This online-first version will be replaced with a final version when it is included in the issue. The final version may differ in small ways.
UPDATE Update in Pulmonary Medicine: Evidence Published in 2014 Jess Mandel, MD
T
his article summarizes important studies published in 2014 that have the potential to substantially influence the practice of pulmonary and internal medicine. Key studies were identified from ACP Journal Club and ACP JournalWise and were some of the most frequently accessed and highest-ranked articles in 2014. Beneficial therapies were reported for idiopathic pulmonary fibrosis, a disease that heretofore has eluded effective therapy. A monoclonal antibody– based therapy may substantially benefit a select group of patients with severe asthma refractory to traditional therapies. Another trial demonstrated that inhaled corticosteroids may be withdrawn from the treatment of some patients with stable chronic obstructive pulmonary disease (COPD). Analysis of data from a randomized trial found that azithromycin most effectively reduces acute exacerbations of COPD that necessitate antibiotics and glucocorticoids in certain subsets of patients. An analysis reported that screening for lung cancer with low-dose computed tomography in the appropriate patient groups can be cost-effective. A meta-analysis of pointof-care ultrasonography for the diagnosis of acute cardiogenic pulmonary edema found high sensitivity and specificity when experienced operators performed the test. Finally, another meta-analysis found that oseltamivir was modestly effective for the treatment of influenza in adults but with adverse effects, emphasizing the need for thoughtful patient selection.
Diffuse Parenchymal Lung Disease Effective Treatments Are Demonstrated for Idiopathic Pulmonary Richeldi L, du Bois RM, Raghu G, et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071-82. [PMID: 24836310] doi:10.1056/NEJMoa1402584 King TE Jr, Bradford WZ, Castro-Bernardini S, et al; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:208392. [PMID: 24836312] doi:10.1056/NEJMoa1402582 Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2093-101. [PMID: 24836309] doi: 10.1056/NEJMoa1401739
Background: Idiopathic pulmonary fibrosis is a progressive condition of unknown cause and high mortality that has long eluded effective treatment. Historically, the condition has been conceptualized as stemming from 1 or more unknown insults that produce inflammation, which in turn leads to fibrosis in the lung. More Ann Intern Med. doi:10.7326/M15-0262 For author affiliation, see end of text. This article was published online first at www.annals.org on 30 April 2015. www.annals.org
Downloaded From: http://annals.org/ by a Oakland University User on 05/03/2015
recently, this pathophysiologic model has been questioned, and interest has turned to agents that are antifibrotic rather than anti-inflammatory in mechanism (1). Findings: These 3 randomized trials were published simultaneously in May 2014. The first randomly assigned 1066 patients to receive placebo or the orally active tyrosine kinase inhibitor nintedanib. After 52 weeks of follow-up, nintedanib-treated patients had a significantly decreased annual rate of decline in FVC. The second trial, which randomly assigned 555 patients to the oral antifibrotic agent pirfenidone or to placebo, also found a reduction in the decline in FVC at 52 weeks with active drug compared with placebo. The third trial did not find significant differences between placebo and acetylcysteine in the rate of FVC decline after 60 weeks. Cautions: It is unknown whether the beneficial effects of nintedanib or pirfenidone on FVC decline persist beyond 52 weeks. Also unclear is whether these agents ultimately reduce the mortality rate of idiopathic pulmonary fibrosis or potentially affect other patientcentered measures of effectiveness. It is unknown which of the agents is more efficacious, whether there is synergy between them, and whether they will benefit patients with disease more severe (for example, those with an FVC 50% of predicted) and treatment with corticosteroids, azathioprine, and other immunosuppressive treatments is avoided. Patients must be counseled that neither of the new agents reverses fibrosis but instead may slow the rate of disease progression. Patients with idiopathic pulmonary fibrosis still warrant early referral to a specialized center for evaluation of candidacy for lung transplantation (2).
Asthma Mepolizumab Improves Disease Control in Patients With Eosinophilic Asthma Bel EH, Wenzel SE, Thompson PJ, et al; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosino-
Annals of Internal Medicine Annals of Internal Medicine
1
This online-first version will be replaced with a final version when it is included in the issue. The final version may differ in small ways.
UPDATE philic asthma. N Engl J Med. 2014;371:1189-97. [PMID: 25199060] doi:10.1056/NEJMoa1403291 Ortega HG, Liu MC, Pavord ID, et al; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-207. [PMID: 25199059] doi:10.1056/NEJMoa1403290
Background: Recently, interest in better classifying asthma phenotypes and endotypes (subtypes of a condition with distinct pathophysiologic mechanisms) has increased. Researchers hope to identify targeted therapies that may be effective in specific groups of patients despite less impressive results when applied to a group with undifferentiated asthma. One such severe asthma phenotype is eosinophilic asthma, characterized by eosinophilia and either a requirement for longterm systemic corticosteroid therapy or frequent symptoms and exacerbations with conventional therapies (3). Findings: These 2 randomized, placebo-controlled trials examined the effect of the anti–interleukin-5 monoclonal antibody mepolizumab, administered parenterally every 4 weeks, in patients with eosinophilic asthma. The first study, which included 135 patients, documented a median 50% reduction in corticosteroid dose in the mepolizumab group at 24 weeks, accompanied by a reduced rate of exacerbations and improvement in Asthma Control Questionnaire scores. The second trial, which enrolled 576 patients, showed a roughly 50% decrease in exacerbations in mepolizumab-treated individuals, accompanied by improvements in FEV1 and several symptom scores. Cautions: Benefits of mepolizumab occurred in populations carefully selected for disease severity and eosinophilic phenotype. Some previous trials of anti– interleukin-5 therapies in patients with less severe asthma who had less stringent phenotyping have not found efficacy across multiple outcome measures. Regulatory submissions for mepolizumab have been made, and, if approved, the drug is anticipated to be expensive. Its manufacturer has not released price data at the time of publication. Implications: These studies suggest that the use of monoclonal antibody– based therapies may substantially benefit some patients with severe asthma that is refractory to traditional, less expensive therapies. However, patient selection for these newer therapies is critical, particularly because they cost far more than standard asthma treatments.
