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 Based on random assignment, participants either continued triple therapy or had their fluticasone withdrawn in a step-wise fashion.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

January 2015 Phoenix Pulmonary Journal Club: Noninvasive Ventilation In Acute Respiratory Failure

Noninvasive positive pressure ventilation has expanded its role in the treatment of both chronic and acute respiratory failure. Its initial use in conditions such as obstructive sleep apnea, neuromuscular disease and tracheobronchomalacia, have been shown to improve quality of life and reduce mortality. Over the past 20 years studies have looked at using noninvasive ventilation in the management of acute respiratory failure from pulmonary edema, asthma and COPD exacerbations. During this month's journal club we reviewed 3 articles evaluating the efficacy of noninvasive ventilation in acute respiratory failure.

Gupta D, Nath A, Agarwal R, Behera D. A prospective randomized controlled trial on the efficacy of noninvasive ventilation in severe acute asthma. Respir Care. 2010;55(5):536-43. [PubMed]

This was a small unblinded randomized controlled trial (RCT) looking at the efficacy using noninvasive ventilation (NIV) in acute asthma. A total of 53 patients were included and divided into 2 groups of 28 patients (NIV) and 25 patients (standard). Both groups were treated with oxygen, intravenous corticosteroids and nebulizer treatments. Patients randomized to the NIV arm were then placed on Bilevel positive airway pressure (BiPAP) 8/4 cm H₂O and pressure was titrated to maximum of 20/10 based on serial spirometry and arterial blood gases (ABG) taken at 1, 2, and 4 hrs. The primary outcome was an improvement in forced expiratory volume in 1 second (FEV1) by 50% and length of hospital stay. The results showed that there was no statistical difference in within the 2 groups with regards to improvement in FEV1. There was a small decrease in length of ICU stay by 14 hours and a reduction in hospital stay by 16 hours. A secondary outcome did show that there were lower doses of salbutamol and ipratropium required within the NIV group. The study showed that the role of NIV in asthma has little benefit over usual therapy alone. A Cochran review of 5 studies evaluating the role of NIV in asthma was done in 2013 (1). The aggregate size was 203 patients. The review showed no reduction in mortality or need for intubation when NIV is used in the treatment of asthma. The role of NIV in asthma remains unproven and should be considered as non-standard therapy.

Gray A, Goodacre S, Newby DE, Masson M, Sampson F, Nicholl J; 3CPO Trialists. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008;359(2):142-51. [CrossRef] [PubMed]

This was a large prospective RCT looking at the effect of NIV in the acute treatment of cardiogenic pulmonary edema. The primary endpoint was mortality and need for intubation within 7 days. 1069 patients were enrolled and divided among three arms: 1. Standard therapy with oxygen (367 patients); 2. CPAP (346 patients); and 3. NIV (356 patients). Inclusion criteria included radiographic pulmonary edema on chest x-ray, pH < 7.35 and respiratory rate > 20. The average continuous positive airway pressure (CPAP) was 10 cm H20 and average BIPAP pressure was 14:7 cm.

The results showed that there was no difference in mortality rates or need for intubation among the 3 groups. There was an improvement in dyspnea, acidosis, and hypercapnia in the groups receiving CPAP or BIPAP. The study was well done and presented a large sample size. The results did not show any short term benefit in mortality, however, a Cochrane review in 2013 further analyzed a total of 32 studies with > 2000 patients and did show that use of either CPAP or BIPAP resulted in lower rates of intubation and mortality (2). In addition, it reduced ICU length of stay by 1 day. The role of CPAP or BIPAP in the treatment of cardiogenic pulmonary edema may be of benefit and offers little downside. CPAP has been advocated to be more beneficial in the management of systolic heart failure.

Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1995;333(13):817-22. [CrossRef] [PubMed]

This was a prospective RCT looking at the management of acute COPD exacerbations by standard treatment with antibiotics, steroids and oxygen verses standard therapy + NIV. A total of 85 patients were divided in 2 groups of 43 patients (standard treatment) and 42  patients (NIV). Inclusion criteria were shortness of breath, diagnosis of COPD by PFTS, pH< 7.35, respiratory rate > 30, and PaO2 < 45. Primary outcomes were need for intubation, mortality and length of hospital stay. Patients in the noninvasive NIV group received at least 6 hours per day of inspiratory pressure of 20 cm H₂O. The results showed that the use of noninvasive ventilation reduced the need for intubation from 74% (3 patients in standard arm) to 26% (11 patients in NIV arm). The use of NIV also resulted in reduced mortality, 29% (12 patients in Standard Arm) vs 9% (4 patients in NIV arm). Other clinical parameters such as respiratory rate, encephalopathy, and blood gas results were also improved at a greater level with the use of NIV. The length of stay was reduced in the NIV group regardless of whether the patient required intubation or not. Although this was a smaller study the results were compelling for the benefits of using NIV in acute COPD exacerbation. Subsequent studies looking at the role of NIV both in acute COPD exacerbation as well as chronic stable COPD have also been positive. Although there are no optimal pressures outlined for NIV settings, this study showed that a higher pressure of 20 cm H₂O of Inspiratory pressure was a good starting point. The use of NIV in acute COPD exacerbations has been shown to be beneficial and should be used with other standard pharmacological therapies.

