August, 2011 Pulmonary Journal Club

Reference as: Mathew M. August 2011 pulmonary journal club. Southwest J Pulm Crit Care 2011;3:52-3. (Click here for a PDF version)

The National Lung Screening Research Team. Reduced lung cancer mortality with low dose computed tomographic screening. N Engl J Med 2011;365:395-409.

Lung cancer remains the number one cause of cancer related deaths among men and women. It is more fatal than colon, breast and prostate cancer combined. The poor prognosis is largely due to advanced cancer stage at the time of diagnosis. More than 75% of lung cancer cases are diagnosed with a stage 2 or higher and greater than 50% are diagnosed with stage 4. The best prognosis is early stage 1 with a 5 year survival of greater than 65%. Unfortunately the large bulk of early stage 1 cases come as incidental findings when patients receive either a chest x-ray or computerized tomography scan for an unrelated evaluation. Prior studies looking at lung cancer screening with chest x-rays and sputum cytology have not been shown to improve mortality due to poor sensitivity. Prior studies with low dose computed tomography (LDCT) show markedly improved sensitivity when compared to chest x-ray but failed to show improved mortality mainly due to lack of randomization and a control group (1-7). This study performed by the National Lung Screening Research Team was to date the largest randomized, controlled trial looking at low dose computed tomography as a lung cancer screening modality. The study performed from 2002 – 2007 was to determine whether screening with low LDCT improved lung cancer mortality. Inclusion criteria were age 55-74, smoking history of 30 pack/years and former smokers who have quit within the past 15 years. Patients with a prior history of lung cancer or had a LDCT scan within the past 18 months were excluded. A total 53,454 pts were enrolled and with 26732 received screening with a chest x-ray annually for 3 years and 26722 received screening with LDCT annually for 3 years. The results showed that there were significantly more abnormalities detected in the screening LDCT scan and this led to higher rates of evaluation and subsequently showed a 20% reduction in lung cancer mortality. The number needed to screen with LDCT to prevent 1 death from lung cancer was 320 patients. To put his into perspective the number of screening colonoscopies needed to prevent 1 death is 492 and the number of screening mammographies needed to prevent 1 death from breast cancer is 1224 (8). The study was well done and it did accomplish its primary objective. Although the results look promising additional validation is needed before a mass screening program is initiated. Several factors need to be addressed on subsequent studies, mainly who does the radiographic interpretation and a detailed cost analysis. A radiologist with a special interest in chest radiology may need to be designated before a screening program is released. Furthermore we still do not know the long term effects of even low dose radiation. In the accompanying editorial by Harold Sox it was well noted that patients seeking a screening LDCT may also need additional counseling on smoking cessation. Since lung cancer remains for the most part a preventable smoking related illness an equally aggressive (if not more aggressive) approach to smoking cessation needs to be implemented in conjunction with any screening program.

Manoj Mathew, MD, FCCP MCCM

Associate Editor, Pulmonary Journal Club

References

1. Sone S, Takashima S, Li F, et al. Mass screening for lung cancer with mobile spiral computed tomography scanner. Lancet 1998;351:1242-5.
2. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99-105.
3. Swensen SJ, Jett JR, Sloan JA, et al. Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med 2002;165:508-13.
4. Nawa T, Nakagawa T, Kusano S, Kawasaki Y, Sugawara Y, Nakata H. Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies. Chest 2002;122:15-20.
5. Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile lowdose spiral computed tomography scanner. Br J Cancer 2001;84:25-32.
6. Jett JR. Spiral computed tomography screening for lung cancer is ready for prime time. Am J Respir Crit Care Med 2001;163:812, discussion 814-5.
7. Diederich S, Wormanns D, Semik M, et al. Screening for early lung cancer with low-dose spiral CT: prevalence in 817 asymptomatic smokers. Radiology 2002;222:773-81.
8. Humphrey LL. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task F

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.

May, 2011 Pulmonary Journal Club

Attridge RT, Frei CR, Restrepo MI, Lawson KA, Ryan L, Pugh MJV, Anzueto A, Mortensen EM. Guideline-Concordant Therapy and Outcomes in Healthcare-Associated Pneumonia. E Resp J Published online before print March 24, 2011, doi: 10.1183/​09031936.00141110 (Click here for abstract)

Reference as: Mathew M. May 2011 pulmonary journal club. Southwest J Pulm Crit Care 2011;2:65-66. (Click here for PDF version of journal club)

     The use of guidelines in patient management has not only become standard of care but often the benchmark by which quality of care has been measured.  Certain guidelines have shown clear benefit as seen with the management of acute myocardial or stroke. Other guidelines have been met with reluctance given the level of evidence reinforcing them.  This study by Attridge et al. looks at the effect of implementing and following guidelines in the management of healthcare associated pneumonia (HCAP) within the VA system.

     In 2005 a combined effort from the ATS and IDSA created a new clinical entity known as Health Care Associated Pneumonia (HCAP) (1). This entity is believed to be different from community acquired pneumonia based on the pathogens involved, i.e., methicillin resistant Staphylococcus aureus and Pseudomonas versus Streptococcus. The guidelines created in 2005 defined HCAP as an entity in which the patient was hospitalized > 48h within the past 90 days, on dialysis, on home infusions, a current nursing home resident, undergoing home wound care, or in contact with a family member with multi-drug resistant pathogen. The inclusion of any one of these criteria would categorize the patient as having the diagnosis of HCAP and warrant treatment as such.     

