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Tiotropium discontinuation in patients with early-stage COPD: a prospective observational cohort study

Chenglong Li, Yumin Zhou, Sha Liu, Mengning Zheng, Jinzhen Zheng, Huanhuan Peng, Zhishan Deng, Nanshan Zhong, Pixin Ran
ERJ Open Research 2019 5: 00175-2018; DOI: 10.1183/23120541.00175-2018
Chenglong Li
1The State Key Laboratory of Respiratory Disease, National Clinical Researcher Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
4These authors contributed equally to this study
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Yumin Zhou
1The State Key Laboratory of Respiratory Disease, National Clinical Researcher Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
4These authors contributed equally to this study
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Sha Liu
1The State Key Laboratory of Respiratory Disease, National Clinical Researcher Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
2Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital of the University of South China, Hunan, China
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Mengning Zheng
1The State Key Laboratory of Respiratory Disease, National Clinical Researcher Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
3Department of Respiratory and Critical Care Medicine, Guizhou Provincial People's Hospital, Guiyang, China
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Jinzhen Zheng
1The State Key Laboratory of Respiratory Disease, National Clinical Researcher Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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Huanhuan Peng
1The State Key Laboratory of Respiratory Disease, National Clinical Researcher Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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Zhishan Deng
1The State Key Laboratory of Respiratory Disease, National Clinical Researcher Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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Nanshan Zhong
1The State Key Laboratory of Respiratory Disease, National Clinical Researcher Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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Pixin Ran
1The State Key Laboratory of Respiratory Disease, National Clinical Researcher Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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  • ORCID record for Pixin Ran
  • For correspondence: pxran@gzhmu.edu.cn
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  • FIGURE 1
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    FIGURE 1

    Study flow chart. Tie-COPD: Tiotropium in Early-Stage COPD (chronic obstructive pulmonary disease).

  • FIGURE 2
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    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

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  • TABLE 1

    Characteristics of patients at enrolment and after withdrawal of tiotropium#

    PlaceboTiotropiump-value¶
    Subjects n126136
    At enrolment (Tie-COPD)
     Age years62.4±8.362.4±7.40.98
     Male104 (82.5)120 (88.2)0.19
     BMI kg·m−221.8±3.222.2±3.40.35
     Smoking status0.62
      Never-smokers28 (22.2)27 (19.9)
      Current smokers60 (47.6)73 (53.7)
      Ex-smokers38 (30.2)36 (26.5)
     Smoking index pack-years48.1±26.744.7±21.90.52
     Duration of COPD days179±436125±2750.97
     Respiratory disease2 (1.6)4 (2.9)0.69
     Previous respiratory medications13 (10.3)16 (11.8)0.71
     Baseline before bronchodilator spirometry
      FEV1 L1.88±0.581.97±0.550.22
      FEV1 % pred77.2±19.577.6±18.30.89
      FVC L3.17±0.773.27±0.760.29
      FEV1/FVC ratio59.0±8.460.0±7.90.32
     Baseline after bronchodilator spirometry
      FEV1 L2.00±0.552.11±0.520.11
      FEV1 % pred82.2±17.983.0±16.60.68
      FVC L3.26±0.763.38±0.720.18
      FEV1/FVC ratio61.2±7.662.2±6.90.25
     Reversibility+22 (17.5)29 (21.3)0.43
     GOLD stage§0.60
      I72 (57.1)82 (60.3)
      II54 (42.9)54 (39.7)
     CAT scoreƒ
      Mean score4.0±3.34.5±4.20.53
      Distribution0.22
       <10119 (94.4)123 (90.4)
       ≥107 (5.6)13 (9.6)
     mMRC score##
      Mean score0.60±0.660.50±0.620.19
      Distribution0.39
       <2114 (90.5)127 (93.4)
       ≥212 (9.5)9 (6.6)
     CCQ score¶¶0.65±0.530.66±0.560.99
    At follow-up (post-Tie-COPD)
     Respiratory medications0.35
      Use of respiratory medications41 (32.5)37 (27.2)
      No respiratory medications85 (67.5)99 (72.8)
     Bronchodilators0.54
      Use of bronchodilators27 (21.4)25 (18.4)
      No bronchodilators99 (78.6)111 (81.6)
     Smoking status0.73
      Never-smokers28 (22.2)25 (18.4)
      Current smokers59 (46.8)68 (50.0)
      Quit smoking39 (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)#

