June 2012 Pulmonary Journal Club

Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012;366:1968-77. (click here for abstract)

Idiopathic Pulmonary Fibrosis (IPF) continues to be a devastating disease with no clinically significant treatment options. For years the treatment of IPF centered on a trial of prednisone followed by the addition of either cyclophosphamide or azathioprine as a ‘lets see if this helps’ approach. The 2011 ATS Consensus statement on IPF declared that the use of prednisone as monotherapy was not recommended. The consensus statement also yielded a weak recommendation for N-acetylcysteine (NAC) as monotherapy, and a weak recommendation of prednisone, azathioprine and NAC as combination therapy. This study is the first large multicenter, double-blind, placebo controlled trial looking at lung function in groups of patients treated with NAC monotherapy verses combination therapy (prednisone + azathioprine + NAC) versus placebo.

The study was performed throughout 25 centers from 2009-2011. Inclusion criteria were a diagnosis of IPF, age 35-85, FVC > 50% and DLC0 > 30%. A total of 236 patients were included in the study and randomized into 3 groups…81 patients NAC monotherapy, 77 patients prednisone + azathioprine + NAC, and 78 patients  placebo. The primary outcome was the change in FVC over a 60 week period. Secondary outcomes looked at were mortality rates, frequency of exacerbations, and disease progression.

The study was intended to proceed for duration of 60 weeks. Midpoint analysis at 30 weeks revealed the prednisone + azathioprine + NAC group had higher rates of respiratory and non-respiratory related death, hospitalizations, and exacerbations,  Study data on NAC is unknown as the trial  remains ongoing for Placebo verses NAC.

First do no harm is used often in medicine and perhaps it should now be included into the IPF treatment algorithm. This study supports prior data that targeting this disease with anti-inflammatories and immune-modulators is not only ineffective but harmful. Our attempts at understanding and treating this disease remain futile and with the exception of lung transplantation…. ineffective. Although I am curious to see what if any benefit NAC will have against placebo, I am doubtful it will be significant. If NAC does prove to be beneficial, I would like to see a follow up study incorporating NAC in combination with esophageal reflux therapy in the treatment of IPF.

Manoj Mathew, MD, FCCP, MCCM

Associate Editor, Pulmonary Journal Club

Reference as: Mathew M. June 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;4:222. (click here for a PDF version of the journal club)

May 2012 Pulmonary Journal Club

EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366:1287-97. (Click here for abstract)

Oral vitamin K antagonists such as warfarin have been the mainstay of treatment in venous thromboembolism and pulmonary embolism since its approval in 1954. Clinicians can not only attest to its effectiveness but also the burden that patients face in maintaining a therapeutic level. In 2010 the EINSTEIN-PE investigators published its review on rivaroxaban in the treatment of venous thromboembolism (1). The results of this large 3449 pt trial were favorable showing non inferiority to vitamin K antagonists. This study now looks at rivaroxaban as a therapeutic alternative to vitamin K antagonists in the treatment of pulmonary embolism. The main advantage of rivaroxaban is a standard once daily dosing regimen without the need for blood monitoring.

The study was a large randomized open label trial performed at 263 sites over 38 countries between 2007–2011. Inclusion criteria were imaging confirmed symptomatic pulmonary embolism with or without deep vein thrombosis. Exclusion criteria were extensive, however they did allow for 1 single dose of a vitamin K antagonist, or enoxaparin, heparin, fondaparinux to be given for less than for 48 hours. This is certainly reasonable as it would be unethical to leave diagnosed pulmonary embolism untreated for 48 hours. 4833 patients were included in the study. 2413 patients were randomized to standard therapy with vitamin K antagonists while 2420 were assigned to receive rivaroxaban 15mg twice daily for 3 weeks then 20mg daily thereafter. The average treatment length was 9 months and there were statistically significant differences in patient demographics. The primary outcomes were rates of recurrent venous thromboembolism as well and major and minor bleeding.

This study set out to prove that rivaroxaban was not inferior to vitamin K .antagonists. It accomplished this goal. The results showed that there were no statistically significant differences in rates of recurrent venous thromboembolism, however, there were increased incidences of major bleeding episodes within the standard (vitamin K antagonist) group at 52 events vs. 26 events in the rivaroxaban  group (p=0.003).

