Abstract
BackgroundCOX-2 selective inhibitors are associated with myocardial infarction (MI). We sought to determine whether population health monitoring would have revealed the effect of COX-2 inhibitors on population-level patterns of MI.Methodology/Principal FindingsWe conducted a retrospective study of inpatients at two Boston hospitals, from January 1997 to March 2006. There was a population-level rise in the rate of MI that reached 52.0 MI-related hospitalizations per 100,000 (a two standard deviation exceedence) in January of 2000, eight months after the introduction of rofecoxib and one year after celecoxib. The exceedence vanished within one month of the withdrawal of rofecoxib. Trends in inpatient stay due to MI were tightly coupled to the rise and fall of prescriptions of COX-2 inhibitors, with an 18.5% increase in inpatient stays for MI when both rofecoxib and celecoxib were on the market (P<0.001). For every million prescriptions of rofecoxib and celecoxib, there was a 0.5% increase in MI (95%CI 0.1 to 0.9) explaining 50.3% of the deviance in yearly variation of MI-related hospitalizations. There was a negative association between mean age at MI and volume of prescriptions for celecoxib and rofecoxib (Spearman correlation, −0.67, P<0.05).Conclusions/SignificanceThe strong relationship between prescribing and outcome time series supports a population-level impact of COX-2 inhibitors on MI incidence. Further, mean age at MI appears to have been lowered by use of these medications. Use of a population monitoring approach as an adjunct to pharmacovigilence methods might have helped confirm the suspected association, providing earlier support for the market withdrawal of rofecoxib.
Highlights
Our findings demonstrate striking longitudinal trends in the population rate of myocardial infarction (MI) and strongly suggest a population-level impact of rofecoxib and celecoxib on MI
Temporal trends in inpatient stays due to MIs are tightly coupled to the rise and fall of prescription of COX-2 inhibitors, with an 18.5 percent increase in inpatient stays for MI during the time when rofecoxib was on the market
These results are consistent with prior reports demonstrating cardiovascular effects of rofecoxib and celecoxib. [9,10,11,12,13,14,15,17,27] Further, mean age at MI appears to have been lowered by use of these medications
Summary
In the United States, almost a million people are hospitalized, and 200,000-300,000 die each year of myocardial infarction (MI).[1,2] Rates of MI have increased over the last century and are attributable to lifestyle risk factors, including smoking, obesity, exercise and diet.[3,4,5] While non-cardiovascular target drugs such as fenfluramine, dexfenfluramine, terfanadine and cisapride have been shown to be risk factors for cardiovascular events [6,7,8], their effects are rare and are not considered as contributors to long term trends in morbidity and mortality.Nonsteroidal anti-inflammatory drugs (NSAIDs) are increasingly implicated in cardiovascular morbidity [9] and Cyclooxygenase-2 (COX-2) selective inhibitors, a class of NSAIDs, have been, in particular, associated with increased risk of MI. [9,10,11,12,13,14,15,16] Rofecoxib was withdrawn from the market after a randomized placebo-controlled trial revealed increased cardiovascular risk in patients with colorectal polyps.[17]. Many studies have supported an increased individual risk of MI, but the population-level impact of COX-2 selective inhibitor prescription has not been described or quantified despite their substantial market penetration and delayed market withdrawal. There was a population-level rise in the rate of MI that reached 52.0 MI-related hospitalizations per 100,000 (a two standard deviation exceedence) in January of 2000, eight months after the introduction of rofecoxib and one year after celecoxib. Trends in inpatient stay due to MI were tightly coupled to the rise and fall of prescriptions of COX-2 inhibitors, with an 18.5% increase in inpatient stays for MI when both rofecoxib and celecoxib were on the market (P,0.001). Use of a population monitoring approach as an adjunct to pharmacovigilence methods might have helped confirm the suspected association, providing earlier support for the market withdrawal of rofecoxib
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