1Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom2Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany3Boehringer Ingelheim Pharma Ltd, Bracknell, United Kingdom4Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; and5Johns Hopkins University School of Medicine, Baltimore, Maryland
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Rationale:There is continuing debate about whether to define airflow obstruction by a post-bronchodilator ratio of forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) below 0.70, or by ratio values falling below the age-dependent lower limit of normal (LLN) derived from general population data.Objectives:To determine whether using the LLN criterion affects the classification and outcomes of patients previously defined as having chronic obstructive pulmonary disease by the fixed FEV1/FVC ratio.Methods:We applied the LLN definition to pooled data from the Tiotropium Safety and Performance in Respimat study that used the fixed FEV1/FVC ratio for the clinical diagnosis of chronic obstructive pulmonary disease.Results:A total of 17,072 patients were analyzed; of these, 1,807 (10.6%) patients had a ratio greater than or equal to LLN. Patients with a ratio greater than or equal to LLN had similar risks of death from any cause and fatal major adverse cardiovascular (CV) event as those below LLN. Patients with a ratio below LLN had a significantly lower risk of major adverse CV events (hazard ratio = 0.69; 95% confidence interval [CI] = 0.55-0.86; P = 0.001), and had significantly greater risks of moderate to severe exacerbation (rate ratio = 1.48; 95% CI = 1.36-1.61; P < 0.0001) and severe exacerbation (rate ratio = 2.01; 95% CI = 1.68-2.40; P < 0.0001) when compared with patients greater than or equal to LLN. Study outcomes by treatment arm (5 μg tiotropium Respimat vs. 18 μg HandiHaler) were comparable.Conclusions:Using the LLN to define airflow obstruction would have excluded patients in the Tiotropium Safety and Performance in Respimat study with a higher risk of nonfatal major adverse CV events and a lower risk of exacerbation; study outcomes by treatment arm (2.5 μg/5 μg tiotropium Respimat vs. 18 μg HandiHaler) remained similar.Clinical trial registered with www.clinicaltrials.gov (NCT01126437).