Is rivaroxaban ready for prime time and will it replace warfarin as the new standard of care in the treatment of venous thromboembolic disease? The initial data certainly looks promising, although we need to proceed with caution given that this is a non reversible, non-dialyzable agent. Cost will be a major limiting factor as 1 month supply of rivaroxaban is estimated at $900 vs. $20 for warfarin. A cost-effectiveness analysis looking at laboratory fees and rates of readmission for bleeding events will most likely be needed. Further longitudinal studies extending beyond 1 year may also be needed to establish safety and efficacy. For now this medication offers promise that the treatment of venous thromboembolic disease is about to change.

Manoj Mathew, MD FCCP MCCM

Associate Editor, Pulmonary Journal Club

Reference

1. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499-2510.

Reference as: Mathew M. May 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;4:180-1. (Click here for a PDF version of the journal club)

April 2012 Pulmonary Journal Club

Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB; TELICAST Investigators. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med 2006;354:1589-1600. (Click here for a PDF version of article)

Acute asthma exacerbations are typically treated with inhaled beta agonists, inhaled anticholinergics, and systemic glucocorticoids.  There has been minimal evidence for the use of antibiotics in treating acute asthma exacerbations including only 2 small placebo-controlled studies that demonstrated no benefit.

The Telithromycin, Chlamydophilia, and Asthma Trial (TELICAST) was a double-blinded, randomized, placebo-controlled study to determine the effect of telithromycin in patients with acute asthma exacerbations in addition to standard therapy.  Of the 278 patients who were enrolled, 270 underwent randomization to receive placebo (136 participants), or telithromycin (134 participants) for 10 days of therapy which was initiated within 24 hours after initial presentation.  The investigators found improvement of symptoms in the telithromycin group (40.4% reduction vs. 26.5%, p=0.005), however, there was no difference in peak expiratory flow rates (78.3 L per minute vs. 66.8 L per minute, p=0.28).  There was also a reduction in the asthma symptom score (51.1% vs. 28.5%, p=0.003) and an improvement in the FEV1 (0.63 L vs. 0.34 L, p=0.001) after 10 days of treatment.  Patients infected with C. penumoniae, M. pneumonia, or both in the telithromycin group had greater improvement in their FEV1 (0.67 vs. 0.38, p=0.002), while those without these infections had no statistically significant improvement in their FEV1 (0.58 L vs. 0.46 L, p=0.486).  Nausea was a common symptom in the telithromycin group as well as mild liver enzyme elevation in 2 patients.

This study demonstrates the possible benefits of treating acute asthma exacerbations with antibiotics, suggesting treating atypical bacteria may result in an improvement of symptoms and lung function.  Given conflicting data on this topic further study is needed to duplicate these results in addition to determining whether these results are due to the antimicrobial activity or immunomodulatory effects of macrolides.  This may be challenging due to the inherent difficulty in isolating atypical respiratory organisms.  When treating acute asthma exacerbations the use of macrolides in addition to standard therapy warrants consideration.

Jonathan Olsen, DO

Manoj Mathew, MD, FCCP, MCCM

Associate Editor, Southwest Journal of Pulmonary

   and Critical Care

Reference as: Olsen J, Mathew M. April 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;4:101. (Click here for a PDF version of the journal club)

March 2012 Pulmonary Journal Club

Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-98. (Click here for full text of article)

