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Published ahead of print on January 26, 2006, doi:10.1164/rccm.200508-1338PP

Am. J. Respir. Crit. Care Med., Volume 173, Number 8, April 2006, 842-846

A more recent version of this article appeared on April 15, 2006
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Submitted on August 29, 2005
Accepted on January 25, 2006

Statistical Treatment of Exacerbations in Therapeutic Trials of COPD

Samy Suissa1*

1 Division of Clinical Epidemiology, McGill University, Montreal, Quebec, Canada

* To whom correspondence should be addressed. E-mail: samy.suissa{at}clinepi.mcgill.ca.

Randomized trials and a meta-analysis suggesting that inhaled corticosteroids reduce exacerbation rates in patients with COPD show major discrepancies that may be due to different approaches to data analysis. These trials used statistical techniques that were either weighted or unweighted for follow-up time, with P-values and confidence intervals estimated with or without accounting for between-patient variability in exacerbation rates. We illustrate the validity of these methods using data from a cohort of 5,454 COPD patients structured to emulate a randomised trial. The "reference" group was defined as patients with a history of exacerbations prior to cohort entry (n=1,137) while the "treated" group included an equal number (n=1,137) of patients with no prior exacerbation. Random samples of 100 and 200 subjects were selected three times from each of two groups to further illustrate the variability in the findings. Exacerbations during follow-up were identified from prescriptions for systemic antibiotics. The correct rate ratio of 0.75 estimated by the weighted approach was underestimated as 0.57 by the unweighted approach. When the weighted approach did not, however, also account for between-patient variability, the P-value was greatly underestimated (example: rate ratio 0.79; P=0.0007 instead of P=0.12) and confidence intervals were much narrower than after properly accounting for this variability. In conclusion, the reports from randomized trials and the meta-analysis that inhaled corticosteroids reduce COPD exacerbation rates are the result of improper statistical analysis techniques. The only two studies that used the correct statistical approach found insignificant effects with these drugs.
Key words: Data analysis; biases; drug effectiveness; databases; methods;




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