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NSAIDS with preferential cyclo-oxygenase 2 inhibitions have been developed.
and etodolac inhibit COX-2 up to 50 times more than COX-1. However they may still
inhibit COX-1 at therapeutic doses (1).
Advice for Prescribers in light
of concerns about cardiovascular safety of COX-2 inhibitors (2)
suggests that selective COX-2 inhibitors, as a class, may cause an increased risk
of thrombotic events (e.g. MI and stroke) compared with placebo and some NSAIDs
and the risk may increase with dose and duration of exposure. It is not possible
to quantify the risk precisely, but it is considered unlikely to exceed one extra
serious thrombotic event per 100 patient years, over the rate for no treatment.
The Medicines and Health Regulatory Agency (MRHA) advice is as follows (2):
patients with established ischaemic heart disease or cerebrovascular disease should
be switched to alternative treatment. In addition, the existing contraindication
for severe heart failure is now extended to include moderate heart failure (NHYA
- for all patients the balance of GI and cardiovascular
risk should be considered before prescribing a COX-2 inhibitor, particularly for
those with risk factors for heart disease (such as hypertension, hyperlipidaemia,
diabetes and smoking, as well as for patients with peripheral arterial disease)
and those taking low dose aspirin, for whom GI benefit has not been clearly demonstrated.
- the lowest effective dose of COX-2 inhibitor should be used for
the shortest necessary period. Periodic re-evaluation is recommended, especially
for osteoarthritis patients who may only require intermittent treatment.
gastroprotective agents should be considered for patients switched to non-selective
NSAIDs, e.g. omperazole 20mg
- the European Medicines Agency has concluded
its action on COX-II inhibitors (3) and has strengthened the following contraindications
and precautions for the COX-2 inhibitors:
- COX-II inhibitors must not
be used in patients with established ischaemic heart disease and/or cerebrovascular
disease, and also in patients with peripheral arterial disease.
caution should be exercised when prescribing COX-II inhibitors to patients with
risk factors for heart disease, such as hypertension, hyperlipidaemia, diabetes
- given the association between cardiovascular risk
and exposure to COX-II inhibitors, doctors are advised to use the lowest effective
dose for the shortest possible duration of treatment.
reactions and rare, but serious and sometimes fatal, skin reactions can occur
with all COX-II inhibitors. In the majority of cases these occur in the first
month of use, and prescribers are warned that patients with a history of drug
allergies may be at greater risk.
- the Committee concluded that "when
prescribed in accordance with these additional contraindications and precautions,
the balance of benefits and risks remains positive for these COX-II inhibitors
used in their target patient populations"
- there has been advice
regarding etoricoxib as follows (2):
- etoricoxib may be associated with
more frequent and severe effects on BP than some other COX-2 inhibitors and NSAIDs,
particularly at high doses.
- etoricoxib treatment should not be initiated
in patients whose hypertension is not under control.
- eareful monitoring
of BP is advised for patients taking etoricoxib.
- the following
reminder has also been issued by the MRHA concerning parecoxib (2):
may be associated with higher rates of serious skin reactions (e.g. Stevens-Johnson
syndrome, Toxic Epidermal Necrolysis) than other COX-2 inhibitors. Treatment should
be stopped at the first signs of skin rash or hypersensitivity react
review stated (4):
- there are few, if any, situations in which a COX-2
inhibitor is unequivocally indicated
- all NSAIDs, including COX-2 inhibitors,
should be avoided, wherever possible, in patients at high risk of gastrointestinal
- there are potential hazards in prescribing a COX-2 inhibitor
to a patient who is at risk from cardiovascular disease, and no advantage for
patients taking low-dose aspirin for cardiovascular prophylaxis
Ltd have voluntarily suspended the marketing and sales of valdecoxib (April 8th
- (1) Warner TD et al (1999). Nonsteroid drug
selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated
with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad
Sci USA, 96, 7563-8.
- (2) Medicines and Healthcare products Regulatory
Agency (February 2005). COX-2 inhibitors - guidance by both the Medicines and
Health Regulatory Agency (MHRA) and the European Medicines Agency (EMA)
European Medicines Agency (EMA) (June 2005). COX-2 inhibitors.
- (4) Drug
and Therapeutics Bulletin (2005); 43(1):1-5.
Last reviewed 03/2021