The Effect of Defining Chronic Obstructive Pulmonary Disease by the Lower Limit of Normal of FEV1/FVC Ratio in Tiotropium Safety and Performance in Respimat Participants

Ann Am Thorac Soc. 2018 Feb;15(2):200-208. doi: 10.1513/AnnalsATS.201703-194OC.


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 (NCT01126437).

Keywords: airflow obstruction; disease exacerbation; mortality; tiotropium.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Age Factors
  • Aged
  • Bronchodilator Agents / administration & dosage
  • Bronchodilator Agents / adverse effects
  • Cardiovascular Diseases* / etiology
  • Cardiovascular Diseases* / mortality
  • Cardiovascular Diseases* / physiopathology
  • Disease Progression
  • Female
  • Forced Expiratory Volume / drug effects*
  • Humans
  • Lung / physiopathology
  • Male
  • Middle Aged
  • Outcome Assessment, Health Care
  • Pulmonary Disease, Chronic Obstructive* / complications
  • Pulmonary Disease, Chronic Obstructive* / diagnosis
  • Pulmonary Disease, Chronic Obstructive* / physiopathology
  • Pulmonary Disease, Chronic Obstructive* / therapy
  • Risk Factors
  • Survival Analysis
  • Tiotropium Bromide* / administration & dosage
  • Tiotropium Bromide* / adverse effects
  • Vital Capacity / drug effects*


  • Bronchodilator Agents
  • Tiotropium Bromide

Associated data