Boehringer Ingelheim GmbH, Medical Affairs, Ingelheim am Rhein, Germany, 1UZ St Rafael, Biostatistical Centre, Leuven, Belgium, 2Medizinische Hochschule Hannover, Abteilung Rheumatologie, Hannover, Germany
Correspondence to F. Degner. E-mail: degner{at}ing.boehringer-ingelheim.com
SIR, Both papers by Layton et al. [1, 2] address an important aspect of providing evidence on the safety of new drugs under real prescribing conditions. The papers report on the results of three prescription-event monitoring (PEM) studies and compare the incidence rates of selected gastrointestinal (GI) events of meloxicam with those of both rofecoxib and celecoxib. The activities to analyse such data from the actual prescribing setting need to be applauded, in particular due to the inherent difficulties in such an uncontrolled setting to control for multiple potential bias. The authors also address these difficulties in concluding that the results of their studies are only useful if evaluated together with results from other studies.
We feel it is important to highlight some potential biases that have not been addressed in the three studies which refer to data collected for meloxicam between December 1996 and March 1997 while data from cohorts of rofecoxib and celecoxib were collected between 1999 and 2000.
The compilation of the overall findings from both studies seems to show similar crude incidence rate estimates for upper GI complications (0.730.90% per yr) obtained for the three drugs monitored. For both the symptomatic upper GI events and the complicated upper GI conditions the KaplanMeier estimates showed no difference in both studies in the log rank tests between meloxicam and celecoxib as well as between meloxicam and rofecoxib (P = 0.61, P = 0.30 and P = 0.85, P = 0.87 respectively). Likewise similar crude rate estimates for those aged between 60 and 79 yr (0.60.8% per yr) and those aged 80+ yr (22.5% per yr) were observed, showing the well-known effect of age as a risk factor for GI complications. The estimates of crude incidence rates for upper GI complications for patients with another well-known risk factor, a history of upper GI problems, are also similar between drugs ranging from 0.91.1% per yr (Table 1).
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Another problem is the significant number of missing values, especially regarding age and NSAID history. The authors performed a sensitivity analysis by leaving out more patients (retaining only those patients with no missing value anywhere) and show that the relative risk (RR) does not vary too much. However, this does not tell us anything about the validity of their approach. Indeed, it could well be possible that the authors have performed an unadjusted analysis, found no significant RR and then continued regressing on more covariates (until they found a significant result?). Thus, it seems odd to us to conclude from their exercise that the significant RR was not generated because of missing values. Indeed, the significant RR of 0.56 for celecoxib versus meloxicam can still be the result of a selection bias because the subgroup upon which this significant RR is based is probably not a random sample of the original patient population.
We wonder how the results would look if one were to take the above factors into consideration when performing statistical analyses.
F. Degner is an employee of Boehringer Ingelheim. E. Lesaffre has collaborated with B.I. in various projects. H. Zeidler has received speakers honoraria from Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Pharmacia and Novartis.
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