Reply

Authors


Reply

To the Editor:

We appreciate Dr. Boers' interest in our report. Table 1 provides the dosage information and results he requests. Calculating dosage from an observational cohort study is not straightforward. We calculated dosage by treating each prescription as a separate exposure period. Thus, if a patient's dosage escalated over time, successive prescriptions at higher dosages were considered separate exposure periods. This method accounts for the varying dosages during different periods of exposure and avoids mixing low- and high-dosage exposure periods, a methodologic flaw inherent in calculating an average daily dose.

Table 1. Cardiovascular events among users of coxibs, by daily dose
Drug, daily dosenMyocardial infarction or stroke
EventsPerson-yearsIncidence rate*Adjusted rate ratio (95% CI)
  • *

    Per 100 person-years.

  • Calculated from Cox proportional hazards models that included age, sex, race, hospitalizations, physician visits, number of other medications, nursing home residence, prior myocardial infarction, prior stroke, angina, congestive heart failure, peripheral vascular disease, revascularization procedures, diabetes, hypertension, use of a statin, use of clopidogrel, renal disease, rheumatoid arthritis, osteoarthritis, and malignancy. All models were stratified on the calendar year of the index date. 95% CI = 95% confidence interval.

Celecoxib26,3661,34211,76811.40.99 (0.92–1.07)
 ≤200 mg21,9569528,71010.90.89 (0.82–0.97)
 201–400 mg3,9973682,94612.50.89 (0.77–1.03)
 >400 mg4132211219.60.91 (0.50–1.65)
Rofecoxib17,9679126,74613.51.15 (1.06–1.25)
 ≤25 mg16,4357655,98112.81.15 (1.06–1.29)
 >25 mg1,53214776519.21.05 (0.81–1.37)
Valdecoxib3,06011298511.40.96 (0.78–1.17)
 ≤10 mg2,105555699.70.96 (0.78–1.17)
 >10 mg9555741613.70.74 (0.18–2.95)
Nonusers23,5321,84717,06710.8Reference

The lack of a dosage gradient in this study is somewhat surprising. We observed such a dosage gradient in a prior observational study of rofecoxib (Solomon DH, Schneeweiss S, Glynn RJ, Kiyota Y, Levin R, Mogun H, et al. Relationship between selective COX-2 inhibitors and acute myocardial infarction. Circulation 2004;109:2068–73). In addition, the Adenoma Prevention with Celecoxib study showed a clear dosage gradient between placebo and high-dose celecoxib (either 200 mg twice daily or 400 mg twice daily) (Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071–80). While we do not have a clear explanation for this apparent discrepancy, it is possible that there may have been channeling of high-risk patients away from higher-dose treatment in our study cohort. As well, with small sample sizes and relatively wide confidence intervals in the higher dose groups, we cannot exclude the possibility of a dosage gradient.

Daniel H. Solomon MD, MPH*, Jerry Avorn MD*, Til Sturmer MD, MPH*, Robert J. Glynn PhD, ScD*, Helen Mogun MS*, Sebastian Schneeweiss MD, ScD*, * Brigham and Women's Hospital, Boston, MA.

Ancillary