inflammatory drugs (N...

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Medicines & Healthcare products

Regulatory Agency (https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatoryagency)

See more information about this Guidance (https://www.gov.uk/government/publications/cox-2-selective-inhibitorsand-non-steroidal-anti-inflammatory-drugs-nsaids-cardiovascular-safety)

Guidance

Published 2 January 2015

Cardiovascular safety of Cox-2 inhibitors

Cardiovascular safety of non-selective NSAIDs
Other issues with selective Cox-2 inhibitors
Further reading

While Cox-2 selective anti-inflammatory medicines may be useful for some patients, the available 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 Rofecoxib (Vioxx, Vioxxacute) was withdrawn in September 2004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.
It is not possible to measure the increased risk precisely from the available evidence, but Cox-2 inhibitors may be
associated with about 3 additional thrombotic events per 1000 patients per year in the general population (see
British Medical Journal http://bmj.bmjjournals.com/cgi/content/full/332/7553/1302).
Information about the European review of the safety of coxibs can be found on the European Medicines Agency
(EMA) website (http://www.ema.europa.eu/htms/human/press/cox2QA.htm).

The cardiovascular safety of non-steroidal anti-inflammatory drugs (NSAIDs) has been reviewed in 2005, 2006,
2012 and 2013 as part of European-wide reviews, in which the UK participated.
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 and risks of the non-selective NSAID diclofenac.

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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.
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.
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 2 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.
A Public Assessment Report (published January 2010) (http://www.mhra.gov.uk/home/groups/pl-p/documents
/websiteresources/con068576.pdf) presents a summary of the results from these 2 studies, and the conclusions

based on the data.

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

Withdrawal of valdecoxib
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.
See voluntary suspension of valdecoxib (http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls
/Safetywarningsandmessagesformedicines/CON1004244)

Suspension of lumiracoxib
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 (http://www.emea.europa.eu/pdfs/human
/press/pr/PR_Lumiracoxib_57930107en.pdf) in all EU Member States where they are approved.

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Non-selective NSAIDs and coxibs

Coxib and traditional NSAID Trialists (CNT) Collaboration (http://dx.doi.org/10.1016/S0140-6736(13)60900-9).
Lancet published online May 20, 2013 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) (http://bmj.bmjjournals.com/cgi/content/full/332/7553/1302). BMJ 2006; 332:
130205.
Hernandez-Diaz S, Varas-Lorenzo, Garcia Rodriguez LA. Non-steroidal anti-inflammatory drugs and the risk of
acute myocardial infarction (http://www.blackwell-synergy.com/doi/abs/10.1111/j.1742-7843.2006.pto_302.) Basic Clin
Pharmacol Toxicol 2006; 98: 26674.
McGettigan P, Henry D. A systematic review of the observational studies of selective and nonselective inhibitors
of cyclooxygenase 2 (http://jama.ama-assn.org/cgi/content/abstract/296/13/1633?%0Amaxtoshow=&HITS=10&hits=10&
RESULTFORMAT=&fulltext=mCgETTIGAN&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT) JAMA 2006; 296:
163344.

Coxibs
Rofecoxib (Vioxx)
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 (http://content.nejm.org
/cgi/content/abstract/352/11/1092) N Engl J Med 2005; 352: 1092102.
Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in
patients with rheumatoid arthritis (http://content.nejm.org/cgi/content/abstract/343/21/1520) VIGOR Study Group. N
Engl J Med 2000; 343: 152028

Celecoxib (Celebrex)
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
(http://jama.ama-assn.org/cgi/content/abstract/284/10/1247?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=1&
andorexacttitle=and&andorexacttitleabs=and&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&
volume=284&firstpage=1247&resourcetype=HWCIT) Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284:

124755.

Lumiracoxib
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 (http://www.thelancet.com/journals/lancet/article/PIIS0140673604168931/abstract) Lancet
2004; 364: 66574.

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