Cox 2 Inhibitors

Cyclo-oxygenase-2 inhibitors

Coxibs or specific COX-2 inhibitors refer to drugs developed as inhibitors of the enzyme, cyclo-oxygenase-2. They are a subgroup of nonsteroidal anti-inflammatories (NSAIDs) and include:

• Celecoxib¹
• Etoricoxib²
• Lumiracoxib(withdrawn)
• Rofecoxib(withdrawn)
• Valdecoxib(suspended)

Etodolac and meloxicam are older NSAIDs and said to be COX-2 'preferential'.

Selective COX-2 inhibitors were developed as successors to non-selective NSAIDs with the aim of targeting beneficial anti-inflammatory and analgesic properties while avoiding COX-1 inhibition mediated risk of gastro-intestinal (GI) toxicity.
They first emerged in the late 1990s and since that time controversy has raged as to their cardiovascular safety.³ Concern has grown that inhibition of vascular COX-2 activity raises thrombotic risk:

• Rofecoxib (Vioxx®) was withdrawn by its manufacturer in September 2004 with accumulating evidence of a significant association with heart attack and stroke. This subsequently appeared to be a class effect rather than specific to rofecoxib.³
• Several potential mechanisms for COX-2 Inhibitors increasing cardiovascular (CV) risk exist:
  • They selectively inhibit prostacyclin in the vascular endothelium which has important anti-aggregator and vasodilator properties, but do not block thromboxane which causes platelet aggregation, increasing propensity for thrombus formation.
  • Loss of protection to ischaemic myocardium normally provided by COX-2.
  • Via detrimental effects on blood pressure.³
• In April 2005 valdecoxib sales were voluntarily suspended by its manufacturer following concerns about severe skin reactions (Stevens-Johnson syndrome and Toxic Epidermal Necrolysis), as well as the cardiovascular risk. Marketing authorisation has now expired.
• Lumiracoxib was withdrawn in November 2007 following concerns regarding adverse liver reactions.
• Evidence has accumulated that some non-selective NSAIDs (diclofenac 150 mg daily, ibuprofen 2400 mg daily) also cause an increased thrombotic risk.
• Current debate centres around when, if ever, a coxib should be chosen ahead of a non-selective NSAID. This seems to be a difficult balance between clinical efficacy, cardiovascular and GI risk and cost.⁴ A key question is: are GI benefits for coxibs over non-selective NSAIDs maintained when both are co-prescribed with a PPI?

Indications are similar to NSAIDs. See individual drug monographs. For example:

• Symptomatic relief in Osteoarthritis (OA) and Rheumatoid Arthritis (RA). Note that NICE guidance for the treatment of OA⁵ currently recommends:
  • Considering paracetamol and/or topical NSAIDs ahead of the use of oral traditional NSAIDs or coxibs.
  • Where oral NSAIDs are deemed necessary, use the lowest effective dose for the shortest time. Choice of NSAID or coxib should be determined by individual risk profiles.
  • Only specifically rules out the use of etoricoxib 60 mg as a first-line choice of drug.
  • A PPI should be co-prescribed regardless of whether a coxib or non-selective NSAID is chosen.
• Some have specific licenses - for acute gout (etoricoxib).²

Practically, COX-2 selective inhibitors have a similar efficacy to naproxen or diclofenac. There is no good evidence that one coxib at optimum effective doses is superior to another for patients with RA or OA.⁶

See individual drug monographs.
Broadly as for non-selective NSAIDs including:

• Allergy
• Pregnancy and breast-feeding
• Coagulation defects
• Active peptic ulceration
• Inflammatory Bowel Disease
• Ischaemic heart disease and/or cardiac impairment (NHYA class II-V heart failure)
• Severe renal impairment

