LSU Journal Club Withdrawal of Inhaled Glucocorticoids and

LSU Journal Club Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD WISDOM study H. Magnussen MD, et al. Nisha Loganantharaj, PGY 1 April 21, 2016

Background • Chronic obstructive pulmonary disease (COPD) exacerbations are associated with an accelerated decline in lung function and health status • Treatment with inhaled glucocorticoids and long acting ßagonist (LABA) reduces exacerbation rate – Recommended in pts with severe COPD or hx of frequent exacerbations • Long acting muscarinic antagonists (LAMAs) have also been shown to prevent exacerbations

Background • Concern for clinical benefit and long term safety of inhaled corticosteroids in COPD patients • Benefit of inhaled glucocorticoids in a treatment regimen that includes both classes of long-acting bronchodilators has not been studied in an adequately powered study

Background • LABAs and LAMAs improve airflow and decreased lung hyperventilation • Combined bronchodilator treatment improves lung function compared to single bronchodilator therapy and could help prevent exacerbations in COPD patient

Research question • Does continuation of inhaled glucocorticoids significantly reduce the risk of subsequent COPD exacerbations in conjunction with combination LAMA and LABA therapy?

Study Design • Randomized, double-blinded, parallel-group active control study. • 200 study centers • 2485 patients in 6 week period received: – 18 µg triotropium daily; 50 µg salmeterol xinafoate BID; 500 µg fluticasone propionate BID • Double blind randomization – Two groups (1: 1 ratio)

Study Design • Group 1: Glucocorticoid continuation – Continued tiotropium, salmeterol and fluticosone at same doses for duration of 52 week study period • Group 2: Glucocorticoid withdrawal – Continued tiotropium and salmeterol – Stepwise reduction in fluticasone every 6 weeks

Study Design

Study Subjects • Inclusion criteria: – Age ≥ 40 – Current or ex-smokers (≥ 10 pack years) – Dx of severe/very severe COPD – Hx of at least one documented exacerbation during 12 month period prior to initial screening visit

Study Subjects • Exclusion criteria: – Presence of ds other than COPD that may compromise study – Current clinical dx of asthma – Hx of pulmonary resection – Unstable or life threatening cardiac arrhythmia – Clinical dx of bronchiectasis – Respiratory tract infection or COPD exacerbation occurring within 6 weeks prior to initial screening – Hx of MI within 3 months prior to initial screening – Hospitalization for cardiac failure within past year

Study Subjects • 3, 426 patients screened, 2, 488 enrolled – 1244 glucocoarticoid continuation group, 1244 glucocorticoid withdrawal group – Completed study: 1016 glucocorticoid continuation, 1011 glucocorticoid withdrawal • • • Mean age 64 82. 5% Male, 17. 5% Female Former smoker 66. 6% Duration of COPD 7. 87 yr 61. 2% FEV 1 30 to 49% of predicted value GOLD 3

Study Subjects

Study design • Primary endpoint: – Time to moderate or severe COPD exacerbation during 12 month study • Secondary end points: – Number of moderate or severe COPD exacerbations – Change from baseline in lung fxn – Assessment of health status; SGRQ – Asessement of dyspnea; m. MRC – Spirometric measurements

Results: Exacerbations

Results: FEV 1

Results: Safety

Conclusions • Following clinical stability, the stepwise withdrawal of glucocorticoids in patients with severe COPD exacerbations did not increase the risk of recurrent exacerbations in patients receiving dual tiotropium and salmeterol therapy relative to individuals in which glucocorticoid therapy was continued • No significant between-group difference in the safety profile.

Conclusions • Following complete withdrawal of glucocorticoids, small but significant between-group difference in FEV 1. – Does not appear to be associated with exacerbations – Apparent after final step of withdrawal

Limitations • Study population – Mainly consisted of white men – No significant difference in outcome on the basis of sex • Observation time – 9 months

Future Research • Longer study? – Further assess safety profile and lung function