Cox 2 Inhibitors

Cyclo-oxygenase-2 inhibitors

Coxibs or specific COX-2 inhibitors refer to drugs developed as COX-2 Inhibitors (celecoxib,¹ etoricoxib,² lumiracoxib,³ rofecoxib[withdrawn], valdecoxib[suspended]) as opposed to etodolac and meloxicam (older NSAIDs said to be COX-2 'preferential').⁴

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 cardio-vascular safety.⁵ 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• Rofecoxib (Vioxx) was withdrawn by its manufacturer in September 2004 with accumulating evidence of a significant association with heart attack and stroke. Further evidence has pointed to this as a class effect^5,6 rather than specific to rofecoxib.
• Several potential mechanisms for COX-2 Inhibitors increasing cardiovascular (CV) risk exist:
  • They selectively inhibit prostocyclin 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.⁵
• 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.
• Contention and research has continued to examine whether non-selective NSAIDs also cause MI and stroke and how their cardio-vascular risk compares to COX-2 Inhibitors.⁵ A new meta-analysis⁷ found:
  • Coxibs do moderately increase cardiovascular events, predominantly MI.
  • High dose ibuprofen (800 mg tds) and diclofenac (75 mg bd) have a similar level of risk to coxibs. Naproxen did not increase risk.
  • Risk increases with long-term use.

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

• Symptomatic relief in Osteoarthritis (OA) and Rheumatoid Arthritis (RA).
• Some have specific licenses - for acute gout (Etoricoxib),² dysmenorrhoea (Lumiracoxib),³ pain associated with dental and orthopaedic surgery (Lumiracoxib).³

However, they are not indicated for routine use in these conditions⁴ and should only be used in preference to standard non-selective NSAIDs when:

• A patient is assessed to be at particularly high risk of GI adverse events. Risk factors for NSAID induced gastric ulceration⁸ include:
  • Age>65years
  • Previous history of peptic ulceration
  • Long term treatment with maximal dose
  • Concomitant treatment with drugs that increase bleeding tendency
• Following an assessment of cardiovascular risk.⁴

Practically, COX-2 selective inhibitors have a similar efficacy to naproxen or diclofenac⁴ and are not suitable for patients who require a more potent NSAID. There is no good evidence that one coxib at optimum effective doses is superior to another for patients with RA or OA.⁹

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)

(These are general points - see individual drugs for full list)

1. Gastrointestinal bleeding
   • Coxibs seem less likely than non-selective NSAIDs to cause dyspepsia and are associated with fewer endoscopic GI ulcers or erosions, but there is less convincing evidence for significant reduction in major ulcer complications.⁹ A systematic review found significant improvement in GI safety and tolerability of celecoxib when compared to diclofenac, naproxen and ibuprofen¹⁰ although alternative analyses of this data have concluded no long term benefit of celecoxib in preventing severe GI complications compared to diclofenac.¹¹ COX-2 selective inhibitors remain associated with serious and fatal GI side-effects.¹² No fully published studies of large RCTs with serious gastrointestinal events as primary outcome are available for etoricoxib or valdecoxib.
   • Any lower risk of GI complications as compared to traditional NSAIDs is eliminated if patients also take an anti-platelet agent such as aspirin.¹³
   • Additional gastro protection in the form of PPIs, H2RAs or misoprostol is not normally recommended for co-prescribing with coxibs although there is some evidence that PPIs can further reduce ulcer risk in patients taking COX-2 Inhibitors.⁵
   • The older COX-2 selective NSAIDs (including etodolac, meloxicam & nabumetone) reduced the risk of symptomatic ulcers but not endoscopic lesions compared to non-selective NSAIDs.⁴
2. Increased cardiovascular risk
   • Celecoxib longterm arthritis safety study (CLASS)¹⁴ showed no statistical difference between cardiovascular event rates between individuals on celecoxib and standard NSAID groups. The study may not have picked up an increased risk for a number of reasons, including insufficient duration of study, bias of patient population towards those with OA and lower risk of CVD compared to RA patients and inclusion of those on low dose aspirin in the study.⁹
   • The Vioxx gastro-intestinal outcomes research (VIGOR) study¹⁵ (randomised RA patients to rofecoxib 50mg od or naproxen 500mg bd) revealed a strong association of cardiovascular disease with rofecoxib. A further trial, analysis of adenomatous polyp prevention on Vioxx (APPROVe),¹⁶ showed a doubling of MI events on rofecoxib.
   • Further placebo-controlled studies^17,6 looking at a range of coxibs confirm an enhanced dose dependent cardiovascular risk suggesting that this is a class effect and not limited to rofecoxib.^5,9
   • For COX-2 preferential drugs (etodolac and meloxicam), there is insufficient data of long enough duration to know whether or not they are associated with a possible increased risk of cardiovascular disease.⁴
   • The absolute risks remain very low. The most recent meta-analysis of 138 RCTs calculated it as a 0.6% cardiovascular event rate per year (compared with 0.3% placebo).⁷ This translates to a number-needed-to-harm of 350.

     CSM advice on the safety of coxibs18
     Patients with established IHD or CVD should be switched to alternative treatment The balance of GI and CV risk should be considered before prescribing a COX-2 inhibitor. Aim for the lowest effective dose for the shortest necessary period. Gastro protection should be considered for those switched to non-selective NSAIDs.

   • Where a patient is on low-dose aspirin for cardiovascular prophylaxis coxibs should not be prescribed as there is no clear evidence of GI benefit in this group.¹⁸
3. Blood pressure effects.
   • In CLASS, celecoxib caused less hypertension than non-selective NSAIDs but peripheral oedema rates were not significantly different.⁹
   • 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 and should not be used in those with uncontrolled hypertension.¹⁸
4. Renal Impairment
   • VIGOR and CLASS found no significant difference between incidence of renal adverse effects in coxibs and non-selective NSAIDs.¹⁹

• There are very few (if any) situations where a coxib is unequivocally indicated.⁹ All NSAIDs, including coxibs, are best avoided where a patient is at high risk of GI complications. Always ask would alternative analgesia suffice? If absolutely necessary, a non-selective NSAID plus PPI is at least as good as use of a COX-2 Inhibitor for patients at high risk.^4,5
• Do not use in those with vascular disease or at high risk of CVD. Where risk factors exist, a non-selective NSAID (but not high dose diclofenac or ibuprofen) is currently preferred to a coxib.⁴
• Prescribe in the lowest dose for the shortest duration possible (as for other NSAIDs). Note that meloxicam is only licensed for short-term use.

• Regular medication reviews are important to monitor efficacy and to prevent unnecessary repeat prescribing. Consider if intermittent treatment or switching to an alternative medication is possible.
• Monitor BP regularly if a NSAID is considered necessary. Consider switching to a standard NSAID (with gastro protection if required) if hypertension is difficult to control.
• 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.
• Report any suspected adverse drug reactions via the yellow card system. Clinical experience of the coxibs is still much more limited compared to the long use of non-selective NSAIDs.