January 2015 Tucson Pulmonary Journal Club: Withdrawal of Inhaled Glucocorticoids in COPD

Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285-94. [CrossRef] [PubMed]

GOLD guidelines recommend various combinations of inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic agonists (LAMA) to treat patients with chronic obstructive pulmonary disease (COPD) who are at high risk of exacerbation.  A substantial portion of patients are ultimately prescribed triple-therapy at some point. The WISDOM trial examined the risk of exacerbation among patients taking triple therapy who were subsequently weaned from their ICS treatment.

The present WISDOM trial was a randomized, double-blind, non-inferiority trial sponsored by Boehringer Ingelheim Pharma. Over 4 years, approximately 2500 participants in 23 non-US countries with severe or very severe COPD were randomized. Participants were eligible if they were >40 years of age, were current or former smokers with ≥10 pack-year history, and had at least one exacerbation within the year prior to screening. Numerous exclusion criteria included significant comorbidity, prior lung resection, asthma or bronchiectasis, chronic oxygen use, oral steroid requirement, recent exacerbation, respiratory tract infection, or pulmonary rehabilitation. The study had 90% power to evaluate a pre-specified non-inferiority margin of 1.20 for the upper limit of the 95% confidence interval for the hazard ratio.

All participants received an initial 6 week treatment with fluticasone 500 mcg BID, salmeterol 50 mcg BID, and tiotropium 18 mcg daily. Based on random assignment, participants either continued triple therapy or had their fluticasone withdrawn in a step-wise fashion. The primary outcome was the time to first moderate or severe COPD exacerbation during the 52 week study period. Eighty-three percent of participants were men, the overall mean age was 64 years, and the mean FEV₁ was 0.93 liters (33% of predicted). Approximately 40% were receiving triple therapy prior to enrollment. Approximately 20% of participants did not complete the study.

The non-inferiority margin was confirmed with a hazard ratio of 1.06 (CI_95% 0.94 - 1.19). The mean reduction in FEV₁ for the ICS withdrawal group was 38 mL greater than the reduction for the control group at week 18, and this difference increased to 43 mL by the end of the study (p<0.001). The difference in the St. George’s Respiratory Questionnaire (SGRQ) score were statistically significant at week 52, an increase of 1.15 in the withdrawal group vs. decrease of 0.07 in the continuation group (p = 0.047). Adverse events did not differ among the two groups.

The results suggest that gradual withdrawal of ICS from a triple therapy regimen is not associated with a meaningfully increased risk of exacerbation among patients with moderate-to-severe COPD. However, there were statistically significant, but perhaps not clinically meaningful, deterioration in FEV₁ and SGRQ scores. Strengths of this study included a large participant population, a year-long follow-up, and use of clinically relevant and patient-centered outcomes. While the study was conducted in many countries, most participants were white and male. The homogeneity of this group makes it difficult to generalize to other patient groups. Patients who had no exacerbations in the prior year (arguably the group most appropriate to step-down therapy) were not included. It also does not provide information on the safety of abrupt withdrawal of ICS. The long-term consequences of the small reductions in FEV₁ and health status are uncertain. For patients intolerant to or reluctant to consider ICS treatment, dual LABA and LAMA treatment appears to yield clinically similar outcomes.

Candy Wong MD, Cristine Berry MD and Joe Gerald PhD

University of Arizona

Tucson, AZ

Reference as: Wong C, Berry C, Gerald J. January 2015 Tucson pulmonary journal club: withdrawal of inhaled glucocorticoids in COPD. Southwest J Pulm Crit Care. 2015;10(2):79-80. doi: http://dx.doi.org/10.13175/swjpcc019-15 PDF

November 2012 Pulmonary Journal Club

Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA 2012;308:987-97. Full Text

No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. The authors compared adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms in 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy. There were no significant differences in time to treatment failure, the primary end point.

This study was designed to be a superiority study to show that one approach was superior to another. Although these 3 strategies did not demonstrate a difference, we cannot conclude noninferiority or equivalence. The absence of superiority is not the same as equivalence. There were few minority patients and about 17% of the patients dropped out of the study.

Based on this trial it seems unlikely that exhaled nitric oxide adds much to asthma management in patients with mild persistent asthma. It remains to be seen whether patients with moderate or severe asthma might benefit from a biomarker approach such as exhaled nitric oxide.

 Richard A. Robbins, MD

Reference as: Robbins RA. November 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;5: 268. PDF