Figures
- FIGURE 1
Study flow chart. Tie-COPD: Tiotropium in Early-Stage COPD (chronic obstructive pulmonary disease).
- FIGURE 2
Mean forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) before and after bronchodilator use. a) Tiotropium resulted in a significantly higher FEV1 both before and after bronchodilator use than placebo at each visit from month 1 to month 25 (ranges of mean differences 0.10–0.2 L in FEV1 before bronchodilator use and 0.07–0.12 L in FEV1 after bronchodilator use; p<0.001 for all comparisons). b) FVC before bronchodilator use was significantly higher in the tiotropium group than in the placebo group at each visit from month 1 to month 24 (ranges of mean differences 0.10–0.19 L) and there was significant difference of 0.09 L in FVC after bronchodilator use only at month 6 between the two groups (p<0.05 for all comparisons). However, there was no significant difference in FEV1 and FVC either before or after bronchodilator use between the two groups at each visit of tiotropium withdrawal from 1 to 3 years (ranges of mean differences 0.04–0.08 L in FEV1 both before and after bronchodilator use; 0.03–0.12 L in FVC before bronchodilator use; and 0.02–0.09 L in FVC after bronchodilator use; p>0.05 for all comparisons). Bars indicate ±1 se.
Tables
- TABLE 1
Characteristics of patients at enrolment and after withdrawal of tiotropium#
Placebo Tiotropium p-value¶ Subjects n 126 136 At enrolment (Tie-COPD) Age years 62.4±8.3 62.4±7.4 0.98 Male 104 (82.5) 120 (88.2) 0.19 BMI kg·m−2 21.8±3.2 22.2±3.4 0.35 Smoking status 0.62 Never-smokers 28 (22.2) 27 (19.9) Current smokers 60 (47.6) 73 (53.7) Ex-smokers 38 (30.2) 36 (26.5) Smoking index pack-years 48.1±26.7 44.7±21.9 0.52 Duration of COPD days 179±436 125±275 0.97 Respiratory disease 2 (1.6) 4 (2.9) 0.69 Previous respiratory medications 13 (10.3) 16 (11.8) 0.71 Baseline before bronchodilator spirometry FEV1 L 1.88±0.58 1.97±0.55 0.22 FEV1 % pred 77.2±19.5 77.6±18.3 0.89 FVC L 3.17±0.77 3.27±0.76 0.29 FEV1/FVC ratio 59.0±8.4 60.0±7.9 0.32 Baseline after bronchodilator spirometry FEV1 L 2.00±0.55 2.11±0.52 0.11 FEV1 % pred 82.2±17.9 83.0±16.6 0.68 FVC L 3.26±0.76 3.38±0.72 0.18 FEV1/FVC ratio 61.2±7.6 62.2±6.9 0.25 Reversibility+ 22 (17.5) 29 (21.3) 0.43 GOLD stage§ 0.60 I 72 (57.1) 82 (60.3) II 54 (42.9) 54 (39.7) CAT scoreƒ Mean score 4.0±3.3 4.5±4.2 0.53 Distribution 0.22 <10 119 (94.4) 123 (90.4) ≥10 7 (5.6) 13 (9.6) mMRC score## Mean score 0.60±0.66 0.50±0.62 0.19 Distribution 0.39 <2 114 (90.5) 127 (93.4) ≥2 12 (9.5) 9 (6.6) CCQ score¶¶ 0.65±0.53 0.66±0.56 0.99 At follow-up (post-Tie-COPD) Respiratory medications 0.35 Use of respiratory medications 41 (32.5) 37 (27.2) No respiratory medications 85 (67.5) 99 (72.8) Bronchodilators 0.54 Use of bronchodilators 27 (21.4) 25 (18.4) No bronchodilators 99 (78.6) 111 (81.6) Smoking status 0.73 Never-smokers 28 (22.2) 25 (18.4) Current smokers 59 (46.8) 68 (50.0) Quit smoking 39 (31.0) 43 (31.6) Data are presented as mean±sd or n (%), unless otherwise stated. Percentages may not sum to 100 because of rounding. Tie COPD: Tiotropium in Early COPD (chronic obstructive pulmonary disease); BMI: body mass index; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Lung Disease; CAT: COPD Assessment Test; mMRC: modified Medical Research Council; CCQ: Clinical COPD Questionnaire. #: there were no significant between-group differences for characteristics at enrolment. The analysis set included patients who underwent both Tie-COPD and post-Tie-COPD follow-up and had at least one available spirometric data measurement after bronchodilator use at Tie-COPD and at least one measurement at post-Tie-COPD follow-up; ¶: p-values for continuous variables were calculated using t-test or the Wilcoxon rank-sum test, and p-values for categorical variables were calculated using the Chi-squared test; +: defined as an FEV1 value obtained after bronchodilator use that increased by ≥200 mL and by ≥12% from the measurement obtained before bronchodilator use; §: the GOLD staging system is used to assess the severity of lung disease. Stages range from 1 to 4, with higher stages indicating more severe disease. Stage 1 (mild disease) is defined as FEV1 ≥80% of the predicted value, and stage 2 (moderate disease) as FEV1 50–79% pred; ƒ: scores on the CAT range from 0 to 40, with higher scores indicating more severe disease; ##: the mMRC dyspnoea scale ranges from 0 to 4, with higher scores indicating more severe breathlessness; ¶¶: CCQ scores range from 0 to 6, with higher scores indicating worse clinical control.
