Annual rates of change in pre- vs. post-bronchodilator FEV1 and FVC over 4 years in moderate to very severe COPD

Abstract

While the slope of decline in FEV1 has traditionally been calculated from the post- rather than the pre-bronchodilator measurement in COPD interventional trials, it is not clear whether and to what extent these two slopes differ in symptomatic patients with COPD. Therefore, we used data from the 4-year UPLIFT trial of tiotropium 18 mcg QD vs. placebo to compare annual rates of change in pre- vs. post-bronchodilator FEV1 in 5041 patients with moderate to very severe COPD (mean FEV1 48% pred) in whom the post-bronchodilator FEV1 was measured after 4 inhalations of two different classes of short-acting inhaled bronchodilators at baseline and 1 month and every 6 months post-randomization over 4 years. Linear mixed effects models were used to estimate annual rates of decline in FEV1 and FVC pre- and post-bronchodilator in each treatment group separately, after adjusting for height, gender, smoking status, baseline % predicted FEV1 or FVC, and baseline acute % improvement in lung function. The slopes of the post-bronchodilator FEV1 and FVC were significantly steeper than the pre-bronchodilator slopes regardless of treatment arm (p < 0.001), while the estimated variances of the slopes were similar. Post-bronchodilator increases in FEV1 and FVC diminished progressively and significantly (p < 0.0001) over the 4-year trial, suggesting a possible explanation for the significant differences between the pre- and post-bronchodilator slopes. While the reasons for these differences are not completely clear, they are important to consider when assessing treatment effects on rates of decline in FEV1 and FVC.

Keywords: COPD; Post-bronchodilator; Slope of FEV(1) decline; UPLIFT.

Figure 1

Mean (± SE) observed values of pre- and post-bronchodilator FEV1 over 4 years in (A) the tiotropium group and (B) the placebo group.

Figure 2

Mean (± SE) observed values of pre- and post-bronchodilator FVC over 4 years in (A) the tiotropium group and (B) the placebo group.

Figure 3

Estimated slopes of annual decline in pre- and post-bronchodilator FEV1 in the tiotropium (A) and placebo (B) groups derived from the mixed effects model with adjustment for covariates over 4 years (solid lines) and the acute absolute increases in FEV1 (in ml) from the pre-bronchodilator value following bronchodilator administration at each time point except for the 1-month visit (dotted vertical arrows). The diminishing acute bronchodilator response over the 4 years of the trial appears to account for the steeper post-bronchodilator slope compared to the pre-bronchodilator slope.