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Southwest Pulmonary and Critical Care Fellowships
In Memoriam

Pulmonary Journal Club

(Click on title to be directed to posting, most recent listed first)

May 2017 Phoenix Pulmonary/Critical Care Journal Club
October 2015 Phoenix Pulmonary Journal Club: Lung Volume Reduction
September 2015 Tucson Pulmonary Journal Club: Genomic Classifier
   for Lung Cancer
April 2015 Phoenix Pulmonary Journal Club: Endo-Bronchial Ultrasound in
   Diagnosing Tuberculosis
February 2015 Tucson Pulmonary Journal Club: Fibrinolysis for PE
January 2015 Tucson Pulmonary Journal Club: Withdrawal of Inhaled
    Glucocorticoids in COPD
January 2015 Phoenix Pulmonary Journal Club: Noninvasive Ventilation In 
   Acute Respiratory Failure
September 2014 Tucson Pulmonary Journal Club: PANTHEON Study
June 2014 Tucson Pulmonary Journal Club: Pirfenidone in Idiopathic
   Pulmonary Fibrosis
September 2014 Phoenix Pulmonary Journal Club: Inhaled Antibiotics
August 2014 Phoenix Pulmonary Journal Club: The Use of Macrolide
   Antibiotics in Chronic Respiratory Disease
June 2014 Phoenix Pulmonary Journal Club: New Therapies for IPF
   and EBUS in Sarcoidosis
March 2014 Phoenix Pulmonary Journal Club: Palliative Care
February 2014 Phoenix Pulmonary Journal Club: Smoking Cessation
January 2014 Pulmonary Journal Club: Interventional Guidelines
December 2013 Tucson Pulmonary Journal Club: Hypothermia
December 2013 Phoenix Pulmonary Journal Club: Lung Cancer
   Screening
November 2013 Tucson Pulmonary Journal Club: Macitentan
November 2013 Phoenix Pulmonary Journal Club: Pleural Catheter
   Infection
October 2013 Tucson Pulmonary Journal Club: Tiotropium Respimat 
October 2013 Pulmonary Journal Club: Pulmonary Artery
   Hypertension
September 2013 Pulmonary Journal Club: Riociguat; Pay the Doctor
August 2013 Pulmonary Journal Club: Pneumococcal Vaccine
   Déjà Vu
July 2013 Pulmonary Journal Club
June 2013 Pulmonary Journal Club
May 2013 Pulmonary Journal Club
March 2013 Pulmonary Journal Club
February 2013 Pulmonary Journal Club
January 2013 Pulmonary Journal Club
December 2012 Pulmonary Journal Club
November 2012 Pulmonary Journal Club
October 2012 Pulmonary Journal Club
September 2012 Pulmonary Journal Club
August 2012 Pulmonary Journal Club
June 2012 Pulmonary Journal Club
June 2012 Pulmonary Journal Club
May 2012 Pulmonary Journal Club
April 2012 Pulmonary Journal Club
March 2012 Pulmonary Journal Club
February 2012 Pulmonary Journal Club
January 2012 Pulmonary Journal Club
December 2011 Pulmonary/Sleep Journal Club
October, 2011 Pulmonary Journal Club
September, 2011 Pulmonary Journal Club
August, 2011 Pulmonary Journal Club
July 2011 Pulmonary Journal Club
May, 2011 Pulmonary Journal Club
April, 2011 Pulmonary Journal Club
February 2011 Pulmonary Journal Club 
January 2011 Pulmonary Journal Club 
December 2010 Pulmonary Journal Club

 

Both the Phoenix Good Samaritan/VA and the Tucson University of Arizona fellows previously had a periodic pulmonary journal club in which current or classic pulmonary articles were reviewed and discussed. A brief summary was written of each discussion describing thearticle and the strengths and weaknesses of each article.