Manoj Mathew, MD FCCP, MCCM

References

1. Landry A, Foran M, Koyfman A. Does noninvasive positive-pressure ventilation improve outcomes in severe asthma exacerbations? Ann Emerg Med. 2013;62(6):594-6. [CrossRef] [PubMed]
2. Vital FM, Ladeira MT, Atallah AN. Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema. Cochrane Database Syst Rev. 2013 May 31;5:CD005351. [CrossRef] [PubMed] 

Reference as: Mathew M. January 2015 Phoenix pulmonary journal club: noninvasive ventilation in acute respiratory failure. Southwest J Pulm Crit Care. 2015;10(1):52-3. doi: http://dx.doi.org/10.13175/swjpcc011-15 PDF

September 2014 Tucson Pulmonary Journal Club: PANTHEON Study

Zheng JP, Wen FQ, Bai CX, Wan HY, Kang J, Chen P et al. for the PANTHEON study group. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomized, double-blind placebo-controlled trial. Lancet Respir Med. 2014; 2(3):187-94. [CrossRef] [PubMed]

Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity, mortality, and healthcare utilization. Oxidative stress is thought to be important in COPD pathogenesis, and thus antioxidant therapy has been of great interest, including N-Acetylcysteine (NAC). However, prior studies of NAC in COPD patients have shown varied results. The PANTHEON study was designed to examine the effects of NAC on exacerbation rate in Chinese patients with COPD using a daily dose that is twice as high as that previously studied.

PANTHEON was a randomized double-blinded placebo-controlled trial that enrolled patients aged 40-80 years with GOLD class II, III and IV COPD from 34 academic pulmonary clinics in China. Patients with asthma, oxygen dependence, or poor compliance were excluded. The primary outcome was the COPD exacerbation rate following one year of observation. Exacerbations were defined using the Anthonisen instrument which relies on daily diary reporting. Important secondary outcomes included time to first exacerbation, time to subsequent exacerbations, number of patients requiring antibiotics or steroids, and number of patients requiring hospitalization. The enrollment goal was 1250 patients which would have provided have 95% power to detect a 20% reduction in the exacerbation; however, only 1006 patients were actually randomized. Nevertheless, the study was adequately powered for the primary outcome.

More than 80% of the patients were males; 46% had GOLD II severity, 53% had GOLD III severity, and 1% had GOLD IV severity. Mean FEV1 was 1.2 L. Twenty-five percent were non-smokers; 48% were using both ICS and a long-acting bronchodilator at enrollment; and 27% were taking theophylline.

As compared to placebo, twice daily treatment with 600mg of NAC led to a significant reduction in the annual COPD exacerbation rate (RR 0.78, 95% CI 0.67–0.90; p=0.001) and the rate of steroid or antibiotic-requiring exacerbations (RR 0.83 95% CI 0.69-0.99; p=0.04) but not the annual rate of hospitalizations. Interestingly, the time to first exacerbation did not differ between the groups but the time to second and third exacerbations was longer in the NAC group.

This study suggests that NAC, a relatively inexpensive compound that is available over-the-counter, may reduce exacerbation risk among patients with COPD. Given that NAC is safe and the costs would be borne entirely by the patient, it is reasonable to advise patients of this potential treatment option. Patients should be cautioned that the data supporting the benefits of NAC are not conclusive and the magnitude of benefit is likely to be modest. The major limitation includes reliance on a Chinese population of COPD patients in whom the benefits may not be generalizable to US patients. Of unknown importance is the fact that treatment benefits were limited to self-reported outcomes rather than objective observation of hospitalizations. To the extent that the self-reported data is free of bias, the failure to detect differences in hospitalizations may not matter to patients.

