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Non-specific non steroidal anti-inflammatory drugs (NSAID) and cardiovascular (CV) risk

Last reviewed dd mmm yyyy. Last edited dd mmm yyyy

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  • non-steroidal anti-inflammatory drug (NSAID)s work via inhibition of the enzyme, cyclo-oxygenase (COX), also known as prostaglandin synthetase
    • NSAIDs are a heterogeneous class including aspirin and various other nonselective and selective inhibitors of cyclooxygenase (COX)
      • aspirin is the only NSAID used for prevention and treatment of cardiovascular disease
  • cyclo-oxygenase is present in different forms
    • cyclo-oxygenase 1 (COX1)
      • COX-1 isozyme is essential for the maintenance of normal physiologic states in many tissues including the kidney, gastrointestinal tract, and platelets
      • thromboxane A2 is primarily synthesized in platelets through COX-1 activity, causes platelet aggregation, vasoconstriction, and smooth muscle proliferation
    • cyclo-oxygenase 2 (COX2) is less widely expressed - however it is readily induced by pro-inflammatory stimuli, and catalyses production of prostaglandins that mediate inflammation
      • in vascular endothelium, it mediates production of prostaglandin PGI2
        • prostaglandin PGI2 is a vasodilator and inhibitor of both platelet aggregation and proliferation of vascular smooth muscle cells
  • NSAIDs vary in their relative inhibitory effects on COX-1 and COX-2
    • aspirin is approximately 166 times more potent an inhibitor of COX-1 as compared with COX-2 (1)
    • aspirin irreversibly acetylates and inhibits the COX-1 isozyme - this results in complete platelet inhibition for the life of the platelet
    • nonselective NSAIDs (e.g., naproxen, ibuprofen) cause varying degrees of COX-1 and COX-2 inhibition and produce reversible platelet inhibition
      • in vivo studies have shown that 95% suppression of platelet COX-1 activity is required to inhibit thromboxane A2-dependent platelet aggregation (2)
        • low-dose aspirin use achieves this degree of inhibition. However other nonselective NSAIDs produce variable COX inhibition ranging from 50% to 95% in a reversible time-dependent fashion (2). It is hypothesised that this inhibitory pattern may be insufficient to provide cardioprotection throughout the dosing interval and may explain the greater cardiovascular protection provided by aspirin
      • further study evidence showed an absence of a protective effect of naproxen or other non-selective NSAIDs on risk of coronary heart disease (4). The authors suggest that these drugs should not be used for cardioprotection
      • there is also evidence that non-selective NSAIDs vary in their interaction with aspirin
        • there is study evidence to support the hypothesis that ibuprofen may interact with the cardioprotective effects of aspirin, at least in patients with established cardiovascular disease (5)
    • there has been advice from the UK Committee on Safety of Medicines concerning the use of NSAIDs and relation to cardiovascular risk:
      • it was noted that any CV risk of non-selective NSAIDs is likely to be small and associated with continuous long-term treatment and higher doses
      • the CSM advises that (6,7):
        • prescribing should be based on overall safety profiles of NSAIDs (particularly GI safety) as set out in product information, and risk factors for individual patients
        • switching treatment between non-selective NSAIDs is not justified on the available evidence
        • all patients should take the lowest effective dose of NSAIDs for the shortest time necessary to control symptoms
        • co-prescription with aspirin should be avoided unless absolutely necessary
    • a more recent meta-analysis (8) to assess the effects of selective cyclo-oxygenase-2 (COX 2) inhibitors and traditional non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of vascular events has been undertaken
      • when selective COX-2 inhibitors were compared with traditional NSAIDs, there was a significantly increased risk versus naproxen, but not versus other traditional NSAIDs or NSAIDs as a whole
      • the study authors concluded 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 - however a review of the study concluded that"..Naproxen may confer slightly less CV risk than other NSAIDs but until this is confirmed with further evidence, naproxen should continue to be prescribed with the same precautions as other NSAIDs.."(9)
    • a MeReC review stated that (10):
      • 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
    • increased CV risk associated with rofecoxib persists after stopping treatment
      • analysis of final data from the APPROVe study suggests that rofecoxib is associated with an increased risk of CV events that is present soon after treatment is started, and which persists for a year after treatment is stopped (11)


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