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Entries in tiotropium (2)

Monday
Nov252013

October 2013 Tucson Pulmonary Journal Club: Tiotropium Respimat 

Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, Dusser D, Joseph E, Kattenbeck S, Koenen-Bergmann M, Pledger G, Calverley P; TIOSPIR Investigators. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369(16):1491-501. [CrossRef] [PubMed]

Tiotropium, a long-acting inhaled anticholingeric bronchodilator, is commonly used to prevent COPD exacerbations (1).  Tiotropium is available as a dry powder (HandiHaler) or aqueous solution (Respimat).  Direct comparisons of the two formulations are lacking.  Prior post-hoc analyses suggest that that Respimat may be more efficacious than HandiHaler (2) but it may also increase the risk of death, particularly among those with cardiac dysrhythmias (3-6).  

The two were recently compared in a large randomized, double-blind, parallel trial of once daily treatment with Respimat (2.5 µg or 5 µg) or HandiHaler (18 µg).[add REF here]  Inclusion criteria included a COPD diagnosis, a 10 pack year smoking history, and post-bronchodilator FEV1/FVC ratio ≤ 0.70 and FEV1 ≤ 70% of predicted.  Major exclusion criteria included a myocardial infarction within past 6 months, hospitalization for Class III or IV heart failure, or unstable or life-threatening arrhythmia requiring new treatment within the previous 12 months.  The primary safety outcome was all cause mortality and the primary efficacy outcome was first COPD exacerbation.  Importantly, mortality was tested using a non-inferiority approach with a pre-specified non-inferiority margin of 1.25.

Approximately 17,000 participants (71% male) were followed for a median of 2.3 years.  Their mean age was 65 years, average FEV1 was 48% of predicted, previous ischemic heart disease was present in 15%, and previous cardiac dysrhythmia was present in 10%.  During the study, 1302 (7.6%) deaths were recorded.  The hazard ratio for all-cause mortality comparing Respimat 5 µg versus HandiHaler 18 µg (referent) was 0.96 (CI95% 0.84-1.09) indicating that Respimat was non-inferior to HandiHaler.  The hazard ratio for first exacerbation was 0.98 (CI 95% 0.93-1.03) indicating that Respimat was not superior to HandiHaler.  While mortality among participants with prior cardiac dysrhythmias was not higher in the Respimat group, HR 0.81 (CI95% 0.58-1.12), myocardial infarctions among the Respimat group were marginally more frequent HR 1.41 (CI95% 0.98-2.00; p=0.06).  

Notable strengths of the study included its large, prospective, head-to-head design with double-blinding of treatment assignment.  Follow-up was lengthy and well described; loss-to-follow-up was negligible.  The non-inferiority analysis of all-cause mortality provides convincing evidence that no meaningful difference in the risk of death is likely between the two Tiotropium formulations.

Without a placebo control, this study does not provide information with regard to the potential class effect of Tiotropium on all-cause or cardiac specific mortality.  The weak (p=0.06) signal suggesting a link between Respimat and increased risk of myocardial infarction was unexpected and remains unexplained.  During our discussion, we could not identify a mechanistic pathway that might account for a differential effect of the aqueous and dry powder Tiotropium formulations.   Without a credible link, the probability of a false positive signal is high.  Nevertheless, future analyses of secondary and/or claims data looking for evidence to support a link between Respimat and ischemic events may be warranted.

Abdulmagid Eddib MD

Joe Gerald MD PhD

Cristine Berry MD

University of Arizona

Tucson, Arizona

References

  1. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093-103. [CrossRef] [PubMed]
  2. Asakura Y, Nishimura N, Maezawa K, Terajima T, Kizu J, Chohnabayashi N. Effect of switching tiotropium HandiHaler® to Respimat® Soft Mist™ Inhaler in patients with COPD: the difference of adverse events and usability between inhaler devices. J Aerosol Med Pulm Drug Deliv. 2013 Feb;26(1):41-5. [CrossRef] [PubMed]
  3. Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomized controlled trials. BMJ 2011;342:d3215. [CrossRef] [PubMed]
  4. Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;7:CD009285. [CrossRef] [PubMed]
  5. Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomized controlled trials. Thorax 2013;68:48-56. [CrossRef] [PubMed]
  6. Loke YK, Singh S. Risks associated with tiotropium in chronic obstructive pulmonary disease: overview of the evidence to date. Ther Adv Drug Safe 2012;3:123-31. [CrossRef] 

