Our study is the first to examine in detail the effect modification of a previous myocardial infarction on the cardiac risk associated with the use of Cox‐2 inhibitors. Our results show that current users of celecoxib with a history of myocardial infarction, in contrast with those without such a history, have a significantly increased risk of a subsequent myocardial infarction. Rofecoxib was also associated with an increased cardiovascular risk among those with a history of myocardial infarction, although this did not reach statistical significance compared with those without this history. Notably, only rofecoxib was associated with an increased risk among people with no history of myocardial infarction. Our study was unable to reliably confirm a dose–response relationship with these increased risks, perhaps owing to a lack of sufficient power.
Several distinctions are apparent in our observed risk profiles between celecoxib and rofecoxib. Firstly, the point estimates for celecoxib risk were systematically less than for rofecoxib, regardless of dose and patient profile, suggesting a higher risk with rofecoxib. Secondly, celecoxib increased the coronary risk only in users with a previous myocardial infarction. Our previous study9
of a population with no history of myocardial infarction did not detect a significant risk for celecoxib (RR 0.99, 95% CI 0.85 to 1.16), highlighting the importance of examining the cardiovascular risk profile of the population studied when interpreting Cox‐2 inhibitor study results. Although our study population had a higher cardiovascular risk profile than the Adenoma Prevention with Celecoxib population,3
it was generally exposed to much lower doses of celecoxib. Therefore, it seems that differing population risk gradients and dosing regimens may explain the divergent results of previously published trials, especially for celecoxib.3,12
In the past year, there has been intense research activity assessing the cardiovascular safety of Cox‐2 inhibitors, but mostly dealing with subjects who were free of pre‐existing clinically relevant cardiovascular disease. However, in routine practice, many people requiring NSAIDs are likely to have pre‐existing cardiac disease. Two studies on valdecoxib after coronary artery bypass surgery4,5
showed increased risk, further emphasising the need for further research into the cardiovascular safety profile of other Cox‐2 inhibitors among patients with established coronary artery disease. This is the first observational study to specifically assess the coronary risk of celecoxib and rofecoxib in such a high‐risk population, as defined by the occurrence of a previous myocardial infarction. For example, although the Adenomatous Polyp Prevention on Vioxx Trial confirmed increased cardiotoxicity with rofecoxib as compared with placebo (RR 1.92, 95% CI 1.19 to 3.11; p
0.008), there was insufficient power to examine subgroups at high risk as only 9% of the 2586 randomised patients had symptomatic atherosclerotic cardiovascular disease (RR 9.59, 95% CI 1.36 to 416).2
Our study provides evidence that the presence of pre‐existing coronary disease seems to increase the cardiovascular risk profile associated with Cox‐2 inhibitors.
Our observed patterns of risk are consistent with the prevailing hypothesis that cardiovascular toxicity of Cox‐2 selective inhibitors is due to an unbalancing of the prostacyclin/thromboxane equilibrium and the known pharmacodynamic differences between these agents. The Cox‐2 inhibiting potency of celecoxib is nearly 10 times less than that of rofecoxib,24
and may explain why the magnitude of celecoxib risk is consistently less than that observed with rofecoxib, and present only in patients at high risk. It would seem that for potentially highly thrombogenic agents such as rofecoxib, the risk of myocardial infarction is increased regardless of cardiac history, but that for less thrombogenic agents such as celecoxib, the cardiovascular risk profile of an individual becomes an important modifier of cardiotoxicity.
The limitations of our study should be acknowledged. Firstly, although we did not observe any increased risk among people with a previous myocardial infarction with the use of naproxen, traditional NSAIDs or meloxicam, our power to detect meaningful differences was limited by the unexpectedly low usage of these agents. Secondly, only patients with myocardial infarctions admitted to the hospital could be considered in our analysis as cases. Missing events owing to silent myocardial infarctions and sudden death could have resulted in incomplete case ascertainment. Also, the intermittent use that occasionally accompanies NSAID treatment may have led to misclassification of exposure. However, there is no reason to believe that ascertainment or exposure errors would have occurred differentially across drug groups. Thirdly, we did not have information on smoking status, obesity, physical activity, family history and socioeconomic status. If the distribution of these risk factors varied considerably across exposure groups, our results could be biased owing to confounding by indication. Another potential limitation was our inability to account for over‐the‐counter use of aspirin and ibuprofen. However, as we have discussed in our previous publication,9
in the Québec context, these biases are likely to be negligible and any resulting bias would again be directed towards the null, leading to an underestimation of the true risks. Moreover, given that the only source of losses to follow‐up in our study was emigration of beneficiaries from the province and the older age of our study population, losses to follow‐up would have been extremely low. Our results should not be extrapolated to younger populations that have not been studied.
It is also important to consider absolute risks to assess the effect of our findings on public health. In our previous study of people without previous myocardial infarction,9
the excess myocardial infarction rate attributed to low‐dose and high‐dose rofecoxib was estimated at 2.2 and 7.7 myocardial infarctions per 1000 exposed elderly adults, respectively. In the present cohort of elderly adults with a history of myocardial infarction, the baseline annual myocardial infarction rate is threefold higher (35/1000), and assuming causality for our observed associations, rofecoxib and celecoxib may be responsible for an excess 21 and 14 myocardial infarctions per 1000 patients exposed.
Our results provide evidence that the risk of myocardial infarction associated with rofecoxib is approximately doubled by a history of myocardial infarction. Celecoxib was also associated with an increase in the risk of myocardial infarction, but only in those with a history of such an event. Therefore our results, although compatible with the prevailing opinion that the cardiotoxic effects of Cox‐2 inhibitors are a class effect, do suggest the presence of several nuances to this claim, including the importance of the molecule, dosage and overall cardiovascular risk profiles of patients. However, the discordance among previous randomised trials on celecoxib and our limited power to assess the cardiovascular risk of traditional NSAIDs, the risk‐modifying effect of aspirin, combined with the possibility of residual confounding in observational studies, supports the concept of a large randomised trial of celecoxib and traditional NSAIDs in a similar population at high risk.25