Gastrointestinal bleeding⁷

• Coxibs are associated with a reduced risk of GI adverse events compared to traditional NSAIDs at equivalent dose.⁸ They do not eliminate risk - serious adverse GI events and even deaths have been reported in association with coxib use.
• Of traditional NSAIDs, low-dose ibuprofen offers the lowest risk of GI side-effects.
• Coxibs appear to to vary in their gastrointestinal risk. Evidence for reduction in clinically important adverse GI events with etoricoxib is weak.
• Any benefit to GI safety from a coxib is lost if co-administered with aspirin.⁸ Low-dose aspirin for cardiovascular protection usually has priority over the requirement for an NSAID.
• The issue of whether adding a PPI to a coxib or traditional NSAID is the more successful strategy for preventing GI complications in high risk individuals remains unclear.⁷ Using a PPI with a NSAID appeared to reduce GI risk to a similar level compared to a PPI alone.⁹ However, one large observational study in elderly patients failed to show a decrease in risk during periods when PPIs were co-prescribed with coxibs or other NSAIDs, compared to periods when they were prescribed without.¹⁰ Randomised trials should clarify the issue.
• Where coxib use cannot be avoided in patients at high risk of peptic ulceration, gastroprotection (PPI) should be used. Benefits of gastroprotection appear to be related to a patient's baseline risk of GI complications.⁷ NICE guidance for the management of osteoarthritis suggests the use of a PPI with NSAID or coxib regardless of underlying GI risk.⁵

Increased cardiovascular risk

Current evidence suggests:¹¹

• Coxibs do moderately increase cardiovascular events, predominantly MI¹² but also stroke.¹³

  The absolute risks remain low: compared to placebo, coxibs increase the risk of a cardiovascular event by about 3 per 1000 people per year.11

• High dose ibuprofen (800 mg t.d.s.) and diclofenac (75 mg b.d.) have a similar level of risk to coxibs. Naproxen did not increase risk.
• Adverse events may manifest early in treatment but risk increases with longer-term use of coxibs¹² and appears to persist for at least a year after stopping regular use of rofecoxib.¹⁴
• Those with a higher baseline risk of CVD appear to be at disproportionate higher risk of celecoxib-related adverse cardiovascular event.¹⁵

Blood pressure effects

• Coxibs increase the risk of developing hypertension, in particular raising systolic blood pressure.
• In the celecoxib long-term arthritis safety study (CLASS),¹⁶ celecoxib caused less hypertension than non-selective NSAIDs but peripheral oedema rates were not significantly different.⁶
• Fluid retention, oedema and hypertension appear to be dose-related with rofecoxib and occur with increased frequency with chronic use and at higher doses.
• Etoricoxib may be associated with more frequent and severe effects on blood pressure than other coxibs.¹⁷
  

  The European Medicines Agency (EMA) recommends that etoricoxib: Should not be used in those with blood pressure persistently above 140/90 mmHg. Blood pressure should be controlled before starting treatment. Blood pressure should be monitored for two weeks after starting treatment and regularly thereafter.

Renal impairment

• VIGOR (the Vioxx gastro-intestinal outcomes research study)¹⁸ and CLASS found no significant difference between incidence of renal adverse effects in coxibs and non-selective NSAIDs.
• Coxibs vary in their risk of adverse renal reactions - there appears to be an increased risk associated with rofecoxib and decreased risk with celecoxib and etoricoxib.¹⁹

• There are very few (if any) situations where a coxib is unequivocally indicated.⁶ All NSAIDs, including coxibs, are best avoided where a patient is at high risk of GI complications. Always ask: would alternative analgesia suffice?
  

  Which NSAID? Based on current evidence, ibuprofen up to 1200 mg per day or naproxen up to 1000 mg are suggested as first-line choices, ahead of any coxib, when:11 Established history of CVD (including cardiac failure, left ventricular dysfunction, hypertension, or peripheral oedema for any other reason) Risk factors for CVD All aged >65 years regardless of cardiac or renal risk factors

• Prescribe in the lowest dose for the shortest duration possible (as for other NSAIDs).

• Regular medication reviews are important to monitor efficacy and to prevent unnecessary repeat prescribing. Those who are at increased risk of complications should be reviewed more frequently. Consider if intermittent treatment or switching to an alternative medication is possible.¹¹
• Monitor BP regularly if a NSAID is considered necessary.
• As with non-selective NSAIDs, if regular treatment is undertaken, renal function should be monitored and treatment stopped if there is evidence of deterioration.
• Remain alert for any evidence of GI complications.