The overall risk of MI does not appear to be substantially increased with standard doses of most traditional NSAIDs and most cyclo‐oxygenase‐2‐specific drugs. Rofecoxib consistently showed a significant increase in the risk of MI in all types of study. Some other cyclo‐oxygenase‐2‐specific drugs and some traditional NSAIDs showed small increases in the risk of an MI in certain types of study, particularly in case‐control studies analysed using a fixed‐effects OR model. This analysis includes all types of peer‐reviewed evidence, ranging from observational studies of NSAID use in MI patients to RCTs in colonic adenoma and an overview of NSAID RCTs in arthritis. It compares MI and GI risks in RCTs of NSAIDs. It is also independent of pharmaceutical companies and government agencies.
The most definitive evidence that NSAIDs increase the risk of MI comes from RCTs in patients with colonic adenoma who, in comparison with patients with rheumatoid arthritis, do not have a specific pre‐existing cardiovascular risk. However, as the number of these trials is small, caution is required in generalising their findings. One RCT involved a supratherapeutic dose of celecoxib (800 mg daily) and may not be relevant to patients using standard doses. The apparent risk with aspirin is based on limited evidence; one RCT on aspirin that was evaluated showed a high RR of 5.0 (95% CI 0.6 to 43.5) for MI, but the study's small size means that this risk is not significant.38
However, in support of the view that anti‐inflammatory doses of aspirin may increase serious vascular side‐effects, the combined frequency of MI and stroke with 323 mg aspirin was significantly increased in this trial (10 events with aspirin, one event with placebo; RR 10.0 (95% CI 1.3 to 77.7)). These findings must be set against the negative effects of low‐dose aspirin in the same study (omitted from the formal systematic review), which suggests that dosing may be of critical importance.
Although RCTs in arthritis comparing cyclo‐oxygenase‐2‐specific drugs with traditional NSAIDs show an excess of MIs, this finding is heavily influenced by a single RCT of rofecoxib: the Vigor trial.3
Not only did this trial exclusively enrol patients with rheumatoid arthritis, who have an underlying increased frequency of MI, but it also compared double the recommended dose of rofecoxib with traditional doses of naproxen.100
Its relevance to routine practice is therefore uncertain. The data about MI risks from traditional NSAIDs are weak. RCTs performed before 2000 did not routinely report MIs and almost all these studies were of a relatively small size and short duration. Even a 5‐year RCT of traditional NSAIDs that enrolled 802 patients with osteoarthritis did not specifically report MIs, although there were more cardiovascular adverse events with indomethacin (12/202 (6%) cases) than with placebo (8/303 (3%) cases).101
The dearth of data on MI before 2000 makes it impractical to assess cardiac risks in these earlier RCTs.
We found that some case‐control studies showed a small overall increase in the risk of MI, particularly with rofecoxib; however, cohort studies indicated no overall added risk. A number of factors—including small study size, selection of potentially inappropriate controls and the population studied—influenced the assessment of risk. A number of confounding factors may also affect the results in these observational studies. Patients given different NSAIDs may have different underlying MI risks; for example, cyclo‐oxygenase‐2‐specific drugs were recommended for patients over 65 years of age, who often have underlying MI risks, and case‐control studies could therefore overestimate their MI risks. We did not correct for variations in risk factors because individual studies require different types of correction; however, the counter‐arguments in favour of such correction are acknowledged.102
Another confounding factor, confounding by indication, seems more important and cannot be overcome by corrections. It is exemplified by a Danish mortality study with paracetamol, which reported a standardised mortality rate for MI of 1.6 in 50
000 patients prescribed paracetamol.103
The most likely explanation for this relationship is that patients who are unwell with conditions such as ischaemic heart disease often take a readily available symptomatic remedy such as paracetamol. This is an example of confounding by indication, and such confounding may explain some or all of the association of NSAIDs with MIs in observational studies.
Furthermore, many reviews use not only published data but also material provided by pharmaceutical companies or obtained from regulatory bodies, such as the FDA, for the sake of completeness. However, we only evaluated data published in peer‐reviewed journals because we believe that such papers meet a guaranteed standard of reporting that is less prone to idiosyncratic variability and maintains independence.
Given the importance of cardiovascular safety with NSAIDs, it is unsurprising that several groups have reported systematic analyses of RCTs1,41,42,43,44,45
and observational studies.104
These studies have evaluated different data based on varying search and selection strategies. However, their main conclusions mirror our own: a definite risk with rofecoxib, a possible risk with diclofenac, and small or nonexistent risks with other cyclo‐oxygenase‐2‐specific drugs and traditional NSAIDs. The interpretation of the findings varies between reviews, reflecting the different values of individual authors when faced with complex data. Interestingly, although it was published after the search period of our review, the Medal trial—which compared etoricoxib with diclofenac in over 34
000 patients—found no difference in the risk of MI between these two drugs.105
The interpretation of this result depends on the assessment of risk with diclofenac, which the results of our review suggest is above that with some other traditional NSAIDs.
Cyclo‐oxygenase‐2‐specific drugs were developed to meet the need for effective NSAIDs with improved GI safety. In retrospect, this aim was incomplete; the key need is improved overall safety. Falling GI risks with NSAIDs, reflecting the use of reduced doses of traditional NSAIDs and the co‐prescribing of proton‐pump inhibitors, emphasise the need to evaluate overall safety.106
Rofecoxib reduced serious GI toxicity but increased the risk of MI, giving it a different side‐effect profile to traditional NSAIDs. The increased risks of MIs with rofecoxib together with its improved GI safety ensured that overall it was neither more nor less safe than conventional NSAIDs. Part of the concern about rofecoxib107,108
reflects the representation of its relative safety.109,110
In this context, although reports of cardiac risks with cyclo‐oxygenase‐2‐specific drugs imply that naproxen is a safe NSAID, a study of 18
424 deaths in individuals who were prescribed NSAIDs found that mortality was highest with naproxen (2.7 times the mortality with nabumetone) and that it was the least safe of four traditional NSAIDs.111
Taken as a whole, the available evidence suggests that the risks of MI with NSAIDs other than rofecoxib are not large, especially when compared with preventable MI risk factors such as smoking.112
The risks of most side‐effects of NSAIDs are greatest when high doses are given for prolonged periods to elderly patients and such an approach should be avoided. The multiplicity of cardiovascular side‐effects with NSAIDs—particularly hypertension and fluid retention—mean that caution should also be exercised when considering the prescription of NSAIDs for patients with high cardiovascular risk. However, for some patients with severe arthritis there may be no realistic alternative and they will need access to effective treatment with information about its risks and benefits. Giving patients informed choice about risks and being involved in taking decisions about therapy is supported by recent regulatory guidance.113
Finally, economic and decision analyses do not favour cyclo‐oxygenase‐2‐specific drugs in the majority of cases, although they recognise that some patients benefit from these drugs.114,115