- TABLE 2
Changes in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) before and after bronchodilator use after withdrawing tiotropium in early chronic obstructive pulmonary disease (COPD)#
Placebo Tiotropium Difference (tiotropium − placebo)¶ p-value Subjects n 126 136 FEV1 L Before bronchodilator use Month 25 1.79±0.02 1.89±0.02 0.10 (0.04–0.16) 0.0018 Month 36 1.71±0.04 1.78±0.04 0.07 (−0.02–0.15) 0.12 Month 48 1.70±0.03 1.74±0.03 0.04 (−0.03–0.11) 0.23 Month 60 1.69±0.04 1.77±0.04 0.08 (−0.04–0.19) 0.18 After bronchodilator use Month 25 1.92±0.02 1.99±0.02 0.07 (0.01–0.13) 0.0145 Month 36 1.81±0.04 1.85±0.04 0.04 (−0.04–0.12) 0.31 Month 48 1.84±0.03 1.85±0.03 0.008 (−0.06–0.07) 0.79 Month 60 1.80±0.03 1.84±0.03 0.04 (−0.05–0.13) 0.36 FVC L Before bronchodilator use Month 25 3.02±0.03 3.10±0.04 0.08 (−0.01–0.18) 0.09 Month 36 2.93±0.06 2.99±0.06 0.06 (−0.08–0.19) 0.41 Month 48 2.91±0.05 2.93±0.05 0.03 (−0.09–0.14) 0.67 Month 60 2.89±0.07 3.01±0.07 0.12 (−0.07–0.30) 0.21 After bronchodilator use Month 25 3.13±0.03 3.17±0.03 0.04 (−0.04–0.12) 0.36 Month 36 3.03±0.05 3.06±0.05 0.02 (−0.84–0.13) 0.66 Month 48 3.10±0.05 3.07±0.05 −0.02 (−0.13–0.08) 0.67 Month 60 3.00±0.06 3.10±0.06 0.09 (−0.06–0.26) 0.23 Data are presented as mean±se, unless otherwise stated. #: values were measured from month 36 until the end of the study (follow-up from 36 to 60 months after withdrawing tiotropium in early COPD). Multiple linear regression was adopted for each follow-up. For each follow-up visit, the measured value was the dependent variable, and covariates included the individual baseline value, smoking status across the whole follow-up, bronchiectasis status, treatment allocation and participating centre as covariates; ¶: the difference was calculated as the value in the tiotropium group minus the value in the placebo group.
- TABLE 3
Annual decline in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) before and after bronchodilator use after withdrawing tiotropium in early chronic obstructive pulmonary disease (COPD)#
Decline per year p-value Placebo Tiotropium Difference (95% CI)¶ Subjects n 126 136 FEV1 mL Before bronchodilator use 31±21 21±20 10 (−47–67) 0.73 After bronchodilator use 68±16 48±16 20 (−24–64) 0.37 FVC mL Before bronchodilator use 40±35 26±33 14 (−80–107) 0.77 After bronchodilator use 59±31 23±29 36 (−46–118) 0.39 Data are presented as mean±se, unless otherwise stated. #: values were measured from month 36 until the end of the study (follow-up from 36 to 60 months after withdrawing tiotropium in early COPD). Multiple linear regression was adopted for each follow-up. For each follow-up visit, the measured value was the dependent variable, and covariates included the individual baseline value, baseline smoking status, treatment allocation and participating centre. Additionally, for 36–60 months, the p-value was computed by using the individual baseline value, smoking status across the whole follow-up, bronchiectasis status, treatment allocation and participating centre as covariates; ¶: the difference was calculated as the value in the placebo group minus the value in the tiotropium group.
- TABLE 4
Summary of acute exacerbations of chronic obstructive pulmonary disease (COPD) after withdrawing tiotropium in early COPD#
Placebo Tiotropium Relative risk for tiotropium versus placebo (95% CI) p-value Subjects n 126 136 Exacerbations per patient-year¶ Total 0.16±0.03 0.11±0.02 0.69 (0.42–1.13) 0.14 Mild 0.06±0.02 0.03±0.01 0.42 (1.14–1.26) 0.12 Moderate 0.06±0.01 0.06±0.01 0.98 (0.55–1.77) 0.96 Severe 0.04±0.01 0.02±0.01 0.65 (0.27–1.58) 0.34 Of moderate or worse severity 0.10±0.02 0.08±0.01 0.86 (0.54–1.38) 0.52 Data are presented as mean±se, unless otherwise stated. #: exacerbation frequency per patient-year was referred to as the number of exacerbations for a single patient per year; ¶: the relative risks in these categories were calculated using of Poisson regression corrected for treatment exposure and overdispersion.
Supplementary Material
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Supplementary tables 00175-2018_supp
