COX2 inhibitors (lack of anti-platelet activity)

• the VIGOR study compared the long-term gastrointestinal safety of rofecoxib 50 mg daily with naproxen 500 mg twice daily in rheumatoid arthritis patients. This trial showed that the rate of confirmed gastrointestinal events with rofecoxib was significantly lower than with naproxen: 2.1 events per 100 patient-years, compared with 4.5 events per 100 patient-years. However, there was a significantly higher rate of serious thrombotic adverse events (e.g. myocardial infarction) in patients receiving rofecoxib than in the naproxen treated patients: 1.67 events per 100 patient-years compared with 0.70 events per 100 patient-years
  
  
• 'the available evidence suggests that selective COX-2 inhibiting NSAIDS (rofecoxib and celecoxib) do not possess anti-platelet activity, whereas some conventional NSAIDs may exibit antiplatelet effects, potentially benefitting patients at risk of ischaemic events (though therapeutic equivalence to aspirin has not been established) (1)'

Note that there has been a voluntary worldwide withdrawal of the 'COX-2 selective NSAID' rofecoxib (Vioxx/VioxxAcute) by the manufacturer. This follows new clinical trial results showing an increased risk of confirmed serious thrombotic events (including myocardial infarction and stroke) compared to placebo, following long-term use (2).

There has been advice for Prescribers in light of concerns about cardiovascular safety of COX-2 inhibitors (3)

• patients treated with any COX-2 inhibitor who have established ischaemic heart disease or cerebrovascular disease should be switched to alternative (non-COX-2 selective) treatments as soon as is convenient
• for all patients, alternative treatments should be considered in light of an individual assessment of risks and benefits of COX-2 inhibitors, in particular cardiovascular, gastrointestinal and other risk factors
• prescribers are reminded that for all NSAIDs (including COX-2 inhibitors), the lowest effective dose should be used, for the shortest duration necessary
• for patients switched to chronic non-selective NSAIDs, consideration should be given to the possible need for gastro-protective treatments

Notes:

• the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme did NOT show any difference in thrombotic cardiovascular disease risk when comparing etoricoxib (COX-2 inhibitor) and diclofenac (COX-1 inhibitor) (4)
• a meta-analysis (5) revealed that Selective COX 2 inhibitors are associated with a moderate increase in the risk of vascular events, as are high dose regimens of ibuprofen and diclofenac, but high dose naproxen is not associated with such an excess
• a MeReC review stated that (6):
  • highly selective COX-2 inhibitors (e.g. celecoxib, etoricoxib, lumiracoxib), as a class, are associated with a small excess risk of thrombotic events (about three per 1000 users treated for one year) compared with no treatment, and they are contraindicated for patients with established CV disease
  • traditional NSAIDs may also be associated with an increased risk of thrombotic events. Diclofenac 150mg/day appears to be associated with a similar excess risk to that of cox-2 inhibitors, whereas low-dose ibuprofen (<=1200mg/day) and naproxen 1000mg/day appear to be associated with a lower risk
• residual risk after stopping COX2 inhibitor
  • in patients with a history of colorectal adenomas, the COX2 inhibitor rofecoxib was associated with increased risk of cardiovascular events >= 1 year after stopping treatment (7)

Reference:

• (1) Committee on Safety of Medicines (2001), Current Problems in Pharmacovigilance, 27, 1-8.
• (2) Committee on Safety of Medicines (30th September 2004). DOH Cascade.
• (3) Medicines and Healthcare products Regulatory Agency (December 2004). Advice on the use of celecoxib and other selective cox-2 inhibitors in light of concerns about cardiovascular safety.
• (4) Cannon PC et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2006;368:1771-1781.
• (5) Kearney PM et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006 Jun 3;332(7553):1302-8.
• (6) MeReC Extra 2007;30.
• (7) Baron JA et al. Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial.Lancet. 2008 Nov 15;372(9651):1756-64