Reference as: Eddib A, Gerald J, Berry C. October 2013 Tucson pulmonary journal club: tiotropium Respimat. Southwest J Pulm Crit Care. 2013;7(5):313-4. doi: http://dx.doi.org/10.13175/swjpcc170-13 PDF

Thursday
Aug042011

July 2011 Pulmonary Journal Club

Reference as: Mathew MJ. July, 2011 pulmonary journal club. Southwest J Pulm Crit Care 2011;3:25-6. (Click here for PDF version)

Donohue JF, Fogarty C, Lötvall J, Mahler DA, Worth H, Yorgancioglu A, Iqbal A, Swales J, Owen R, Higgins M, Kramer B; INHANCE Study Investigators. Once-Daily Bronchodilators for Chronic Obstructive Pulmonary Disease: Indacaterol Versus Tiotropium. Am J Resp Crit Care 2010;182:155-162. (Click here for full manuscript)

The once-daily, long-acting, beta-2 agonist, indacaterol was initially released in Europe in 2009. On July 1st 2011 it was approved by the FDA for the United States under the trade name Arcapta Neoinhaler. There have been studies demonstrating Indacaterol as an efficacious alternative to twice daily bronchodilators such as formoterol (1). We reviewed the study published by Donahue et al. and examined how Indacaterol compared to the only other once daily long acting bronchodilator tiotropium.

This was a large, two stage, randomized, controlled study performed between April, 2007 – August, 2008. The inclusion criteria were an age > 40, smoking history of > 20 pack/yrs and GOLD criteria COPD of moderate – severe COPD. The study was performed in 2 stages. A total of 2059 patients were included in the 1st stage which was performed to test dose efficacy. In this stage patients were randomized to receive either once daily indacaterol at doses of 75 ug, 150 ug, 300 ug or 600 ug, formoterol, tiotropium or placebo. At the end of this stage, two doses of indacaterol were selected for the second stage based on efficacy and safety. In the second stage, 1683 patients were randomized to once daily indacaterol 150 ug, 300 ug, tiotropium or placebo.

Primary endpoints were FEV1 response against placebo at 24 hours, and again at 12 weeks. The secondary endpoint was to compare FEV1 at 12 weeks against

tiotropium. A total of 1291 patients completed the study. The results showed there was a statistically significant increase in FEV1 at 24hrs and 12 weeks when compared to placebo. The study also demonstrated non-inferiority to tiotropium at 12 weeks with regards to improvement in FEV1 (see table below).

 

The study was not designed to measure clinical outcomes but noted were a decrease in the use of daily albuterol, a decrease in daytime symptoms and nocturnal awakenings in the indacaterol arm vs. placebo. The medication was well tolerated with main side effects being reported as cough, tachycardia and dry mouth.

The study was well done and it accomplished its primary endpoint. The main limitations were the lack of blinding in the tiotropium arm and the relative short study period of 26 weeks. It would have also been useful to extend the study period to 1 year to obtain clinical outcome data.

The availability of a once-daily, long-acting beta-2 agonist is now a promising alternative in the treatment of COPD. Although more studies are needed to demonstrate an improvement in clinical outcomes (such as a reduction in COPD

exacerbations) the once a day dosing offers at the very least, a compliance advantage. The cost of the medication (which is currently unknown) and formulary restrictions will limit initial availability.

 

Manoj Mathew, MD MCCM, FCCP

 

References

1. Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax 2010;65:473–9.