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

Yuji Oba, MD
JAMA. 2009;301(12):1223-1226. doi:10.1001/jama.2008.947
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To the Editor: The meta-analysis of inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease (COPD) by Dr Singh and colleagues1 successfully collected unpublished data and combined it with published studies. However, a 4-year randomized controlled trial involving 5993 patients (Understanding Potential Long-term Impacts on Function With Tiotropium [UPLIFT])2 that was published shortly after this meta-analysis showed no evidence of an increased risk of cardiovascular adverse events with the use of tiotropium. One possible explanation that should be considered for this discordance is publication bias, as might be suggested by a funnel plot.

I am also concerned that there may be errors in data entry and study inclusion in the meta-analysis. The incidence of serious cardiovascular events in the study by Wedzicha et al3 appears to have been 34 in the tiotropium group and 23 in the placebo group; the study by Singh et al used 23 and 13, respectively. The study by Donohue et al4 should have been excluded from the meta-analysis because Brusasco et al5 reported combined results of the study by Donohue and another unpublished study. Inclusion of both seems to have resulted in double counting of the data from Donohue et al.

AUTHOR INFORMATION

Financial Disclosures: None reported.

REFERENCES

Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis [published correction appears in JAMA. 2009;301(12):1227-1230].  JAMA. 2008;300(12):1439-1450
PubMedCrossRef
Tashkin DP, Celli B, Senn S,  et al; UPLIFT Study Investigators.  A 4-year trial of tiotropium in chronic obstructive pulmonary disease [published online ahead of print October 5, 2008].  N Engl J Med. 2008;359(15):1543-1554
PubMedCrossRef
Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA.INSPIRE Investigators.  The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide [published online ahead of print October 4, 2007].  Am J Respir Crit Care Med. 2008;177(1):19-26
PubMedCrossRef
Donohue JF, van Noord JA, Bateman ED,  et al.  A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.  Chest. 2002;122(1):47-55
PubMedCrossRef
Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD [published correction appears in Thorax. 2005;60(2):105].  Thorax. 2003;58(5):399-404
PubMedCrossRef

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Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis [published correction appears in JAMA. 2009;301(12):1227-1230].  JAMA. 2008;300(12):1439-1450
PubMedCrossRef
Tashkin DP, Celli B, Senn S,  et al; UPLIFT Study Investigators.  A 4-year trial of tiotropium in chronic obstructive pulmonary disease [published online ahead of print October 5, 2008].  N Engl J Med. 2008;359(15):1543-1554
PubMedCrossRef
Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA.INSPIRE Investigators.  The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide [published online ahead of print October 4, 2007].  Am J Respir Crit Care Med. 2008;177(1):19-26
PubMedCrossRef
Donohue JF, van Noord JA, Bateman ED,  et al.  A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol.  Chest. 2002;122(1):47-55
PubMedCrossRef
Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD [published correction appears in Thorax. 2005;60(2):105].  Thorax. 2003;58(5):399-404
PubMedCrossRef
March 25, 2009
Steven Kesten, MD; Inge Leimer, PhD; Michele Jara, PhD
JAMA. 2009;301(12):1223-1226.
March 25, 2009
Katherine E. Hodgin, MD; James P. Maloney, MD
JAMA. 2009;301(12):1223-1226.
March 25, 2009
Sonal Singh, MD, MPH; Yoon K. Loke, MBBS, MD; Curt D. Furberg, MD, PhD
JAMA. 2009;301(12):1223-1226.
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