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March 25, 2009

Risk of Major Adverse Cardiovascular Events With Inhaled Anticholinergics in Patients With Chronic Obstructive Pulmonary Disease—Reply

JAMA. 2009;301(12):1223-1226. doi:10.1001/jama.2008.951

In Reply: We agree with Dr Oba about the uncertainty regarding published articles about tiotropium. The study by Brusasco et al (reference 24 in our article) and Casaburi et al (2002) (reference 19) reported trial findings that had already been published, but without clearly acknowledging the respective earlier publications (Donahue et al [reference 25] and Casaburi et al (2000) [reference 23]), thus apparently representing duplicate publication. We have updated our analyses excluding the earlier data, and also have corrected a data extraction error from the study by Chan et al (reference 22). The complete revised results appear as a Correction in this issue of JAMA (see p 1227-1230), but the corrected estimates do not change the direction, magnitude, or statistical significance of the relative risk (RR) estimates for the primary outcome of myocardial infarction, stroke, and cardiovascular death (RR, 1.60; 95% confidence interval [CI], 1.22-2.10; P < .001); the individual end points of myocardial infarction (RR, 1.52 [95% CI, 1.04-2.22]; P = .03), stroke (RR, 1.46 [95% CI, 0.81-2.62]; P = .20), or cardiovascular death (RR, 1.92 [95% CI, 1.23-3.00]; P = .004); or the secondary outcome of all-cause mortality (RR, 1.29 [95% CI, 1.00-1.65]; P = .05). Oba assumes that funnel plot asymmetry is caused by publication bias, but it is more likely due to difficulties in detecting adverse events in small trials.1 The solution to publication bias lies not in asymmetry tests but in performing thorough searches and retrieving unpublished information from US Food and Drug Administration documents and company reports, as we have done.

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