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We recently published a study of certain traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX)-2 inhibitors in relation to acute myocardial infarction (AMI) . This study was restricted to cases of AMI that occurred in 2001 or later in order to allow sufficient time to pass after marketing of rofecoxib and celecoxib, which were not marketed until 1999 and 2000, respectively, in the UK, and we restricted the study to people who began use of their NSAID for the first time after 1999 when rofecoxib was marketed. An unexpected finding of this study was that prolonged use of the NSAID diclofenac increased the risk of AMI.
Since diclofenac, ibuprofen and naproxen had been on the market in the UK for many years prior to 1999, we conducted a new study to evaluate the effect of these NSAIDs on AMI in the years prior to 2001 where we had much additional data on all three drugs and where we could again evaluate the unexpected finding with prolonged use of diclofenac in a separate and larger study population. Many other studies conducted to explore the relation of NSAIDs and AMI have included diclofenac use, but they have not looked specifically at duration of use. These studies are summarized in a recently published meta-analysis . Some of these studies did find a modest increase in the risk of AMI [3, 4] in current diclofenac users of any duration, but some did not .
In the present study of three NSAIDs and the risk of AMI, we employed a study design used in our recently published study . It was designed to assess the relation of long-term use (>10 months) of diclofenac, ibuprofen and naproxen rather than considering current use per se. In addition, as before, we assessed the risk of AMI in patients who had no prior recorded clinically important risk factors for AMI. The study was based on data from the General Practice Research Database (GPRD), a database whose completeness and validity have been repeatedly demonstrated . The study protocol was approved by the Scientific and Ethical Advisory Committee (SEAG) of the GPRD.
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The current study, which was substantially larger than the first one , has again provided persuasive evidence that prolonged use of diclofenac increases the risk of AMI in patients with no prior strong risk factors by around twofold. The RR estimates rose progressively with increasing duration of use and reached around 2.0 at levels of use of ≥ 10 prescriptions, similar to the findings of our earlier study. There was no statistically significantly increased risk for AMI at any level of ibuprofen or naproxen use. The RR estimates for ibuprofen were close to 1.0 for all levels of number of prescriptions except for ≥ 20 prescriptions, where the RR estimate was 1.7 (95% CI 0.9, 3.1). Since our previously published study on NSAIDs and AMI yielded an RR estimate of 1.0 for those who received ≥ 20 prescriptions for ibuprofen, we conclude that the preponderance of evidence from our two studies indicates that ibuprofen does not increase the risk for AMI. However we cannot rule out the possibility of an increased risk, particularly at the highest dose. Naproxen had a pattern of effect similar to that of ibuprofen, and as the randomized VIGOR trial reported that naproxen has a far lower risk for AMI compared with rofecoxib, we conclude that, taken together, these data provide little evidence that naproxen use materially increases the risk of AMI. However, the possibility of an increased risk cannot be excluded, especially with ≥ 20 prescriptions. Moreover, because there are limited data on long-term use of both ibuprofen and naproxen in this study, we have less information on the effects of heavy use of these two NSAIDs than we do for diclofenac.
We controlled for aspirin use in each adjusted model that assessed the risk of a study NSAID on the risk for AMI. Although we are able to capture only aspirin use prescribed by a GP, we did assess the effect of ≥ 10 prescriptions for aspirin compared with <10 prescriptions for aspirin and in no instance was there a material difference in the main effect measures for any of the three study drugs. Nor was there any substantial independent effect of aspirin use on the risk of AMI among users of the three study NSAIDs.
Cumulative dose and total duration of use were highly correlated with the number of prescriptions in each of the three studies. For diclofenac there was a significant effect of increasing cumulative dose when the total amount prescribed to each subject was treated as a continuous variable. We found a 5% increase in risk of AMI for each 10 000-mg unit increase in cumulative dose of diclofenac (range of cumulative dose per subject = 50–335 300 mg). By contrast, the effects of cumulative dose were minimal in the analyses of ibuprofen and naproxen.
It is of note that diclofenac has the highest COX-2 selectivity among the traditional NSAIDs . Therefore, it is not surprising that the effect of diclofenac in this analysis was similar to the effects found for rofecoxib and celecoxib in our previous study .
All patients included in these three studies had filled at least one prescription for the NSAID evaluated in the study. This method was used to obtain some degree of comparability between all subjects and to reduce bias and confounding. Matching on age, gender, calendar time and general practice was used to further control for important potential confounding factors. Subjects with only one prescription for the study NSAID were classified as non-exposed. This reference group was based on randomized studies [7–9] which provided evidence that the receipt of only one prescription does not increase the risk of AMI.
A major difference between our observational studies and those previously published is that, predicated on the results of the clinical trials, we elected to evaluate duration of use for each NSAID as the primary exposure variable rather than currency of use which was used in other studies. In reviewing our results, we noted that only 30% of cases were currently exposed at the index date. Therefore, had we used current use as the primary exposure definition we would have lost 70% of the information available in these data.
The public health implication of this finding is substantial. We estimate, based on the GPRD, that more than 15 million people in the UK have been prescribed diclofenac in the past 20 years. Approximately 11% of these are estimated to have received ≥10 prescriptions. In addition, we estimate, based on US claims data, that over 5 million people in the USA have taken diclofenac in the past 5 years.
Of further public health importance, on 23 August 2006 Reuters reported that Merck had received an ‘approvable letter’ from the Food and Drug Administration for their new COX-2 selective NSAID Arcoxia (http://money.cnn.com/2006/08/23/news/companies/merck.reut/index.htm). Randomized trials comparing the new Merck NSAID with diclofenac found no difference in risk of myocardial infarction between the two drugs. Since the risk of AMI in diclofenac users appears to be elevated, this implies that the risk in the new Merck drug may also be elevated.
In summary, it is the amount of NSAID use that appears to be the critical determinant of the relation of diclofenac to AMI, not the timing of exposure. In the current study, an increased risk appears to be present in diclofenac users, but not in users of ibuprofen or naproxen.