     This study was a large retrospective cohort study done within the VA healthcare system. After inclusion and exclusion criteria, a total of 15071 patients were included and divided into 3 groups.   Patients that met HCAP criteria and that were treated as such, patients that met HCAP criteria but that were treated as community acquired pneumonia (CAP) and patients that met HCAP criteria that were treated via a non-guideline approach. The primary outcomes were 30 day mortality and length of stay.

The results of the study are shown below:

The data demonstrated that compliance with the guidelines resulted in a higher 30 day mortality without change in  length of stay when patients were treated under HCAP guidelines.

     The main strengths of the study are the large patient size and relative uniformity in patient characteristics. The study did have several limitations. The main limitation was that the method of sputum collection outlined in original 2005 guideline to guide antibiotic therapy was not met. Only 9% of all patients had a positive culture, this value is lower than prior reported studies. If the premise of HCAP as a separate entity based on the unique pathogens isolated is to hold valid; then an aggressive approach to sampling of the respiratory tract should be made. The study also reinvigorates the debate on implementing guidelines when the data is still sparse. Unfortunately, guidelines often become surrogate benchmarks for quality assurance. If practice measures are based on whether guidelines are followed than we need to do a better job scrutinizing the data before guidelines are set forth.

Manoj Mathew, MD, FCCP, MCCM

References

1. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171: 388-416.

April, 2011 Pulmonary Journal Club

Calverly P, Rabe K, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet 2009;374:685-94. (Click here for PDF version of article)

Reference as: Mathew M, Hurley J. April, 2011 pulmonary journal club. Southwest J Pulm Crit Care 2011;2:58. (Click here for PDF version of journal club)

The use of phosphodiesterase inhibitors in COPD is not a noveau concept. Since their introduction in the early 1970's its role in COPD has been tangental. Nonselective phosphodiesterase inhibitors such as aminophylline and theophylline showed efficacy as bronchodilators and anti-inflammatories. The nonselective PDE inhibitors fell out of favor due to its side effect profile and narrow therapeutic index. With the approval of roflumilast by the Federal Drug Administration, we reviewed the study by Calverly et al. which reviewed two trials of roflumilast as a selective PDE4 inhibitor and its capacity to improve lung function and reduce COPD exacerbations. The two studies were large multicenter double blinded placebo controlled trials which followed patients over 52 weeks.  Patients with severe COPD were divided into two subsets; a placebo group and a roflumilast treatment group. Primary endpoints were a change in FEV1 and number of COPD exacerbations. The results showed patients on roflumilast had a slight statistically significant improvement in lung function with an increase in prebronchodilator FEV1 of 40ml. The study also showed a reduction in COPD exacerbations by 17% in the treatment arm. Main side effects were severe nausea, vomiting, diarrhea and an average weight loss of 4.2 kg when compared to placebo. The main limitation of this study is that it failed to show that medication related improvements were anything more than a bronchodilator effect. A cost analysis would also have been helpful.

Overall, Roflumilast as a new selective PDE4 inhibitor does show some mild improvement in lung function and reduction in COPD exacerbations. However, the benefits are small and cost may be a factor. Its main role may be limited to very severe COPD patients with cardiac disease and a BMI greater than 30.  

Manoj Mathew, MD, FCCP, MCCM

Jessica Hurley, MD

February 2011 Pulmonary Journal Club

Rice KL, Dewan N, Bloomfield HE, Grill J, Schult TM, Nelson DB, Kumari S, Thomas M, Geist LJ, Beaner C, Caldwell M, Niewoehner DE. Disease Management Program for Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial. Am J Respir Crit Care Med 2010;182:890-6. (Click here for abstract).

Reference as: Park K. February 2011 Pulmonary Journal Club. Southwest J Pulm Crit Care 2011;2:25-26. (Click here for PDF version)

The authors investigated the effect of disease management on chronic obstructive pulmonary disease admissions and emergency room visits. The study was designed as a randomized, controlled trial at five VA medical centers.  The study included high risk COPD patients defined as hospital admission or ED visit for COPD, home oxygen or systemic corticosteroid use for COPD within one year. 

The no intervention group received usual care.  The intervention group received a 1 to 1.5 hour session usually ran by a respiratory care therapist.  The session included education on COPD, smoking cessation, use of inhalers, appropriate vaccines and an action plan.  Patients were educated on early detection and treatment of their disease.  They were also followed up with monthly phone calls.

743 patients were randomized and followed for one year.  VA electronic records were used to follow patients.  Hospital admissions and ED visits outside VA system were reported by the patients.

There was statistically significant 41% decrease in the primary outcome at the end of one year.  All cause hospitalization and ED visits were also decreased by 28% (p<0.05).

This study demonstrates that a relatively simple intervention for disease management can improve hospital admission and ED visits.  Although there is a question of how COPD exacerbations were defined; the potential over use of medication; and whether the intervention is cost effective, this study lends credence to the concept that patient education may have a positive effect in severe COPD.

Prepared by Kevin Park, MD

Click here for accompanying Editorial.