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity and the major cost of COPD care. Chronic use of macrolide antibiotics have been shown to benefit patients with cystic fibrosis, bronchiectasis and COPD by preventing exacerbations presumably by their anti-inflammatory rather than their antibiotic effects. Albert et al. performed a randomized, placebo-controlled, double-blinded trial to determine whether azithromycin decreased the frequency of exacerbations in participants with COPD. A total of 1577 subjects were screened; 1142 (72%) were randomly assigned to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 participants) for 1 year in addition to their usual care. Azithromycin improved the median time to the first exacerbation (266 days vs.174 days, p<0.001); the frequency of exacerbations was (1.48 vs. 1.83 per patient-year, p= 0.01); scores on the St. George’s Respiratory Questionnaire (2.8±12.8 vs.0.6±11.4, p = 0.004); and the percentage of participants with more than the minimal clinically important difference of −4 units (43% vs. 36% p= 0.03). Hearing decrements were slightly more common in the azithromycin group than in the placebo group (25% vs. 20%, p = 0.04). Colonization with respiratory pathogens was lower in the azithromycin group (12 vs. 31%, p<0.001) although when present colonization with macrolide resistant organisms was more frequent (81 vs. 41%, p<0.001). Mortality was low and did not differ between the groups.

This study confirms a previous study by Seemungal et al. (1) who also performed a randomized, double-blind, placebo-controlled study of another macrolide, erythromycin, administered at 250 mg twice daily to 109 patients with COPD over 12 months. Exacerbations for the erythromycin-treated patients were reduced compared with placebo-treated patients (p<0.003). These two well done, randomized studies lend strong support to chronic use of macrolide antibiotics in COPD. In both studies complications were low and antibiotic resistance remained mostly a laboratory observation rather than a clinical problem. Details such as the optimal doses and frequency of antibiotic administration will need further investigation. Other antibiotics such as the tetracyclines also have anti-inflammatory effects and may be alternatives to macrolides (2). It now seems that the concept of chronic use of some antibiotics as anti-inflammatories is well established in respiratory disease and I would urge consideration of their usage in patients who have had or are likely to have a COPD exacerbation.

Richard A. Robbins, M.D.

Editor, Southwest Journal of Pulmonary and Critical Care

 References

1. 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;178:1139-47.
2. Rempe S, Hayden JM, Robbins RA Hoyt JC. Tetracyclines and pulmonary Inflammation. Endocrine, Metabolic & Immune Disorders - Drug Targets 2007;4:232-6.

Reference as: Robbins RA. March 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;4:78-9. (Click here for a PDF version of the journal club)

February 2012 Pulmonary Journal Club

Lee JS, Ryu JH, Elicker BM, Lydell CP, Jones KD, Wolters PJ, King TE Jr, Collard HR. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;184:1390-4. (Click here for the abstract)

The relationship between gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) remains a mystery. Although there is little contestation that the two entities often coexist, the cause and effect nature of GERD causing IPF remains unproven. The prevalence of GERD in IPF has been reported to be in the range of 67-88%. This study looks to see if treating this highly prevalent condition (GERD) impacts disease progression and mortality in patents with IPF.

This study was a prospective cohort study done at 2 institutions between 2001 and 2008. Patients with IPF were diagnosed based on radiographic and or histopathologic criteria. The presence of GERD was identified based on symptoms, uses of GERD medications or prior history of Nissen Fundoplication.

A total of 204 patients participated in the study. The results showed that the presence of GERD, treatment of GERD and history of Nissen Fundoplication were all associated with longer survival times when compared to patients with IPF and no GERD diagnosis. The strength of the study was that it reinforced prior studies that demonstrated that GERD treatment is beneficial in stabilizing IPF progression. The study was limited by its lack of randomization, blinding, and inclusion of smokers in the study group especially since cigarette smoking has been shown to be a risk factor in the development and progression of IPF.

This study reinforces that the prevalence of GERD in IPF is high. It further validates the benefit of treating GERD in patients with IPF. It still remains unclear as to whether GERD serves as a causal factor in the development of IPF. Of note, this study showed that patients with untreated GERD had improved survival (896 days) when compared to patients with IPF and no GERD symptoms (941days). The rationalization of this remains unclear, especially if we are to believe that GERD is a causal factor.  Our review of the study yielded us to concede that treating GERD in patients with IPF is likely to be beneficial and that further randomized controlled trials looking into the causal nature of GERD in IPF need to be done.

Manoj Mathew, MD FCCP, MCCM

Associate Editor, Pulmonary Journal Club

Reference as: Mathew M. February 2012 pulmonary journal club. Southwest J Pulm Crit Care 2012;4:57. (Click here for a PDF version of the journal club)