Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial

Abstract

Background: Guidelines recommend inhaled corticosteroids (ICS) for patients with severe chronic obstructive pulmonary disease (COPD). Most COPD patients are managed in primary care and receive ICS long-term and irrespective of severity. The effect of withdrawing ICS from COPD patients in primary care is unknown.

Methods: In a pragmatic randomised, double-blind, placebo-controlled trial in 31 practices, 260 COPD patients stopped their usual ICS (median duration of use 8 years) and were allocated to 500 mcg fluticasone propionate twice daily (n = 128), or placebo (n = 132). Follow-up assessments took place at three monthly intervals for a year at the patients' practice. Our primary outcome was COPD exacerbation frequency. Secondary outcomes were time to first COPD exacerbation, reported symptoms, peak expiratory flow rate and reliever inhaler use, and lung function and health related quality of life.

Results: In patients randomised to placebo, COPD exacerbation risk over one year was RR: 1.11 (CI: 0.91-1.36). Patients taking placebo were more likely to return to their usual ICS following exacerbation, placebo: 61/128 (48%); fluticasone: 34/132 (26%), OR: 2.35 (CI: 1.38-4.05). Exacerbation risk whilst taking randomised treatment was significantly raised in the placebo group 1.48 (CI: 1.17-1.86). Patients taking placebo exacerbated earlier (median time to first exacerbation: placebo (days): 44 (CI: 29-59); fluticasone: 63 (CI: 53-74), log rank 3.81, P = 0.05) and reported increased wheeze. In a post-hoc analysis, patients with mild COPD taking placebo had increased exacerbation risk RR: 1.94 (CI: 1.20-3.14).

Conclusion: Withdrawal of long-term ICS in COPD patients in primary care increases risk of exacerbation shortens time to exacerbation and causes symptom deterioration. Patients with mild COPD may be at increased risk of exacerbation after withdrawal.

Trial registration: ClinicalTrials.gov NCT00440687.

Figure 1

Participant flow for the WISP trial. ICS = inhaled corticosteroids.

Figure 2

Kaplan-Meier curve for time to first COPD exacerbation.

Figure 3

Symptoms, change in peak expiratory flow rate (PEFR) and change in reliever inhaler use in fluticasone (F) and placebo (P) during study. Figures a) and b) show the proportion of patients in each drug group recording cough and wheeze on their diary card. Reporting of cough was significant between groups in first 3 months only: OR 1.95 (CI 1.16 to 3.29) P < 0.05. Wheeze was significant between groups for whole year: OR 1.83 (CI 1.06 to 3.18) P < 0.05. Figures c) and d) show mean change from baseline for PEFR and reliever inhaler use. Baseline for PEFR and reliever inhaler use was calculated from the mean value from day -8 to -1 prior to randomisation. PEFR was not significant between groups at 12 months: Mean difference 7.86 l/min (CI -1.45 to 17.17) P > 0.05. Reliever inhaler was significant in first month only: Mean difference 0.53 inh/day (CI 0.06 to 1.00) P < 0.05. (inh/day = inhalations of reliever inhaler per day).

Figure 4

Wheeze and reliever inhaler use in fluticasone (F) and placebo (P) groups at time of first COPD exacerbation (-8 to 28 days). Day 0 is the first day of exacerbation as defined in our methods section. Figure a) shows the proportion of patients with wheeze on each day for fluticasone and placebo groups. Reporting of wheeze was significant 28 days from onset of exacerbation: OR 1.85, (CI 1.35 to 2.53) P < 0.05. Figure b) show mean change from baseline for daily reliever inhaler use in each group. Baseline reliever inhaler use was calculated from the mean value from day -14 to -8 prior to onset of exacerbation. Difference in reliever inhaler use between groups was significant day -7 to 28: Mean difference 0.44 inh/day (CI 0.33 to 0.55) P < 0.01. (inh/day = inhalations of reliever medication per day).

Figure 5

Change in forced expiratory volume in one second (FEV₁) at three monthly assessments in study. Baseline FEV₁ was value at randomisation. Mean difference for FEV₁ (mls) at 12 months: fluticasone -41mls, placebo -64mls (P = 0.44).