The risk gradient that we observed for rofecoxib can be divided into 3 levels of susceptibility: high (patients who had their MI in association with their first prescription), moderate (patients who tolerated their first prescription but had an MI upon subsequent exposure) and low (patients who did not have an MI during 2.4 years of follow-up, despite receiving rofecoxib [i.e., uncovered controls]). of celecoxib was not statistically significant (RR 1.29, 95% CI 0.90C1.83). Repeated exposure to rofecoxib was associated with a small but statistically nonsignificant delayed risk (RR 1.17, 95% CI 0.98C1.40), but no risk was seen with celecoxib (RR 0.97, 95% CI 0.82C1.14). Treatment duration was not associated with increasing risk for either agent. The risk remained elevated for the first 7 days after rofecoxib was discontinued (RR 1.23, 95% CI 1.05C1.44) but appeared to return to baseline between day 8 and 30 (RR 0.82, 95% CI 0.61C1.09). Interpretation A small proportion of patients using rofecoxib for the first time had their first MI shortly after starting the drug. This risk did not increase with the length of treatment and returned to baseline shortly after treatment was discontinued. More research is needed to identify those most susceptible to cardiotoxicity mediated by COX-2 inhibitor therapy. Rofecoxib was withdrawn from the market on Sept. 30, 2004, after investigators in the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial reported a 2-fold increase in cardiovascular toxicity after 18 months of use.1,2 In contrast, in the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, a similar increase in risk was reported after only 9 months of treatment.3,4 Of interest, the risk curves in the latter study diverge after the first month of therapy.4 Two additional trials of cyclooxygenase-2 (COX-2) inhibitors have recently been published describing still different timelines for this association. In the Adenoma Prevention with Celecoxib (APC) trial,5 celecoxib was associated with a dose-dependent risk increase after 3 years of use, whereas the combination of injectable parecoxib followed by orally administered valdecoxib6 resulted in an increased risk after only 10 days of treatment. Although these variations in the timing of the risk could be due to differences in the populations, brokers and dosing regimens analyzed, these observations nonetheless suggest the possibility of an early risk, at least in some populations. In addition, it is unclear how duration of use in a real-life setting contributes to this risk and for how long users of COX-2 inhibitors might remain at heightened risk after they discontinue therapy. In a PF-06737007 previous population-based cohort study of elderly people with no history of myocardial infarction (MI) initiating nonsteroidal anti-inflammatory drug (NSAID) therapy,7 we found an increased risk of acute MI among those currently taking rofecoxib. Here, using the data collected on current users of rofecoxib and celecoxib, we evaluated the temporal nature of the risk of a first MI. Methods The study cohort was the object of a previous statement on NSAIDs and acute MI, where the methods are described in detail.7 In brief, the original study populace, identified using the computerized databases of the universal health care programs of the province of Quebec, Canada, consisted of a random sample of 125 000 residents of the province, 66 years of age or older, who were PF-06737007 dispensed an NSAID between Jan. 1, 1999, and June 30, 2002, and had been enrolled in the health plan for a period of at least one year. The date of the first such prescription was taken as cohort access. To identify people starting NSAID therapy, we excluded those who had received such an agent in the year preceding cohort access (= 1193). In addition, we excluded those who experienced received ASA but no other NSAID (= 1552) or experienced received prescriptions from 2 or more NSAID groups on the day of cohort access Rabbit Polyclonal to CAPN9 (= 153). The latter criterion made it possible to define mutually unique exposure groups. To study the risk of a first event, people with a hospital discharge diagnosis of MI (International Classification of Diseases, Ninth Revision [ICD-9] codes 410 and 412, all diagnostic fields) any time before cohort access were also excluded (= 8168). An additional 7 cohort users were excluded because PF-06737007 their follow-up was less than 0 days (possible data errors). The remaining 113 927 people were followed until the earliest of the date of a first study end point, termination of health coverage (i.e., death or emigration), death, or Dec. 31, 2002 (end of study). The beneficiary file, prescription drugs, physician services, hospital admissions and vital statistics databases.The results for celecoxib were less informative since the risk of MI for these patients was not unequivocally increased. Open in a separate window Fig. (RR 1.17, 95% CI 0.98C1.40), but no risk was seen with celecoxib (RR 0.97, 95% CI 0.82C1.14). Treatment duration was not associated with increasing risk for either agent. The risk remained elevated for the first 7 days after rofecoxib was discontinued (RR 1.23, 95% CI 1.05C1.44) but appeared to return to baseline between day 8 and 30 (RR 0.82, 95% CI 0.61C1.09). Interpretation A small proportion of patients using rofecoxib for the first time had their first MI shortly after starting the drug. This risk did not increase with the length of treatment and returned to baseline shortly after treatment was discontinued. More research is needed to identify those most susceptible to cardiotoxicity mediated by COX-2 inhibitor therapy. Rofecoxib was withdrawn from the market on Sept. 30, 2004, after investigators in the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial reported a 2-fold increase in cardiovascular toxicity after 18 months of use.1,2 In contrast, in the Vioxx Gastrointestinal Outcomes Research (VIGOR) study, a similar increase in risk was reported after only 9 months of treatment.3,4 Of interest, the risk curves in the latter study diverge after the first month of therapy.4 Two additional trials of cyclooxygenase-2 (COX-2) inhibitors have recently been published describing still different timelines for this association. In the Adenoma Prevention with Celecoxib (APC) trial,5 celecoxib was associated with a dose-dependent risk increase after 3 years of use, whereas the combination of injectable parecoxib followed by orally administered valdecoxib6 resulted in an increased risk after only 10 days of treatment. Although these variations in the timing of the risk could be due to differences in the populations, agents and dosing regimens studied, these observations nonetheless suggest the possibility of an early risk, at least in some populations. In addition, it is unclear how duration of use in a real-life setting contributes to this risk and for how long users of COX-2 inhibitors might remain at heightened risk after they discontinue therapy. In a previous population-based cohort study of elderly people with no history of myocardial infarction (MI) initiating nonsteroidal anti-inflammatory drug (NSAID) therapy,7 we found an increased risk of acute MI among those currently taking rofecoxib. Here, using the data collected on current users of rofecoxib and celecoxib, we evaluated the temporal nature of the risk of a first MI. Methods The study cohort was the object of a previous report on NSAIDs and acute MI, where the methods are described in detail.7 In brief, the original study population, identified using the computerized databases of the universal health care programs of the province of Quebec, Canada, consisted of a random sample of 125 000 residents of the province, 66 years of age or older, who were dispensed an NSAID between Jan. 1, 1999, and June 30, 2002, and had been enrolled in the health plan for a period of at least one year. The date of the first such prescription was taken as cohort entry. To PF-06737007 identify people starting NSAID therapy, we excluded those who had received such an agent in the year preceding cohort entry (= 1193). In addition, we excluded those who had received ASA but no other NSAID (= 1552) or had received prescriptions from 2 or more NSAID categories on the day of cohort entry (= 153). The latter criterion made it possible to define mutually exclusive exposure groups. To study the risk of a first event, people with a hospital discharge diagnosis of MI (International Classification PF-06737007 of Diseases, Ninth Revision [ICD-9] codes 410 and 412, all diagnostic fields) any time before cohort entry were also excluded (= 8168). An additional 7 cohort members were excluded because their follow-up was less than 0 days (possible data errors). The remaining 113 927 people were followed until the earliest of.