Bhupinder Natt MD¹, Christine Berry MD¹, Joe K. Gerald MD, PhD²

¹Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Arizona Medical Center; Tucson, AZ

²College of Public Health, University of Arizona Medical Center; Tucson, AZ

Reference as: Natt B, Berry C, Gerald JK. September 2014 Tucson pulmonary journal club: PANTHEON study. Southwest J Pulm Crit Care. 2014;9(4):249-50. doi: http://dx.doi.org/10.13175/swjpcc144-14 PDF

August 2014 Phoenix Pulmonary Journal Club: The Use of Macrolide Antibiotics in Chronic Respiratory Disease

This month's journal club reviewed  the role of macrolide antibiotics in chronic respiratory disease. Macrolide usage was suggested from observational studies in Japan in diffuse panbroncholitis, a disorder associated with chronic respiratory infection, usually Pseudomonas aeruginosa (1). Clinical improvement was noted despite doses of antibiotics well below the minimal inhibitory concentration (MIC) of the antibiotic. This  suggested the antibiotic was likely working by an anti-inflammatory effect. These observations were extended to cystic fibrosis (CF) where prophylactic macrolide therapy in CF patients infected with Pseudomonas has become standard therapy (2). More recently, low dose macrolide therapy has been applied to non-CF lung diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis and asthma.

Time did not permit a review of all studies so a representative sample was discussed. In patients with COPD, the four randomized, placebo-controlled trials reviewed all suggested that chronic therapy with macrolide antibiotics reduced COPD exacerbations (3-5). This beneficial effect was confirmed by 2 recent meta-analysis (6,7). Similarly,  three recent randomized trials in bronchiectasis demonstrated a reduction in exacerbations (8-10). In asthma the data is not as clear. A recent trial did not demonstrate an overall reduction in asthma exacerbations or lower respiratory tract infections (11). However, in the patients with non-eosinophilic, predominantly neutrophilic, asthma there was a reduction.  An excellent review of the use of macrolides in acute and chronic asthma was recently published. (12). The article includes a review of the anti-inflammatory and immunomodulatory properties of the macrolides.

The respiratory disorders where macrolides have been shown to have clinic benefit such as diffuse panbroncholitis, cystic fibrosis, COPD, bronchiectasis and non-eosinophilic asthma are all diseases associated an influx of neutrophils into the airways. The beneficial clinic effects of macrolides are consistent with their effect in reducing neutrophil chemotactic factors such as interleukin (IL)-8 (13). However, macrolides have also been reported to have adverse clinical effects such as QT prolongation in patients with heart disease, impaired hearing and development of bacterial resistance (4,6,14). Whether all COPD patients should be treated with macrolides is controversial but most in the audience used these in patients with frequent exacerbations. It was also pointed out that other antibiotics such as the tetracyclines also have anti-inflammatory effects and have been shown to be efficacious in some respiratory diseases (15). Whether the tetracyclines are equally or more effective than the macrolides with fewer serious side effects is unknown.

Richard A. Robbins, MD¹

Allen R. Thomas, MD²

Manoj Mathew, MD³

¹Phoenix Pulmonary and Critical Care Research Foundation, ²Phoenix VA Medical Center, ³Banner Good Samaritan Medical Center.