      PlaceboTiotropiumDifference (tiotropium − placebo)¶p-value
      Subjects n126136
      FEV1 L
       Before bronchodilator use
        Month 251.79±0.021.89±0.020.10 (0.04–0.16)0.0018
        Month 361.71±0.041.78±0.040.07 (−0.02–0.15)0.12
        Month 481.70±0.031.74±0.030.04 (−0.03–0.11)0.23
        Month 601.69±0.041.77±0.040.08 (−0.04–0.19)0.18
       After bronchodilator use
        Month 251.92±0.021.99±0.020.07 (0.01–0.13)0.0145
        Month 361.81±0.041.85±0.040.04 (−0.04–0.12)0.31
        Month 481.84±0.031.85±0.030.008 (−0.06–0.07)0.79
        Month 601.80±0.031.84±0.030.04 (−0.05–0.13)0.36
      FVC L
       Before bronchodilator use
        Month 253.02±0.033.10±0.040.08 (−0.01–0.18)0.09
        Month 362.93±0.062.99±0.060.06 (−0.08–0.19)0.41
        Month 482.91±0.052.93±0.050.03 (−0.09–0.14)0.67
        Month 602.89±0.073.01±0.070.12 (−0.07–0.30)0.21
       After bronchodilator use
        Month 253.13±0.033.17±0.030.04 (−0.04–0.12)0.36
        Month 363.03±0.053.06±0.050.02 (−0.84–0.13)0.66
        Month 483.10±0.053.07±0.05−0.02 (−0.13–0.08)0.67
        Month 603.00±0.063.10±0.060.09 (−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 yearp-value
        PlaceboTiotropiumDifference (95% CI)¶
        Subjects n126136
        FEV1 mL
         Before bronchodilator use31±2121±2010 (−47–67)0.73
         After bronchodilator use68±1648±1620 (−24–64)0.37
        FVC mL
         Before bronchodilator use40±3526±3314 (−80–107)0.77
         After bronchodilator use59±3123±2936 (−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#

          PlaceboTiotropiumRelative risk for tiotropium versus placebo (95% CI)p-value
          Subjects n126136
          Exacerbations per patient-year¶
           Total0.16±0.030.11±0.020.69 (0.42–1.13)0.14
           Mild0.06±0.020.03±0.010.42 (1.14–1.26)0.12
           Moderate0.06±0.010.06±0.010.98 (0.55–1.77)0.96
           Severe0.04±0.010.02±0.010.65 (0.27–1.58)0.34
           Of moderate or worse severity0.10±0.020.08±0.010.86 (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.

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          Tiotropium discontinuation in patients with early-stage COPD: a prospective observational cohort study
          Chenglong Li, Yumin Zhou, Sha Liu, Mengning Zheng, Jinzhen Zheng, Huanhuan Peng, Zhishan Deng, Nanshan Zhong, Pixin Ran
          ERJ Open Research Feb 2019, 5 (1) 00175-2018; DOI: 10.1183/23120541.00175-2018

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          Tiotropium discontinuation in patients with early-stage COPD: a prospective observational cohort study
          Chenglong Li, Yumin Zhou, Sha Liu, Mengning Zheng, Jinzhen Zheng, Huanhuan Peng, Zhishan Deng, Nanshan Zhong, Pixin Ran
          ERJ Open Research Feb 2019, 5 (1) 00175-2018; DOI: 10.1183/23120541.00175-2018
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