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 Based on random assignment, participants either continued triple therapy or had their fluticasone withdrawn in a step-wise fashion.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

September 2012 Pulmonary Journal Club

Dr. Mathew was away this month and we reviewed 4 articles.

Kelly HW, Sternberg AL, Lescher R, Fuhlbrigge AL, Williams P, Zeiger RS, Raissy HH, Van Natta ML, Tonascia J, Strunk RC; CAMP Research Group. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012;367:904-12.

The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children but it is unclear whether the child is permanently shortened or attains a normal adult height. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. The authors measured adult height in 943 of 1041 participants (90.6%). Mean adult height was 1.2 cm lower the budesonide group than in the placebo group (P = 0.001) A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height. This article is somewhat reassuring. Although there was a reduction in adult height, the decrease was minimal and not progressive or cumulative.

Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med 2012;367:913-21.

Exacerbations of chronic obstructive pulmonary disease (COPD) are major causes of morbidity and mortality in COPD. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations. The authors measured pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) using CT scanning. Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; P<0.001). This is useful information that is biologically logical. Although performing a CT scan solely to measure a PA:A ratio is unwarranted, detection of an increased ratio might prompt one to consider therapies that reduce exacerbations such as long-acting bronchodilators and/or chronic antibiotic therapy.

Peters-Golden M, Klinger JR, Carson SS; for the ATS Research Advocacy Committee. The case for increased funding for research in pulmonary and critical care. Am J Respir Crit Care Med. 2012;186:213-215.

With the possibility of sequestration looming and the current economic and political climate, the future funding of the National Institutes of Health (NIH) and other federal biomedical research programs are threatened. This editorial reviews NIH funding in general and allocations directed at respiratory-related research. The authors advocate that is an opportune time to expand investments in biomedical research and that doing so makes sense from the perspectives of improving health, curtailing health care expenditures, job creation and economic growth. They further argue that current levels of allocation toward respiratory research are incommensurate with the medical, economic, and societal burden of respiratory disease in the United States. The editorial is of course self-serving which is why the fellows were asked to review it. They found the article quite convincing and agreed with the authors that research funding for pulmonary, critical care and sleep needs to be increased.

Hunt LM, Kreiner M, Brody H. The changing face of chronic illness management in primary care: a qualitative study of underlying influences and unintended outcomes. Ann Fam Med 2012;10:452-60.

Recently, there has been dramatic increase in the diagnosis and pharmaceutical management of common chronic illnesses. Using qualitative data collected in primary care clinics, the authors assessed how these trends play out in clinical care focusing on management of type 2 diabetes and hypertension. Based on interviews with 58 clinicians and 70 of their patients, and observations of 107 clinical consultations, clinicians focused on helping patients achieve test results recommended by national guidelines, and most reported combining 2 or more medications per condition to reach targets. Medication selection and management was the central focus of the consultations observed. Polypharmacy was common among patients, with more than one-half of the patients taking 5 or more medications. The authors discuss the influence of the pharmaceutical industry on guidelines and pay for performance and conclude that this results in polypharmacy, sometimes at the expense of patient well-being. Although the manuscript deals with primary care, the principles probably apply to the specialties of medicine and give a disturbing insight into the factors that influence medical decisions.

Richard A. Robbins, MD

Reference as: Robbins RA. September 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;5:150-1. (click here for a PDF version of the journal club)