References

1. Nagai H, Shishido H, Yoneda R, Yamaguchi E, Tamura A, Kurashima A. Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration. 1991;58(3-4):145-9. [CrossRef] [PubMed] 
2. Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW 3rd; Macrolide Study Group. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290(13):1749-56. [CrossRef] [PubMed]
3. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178(11):1139-47. [CrossRef] [PubMed]
4. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA Jr, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. [CrossRef] [PubMed]
5. Uzun S, Djamin RS, Kluytmans JA, Mulder PG, van't Veer NE, Ermens AA, Pelle AJ, Hoogsteden HC, Aerts JG, van der Eerden MM. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2(5):361-8. [CrossRef] [PubMed]
6. Li H, Liu DH, Chen LL, Zhao Q, Yu YZ, Ding JJ, Miao LY, Xiao YL, Cai HR, Zhang DP, Guo YB, Xie CM. Meta-analysis of the adverse effects of long-term azithromycin use in patients with chronic lung diseases. Antimicrob Agents Chemother. 2014;58(1):511-7. [CrossRef] [PubMed]
7. Herath SC, Poole P. Prophylactic antibiotic therapy in chronic obstructive pulmonary disease. JAMA. 2014;311(21):2225-6. [CrossRef] [PubMed]
8. Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, Milne D, Fergusson W, Tuffery C, Sexton P, Storey L, Ashton T. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;380(9842):660-7. [CrossRef]  [PubMed]
9. Altenburg J, de Graaff CS, Stienstra Y, Sloos JH, van Haren EH, Koppers RJ, van der Werf TS, Boersma WG. Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic fibrosis bronchiectasis: the BAT randomized controlled trial. JAMA. 2013;309(12):1251-9. [CrossRef] [PubMed] 
10. Serisier DJ, Martin ML, McGuckin MA, Lourie R, Chen AC, Brain B, Biga S, Schlebusch S, Dash P, Bowler SD. Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial. JAMA. 2013;309(12):1260-7. [CrossRef] [PubMed]
11. Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V, Verleden G, Demedts IK, Verhamme K, Delporte A, Demeyere B, Claeys G, Boelens J, Padalko E, Verschakelen J, Van Maele G, Deschepper E, Joos GF. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013 Apr;68(4):322-9. [CrossRef] [PubMed] 
12. Wong EH, Porter JD, Edwards MR, Johnston SL. The role of macrolides in asthma: current evidence and future directions.  Lancet Respir Med. 2014 2:657-70. [CrossRef] [PubMed]
13. Abe S, Nakamura H, Inoue S, Takeda H, Saito H, Kato S, Mukaida N, Matsushima K, Tomoike H. Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 2000;22(1):51-60. [CrossRef] [PubMed] 
14. Albert RK, Schuller JL; COPD Clinical Research Network. Macrolide antibiotics and the risk of cardiac arrhythmias. Am J Respir Crit Care Med. 2014;189(10):1173-80. [CrossRef] [PubMed] 
15. Rempe S, Hayden JM, Robbins RA, Hoyt JC. Tetracyclines and pulmonary inflammation. Endocr Metab Immune Disord Drug Targets. 2007;7(4):232-6. [CrossRef] [PubMed] 

Reference as: Robbins RA, Thomas AR, Mathew M. August 2014 Phoenix pulmonary journal club: the use of macrolide antibiotics in chronic respiratory disease. Southwest J Pulm Crit Care. 2014;9(2):130-2. doi: http://dx.doi.org/10.13175/swjpcc109-14 PDF

March 2014 Phoenix Pulmonary Journal Club: Palliative Care

Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010 Aug 19;363(8):733-42. [CrossRef] [PubMed]

The March journal club focused on the role of palliative care in respiratory diseases such as chronic obstructive lung disease (COPD) and lung cancer. Palliative care is specialized care that focuses on life threatening disease and the relief of pain and stress. Although often initiated near the end of life, palliative care should not be  considered as end of life care. This study reviewed the impact of introducing palliative care in conjunction with oncologic care in the treatment of metastatic non-small cell lung cancer versus oncologic care alone. This was a nonblinded, randomized control trial of 151 patients done at the Massachusetts General Hospital.  Seventy-seven patients were randomly assigned to early palliative care + oncologic care (P + O) and 74 patients were assigned to oncologic care only (O). P + O patients were seen by palliative care services within 3 weeks of enrollment and met with services monthly until their death. Primary outcome was quality of life at baseline and at 12 weeks. The results showed that P + O patients had less depressive symptoms (16% P + O vs. 38% O), received less aggressive end of life care (33% P + O vs. 54% O) , and lived 2.7 months longer (11.6 m P + O vs. 8.9 m O). Although this was a small, nonblinded study it showed that palliative care does not need to be exclusive of ongoing oncologic care and that early referral and involvement can help foster goals of therapy and better symptom control.

Carlucci A, Guerrieri A, Nava S. Palliative care in COPD patients: is it only an end-of-life issue? Eur Respir Rev. 2012 Dec 1;21(126):347-54.  [CrossRef] [PubMed]

The role of palliative care in COPD is underutilized and rarely initiated until the end stages of disease. This review on the role of palliative care in COPD emphasizes that COPD is often a more debilitating disease than lung cancer with even higher rates of anxiety and depression. Palliative care should not be considered as transitional or end of life care, but integrated early to improve symptom control and quality of life. The timing as to when to get palliative care services involved in the outpatient COPD population is debatable, as the resources are limited. This paper suggests that looking at parameters that delineate a decreased 5 year survival in COPD, such as THE BODE INDEX, may be useful.  Patients that have a BODE index score of 7 or more would certainly be good candidates and perhaps starting with a score of 5 or more may even be more appropriate. Palliative care should be considered an integrated and complimentary tool in the management of advanced COPD.

Manoj Mathew, MD FCCP MCCM

Reference as: Mathew M. March 2014 Phoenix pulmonary journal club: palliative care. Southwest J Pulm Crit Care. 2014;8(3):194. doi: http://dx.doi.org/10.13175/swjpcc034-14 PDF