Re: Non-steroidal anti-inflammatory drugs (NSAIDs)
We thank Dr Johnson for his question about our recommendation that a COX-II selective NSAID is preferred to a non-COX selective, conventional NSAID in patients co-prescribed low-dose aspirin. Dr Johnson is concerned that COX-II selective NSAIDs are now well known to be associated with increased cardiovascular risk. (1) The answer to his question is however, unfortunately not straight forward, as we don't yet have definitive, patient based, clinical ‘outcome’ evidence for our recommendation although there is considerable human data that is supportive.
We do know that low-dose aspirin prescribed for cardiovascular prophylaxis should be continued. Low-dose aspirin inhibits platelet aggregation by irreversibly inactivating the platelet’s ability to synthesize and release the prostaglandin thromboxane A2. Thromboxane promotes platelet aggregation. Platelets ‘inhibited’ by aspirin are permanently 'incapacitated'. The result is the platelet’s ability to clump together and contribute to a thrombus is impaired significantly. This effect is not dependent on the patient taking the dose of aspirin every day because of the irreversible effect on the platelets, so the effect of aspirin last days. This is why aspirin is an effective prophylactic therapy in patients at significant risk of cardiovascular events such as a myocardial infarction.
All conventional, non-COX selective NSAIDs, also block platelets by inhibiting thromboxane synthesis but in contrast to aspirin, this effect is reversible. This is why an NSAID is not a satisfactory substitute for low-dose aspirin as a prophylactic therapy for cardiovascular events. As the blood concentration of the NSAID declines, the effect on the platelets also declines and is lost. This loss of platelet inhibitory effect is more pronounced for NSAIDs with shorter half-lives in the body such as ibuprofen, where for significant parts of the 24 hour day, platelets will not be inhibited. This problem is compounded if compliance with the NSAID is not perfect.
There is one other important complication. This effect of aspirin is blocked by concomitant therapy with all non-selective, conventional NSAIDs, except for diclofenac. (2) Also, we now know that the non-selective, conventional NSAIDs also increase the risk of cardiovascular events occurring. Diclofenac happens to be the most risky of the non-selective NSAIDs, and approximately equivalent to available COX-II selective NSAIDs such as celecoxib. (3)
An important distinguishing feature of the COX II selective drugs is that they do not block the effects of aspirin on platelets. Also, the risk for upper GI adverse effects with COX II selective drugs is less than with conventional NSAIDs.
These are the reasons why we suggest that prescribing low doses of a COX-II selective drug is reasonable in patients concomitantly taking low dose aspirin. The effects of the aspirin on platelets will be assured and this will offset the increased risk from the selective COX-II inhibitor. Finally, trying to avoid any NSAID, or at least limiting exposure to them, in patients at risk of cardiovascular disease is recommended.
1. Day RO, Graham GG. Non-steroidal anti-inflammatory drugs (NSAIDs). BMJ 2013;346:f3195
2. Solomon DH, Goodson NJ. The cardiovascular system in rheumatic disease: the newest “extraarticular” manifestation? J Rheumatol 2005;32:1415-7.
3. Coxib and traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper
gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; doi:10.1016/S0140-6736(13)60900-[Epub ahead of print.]
Competing interests: ROD has been involved with consultancies with several drug companies on patents and advice on paracetamol, ibuprofen, selective COX-2 inhibitors, and other drugs used for osteoarthritis; all payments for consultancies were made to a trust fund at St Vincent’s Hospital. We acknowledge the assistance of the National Health and Medical Research Council programme grant (568612) for clinical research relating to patient safety.