The tell-tale heart: population-based surveillance reveals an association of rofecoxib and celecoxib with myocardial infarction

Abstract

Background: COX-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 findings: We 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/significance: The 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.

Figure 1. Cumulative sum (CUSUM) chart of monthly incidence of hospitalizations due to myocardial infarction from January 1, 1997 to March 30, 2006.

Assigning 1997 and 1998 as a baseline period, a target mean of 47.1 hospitalizations due to myocardial infarctions per 100,000 and a standard deviation of 2.8 per 100,000.The threshold for CUSUM was calculated as 1.18, yielding an average-run-length of 50 (dashed red line). An aberration, two standard deviations from baseline, was initially detected in January of 2000, with a CUSUM value of 1.37 and 51.5 myocardial infarction-related hospitalization per 100,000 stays (solid line).

Figure 2. Association between yearly prescriptions for rofecoxib and celecoxib and incidence of myocardial infarctions.

A) Scatter plot reveals the positive relationship between national prescriptions estimates for rofecoxib and celecoxib and hospitalizations due to myocardial infarction. Prescriptions for rofecoxib and celecoxib peaked in 2001 with 52,466,000. Incidence of stays due to myocardial infarction also peaked in 2001 with 62.3 hospitalizations per 10,000. B) Line graphs show the interrupted time series of myocardial infarction-related hospitalizations. Prescriptions for rofecoxib and celecoxib explained approximately 50.3 percent of the deviance in yearly variation of myocardial infarction related hospitalizations.

Figure 3. Association between yearly prescriptions for rofecoxib and celecoxib and mean age of patients hospitalized for myocardial infarctions.

Line graph showing a significant negative association between mean patient age and national prescription volume for rofecoxib and celecoxib (Spearman correlation, 0.67, P<0.05). Prescriptions for rofecoxib and celecoxib peaked in 2001 with 27,060,000 prescriptions dispensed nationally while mean age was 64.6, the lowest in nine years.