COPD Inhaled Glucocorticoids Can Be Withdrawn in Patients With Well-Controlled COPD Magnussen H, Disse B, Rodriguez-Roisin R, et al; WISDOM Investigators. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371:1285-94. [PMID: 25196117] doi:10.1056/NEJMoa1407154 2 Annals of Internal Medicine
Downloaded From: http://annals.org/ by a Oakland University User on 05/03/2015
Update in Pulmonary Medicine
Background: Despite limited evidence that inhaled glucocorticoids benefit unselected patients with COPD, many individuals are prescribed these medications. In contrast to the approach to managing patients with asthma, therapy for COPD is rarely “stepped down,” and all medications are continued even in clinically stable patients. Findings: A total of 2485 patients with severe or very severe COPD (postbronchodilator FEV1
UPDATE Update in Pulmonary Medicine: Evidence Published in 2014 Jess Mandel, MD
T
his article summarizes important studies published in 2014 that have the potential to substantially influence the practice of pulmonary and internal medicine. Key studies were identified from ACP Journal Club and ACP JournalWise and were some of the most frequently accessed and highest-ranked articles in 2014. Beneficial therapies were reported for idiopathic pulmonary fibrosis, a disease that heretofore has eluded effective therapy. A monoclonal antibody– based therapy may substantially benefit a select group of patients with severe asthma refractory to traditional therapies. Another trial demonstrated that inhaled corticosteroids may be withdrawn from the treatment of some patients with stable chronic obstructive pulmonary disease (COPD). Analysis of data from a randomized trial found that azithromycin most effectively reduces acute exacerbations of COPD that necessitate antibiotics and glucocorticoids in certain subsets of patients. An analysis reported that screening for lung cancer with low-dose computed tomography in the appropriate patient groups can be cost-effective. A meta-analysis of pointof-care ultrasonography for the diagnosis of acute cardiogenic pulmonary edema found high sensitivity and specificity when experienced operators performed the test. Finally, another meta-analysis found that oseltamivir was modestly effective for the treatment of influenza in adults but with adverse effects, emphasizing the need for thoughtful patient selection.
Diffuse Parenchymal Lung Disease Effective Treatments Are Demonstrated for Idiopathic Pulmonary Richeldi L, du Bois RM, Raghu G, et al; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071-82. [PMID: 24836310] doi:10.1056/NEJMoa1402584 King TE Jr, Bradford WZ, Castro-Bernardini S, et al; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:208392. [PMID: 24836312] doi:10.1056/NEJMoa1402582 Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2093-101. [PMID: 24836309] doi: 10.1056/NEJMoa1401739
Background: Idiopathic pulmonary fibrosis is a progressive condition of unknown cause and high mortality that has long eluded effective treatment. Historically, the condition has been conceptualized as stemming from 1 or more unknown insults that produce inflammation, which in turn leads to fibrosis in the lung. More Ann Intern Med. doi:10.7326/M15-0262 For author affiliation, see end of text. This article was published online first at www.annals.org on 30 April 2015. www.annals.org
Downloaded From: http://annals.org/ by a Oakland University User on 05/03/2015
recently, this pathophysiologic model has been questioned, and interest has turned to agents that are antifibrotic rather than anti-inflammatory in mechanism (1). Findings: These 3 randomized trials were published simultaneously in May 2014. The first randomly assigned 1066 patients to receive placebo or the orally active tyrosine kinase inhibitor nintedanib. After 52 weeks of follow-up, nintedanib-treated patients had a significantly decreased annual rate of decline in FVC. The second trial, which randomly assigned 555 patients to the oral antifibrotic agent pirfenidone or to placebo, also found a reduction in the decline in FVC at 52 weeks with active drug compared with placebo. The third trial did not find significant differences between placebo and acetylcysteine in the rate of FVC decline after 60 weeks. Cautions: It is unknown whether the beneficial effects of nintedanib or pirfenidone on FVC decline persist beyond 52 weeks. Also unclear is whether these agents ultimately reduce the mortality rate of idiopathic pulmonary fibrosis or potentially affect other patientcentered measures of effectiveness. It is unknown which of the agents is more efficacious, whether there is synergy between them, and whether they will benefit patients with disease more severe (for example, those with an FVC 50% of predicted) and treatment with corticosteroids, azathioprine, and other immunosuppressive treatments is avoided. Patients must be counseled that neither of the new agents reverses fibrosis but instead may slow the rate of disease progression. Patients with idiopathic pulmonary fibrosis still warrant early referral to a specialized center for evaluation of candidacy for lung transplantation (2).
Asthma Mepolizumab Improves Disease Control in Patients With Eosinophilic Asthma Bel EH, Wenzel SE, Thompson PJ, et al; SIRIUS Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosino-
Annals of Internal Medicine Annals of Internal Medicine
1
This online-first version will be replaced with a final version when it is included in the issue. The final version may differ in small ways.
UPDATE philic asthma. N Engl J Med. 2014;371:1189-97. [PMID: 25199060] doi:10.1056/NEJMoa1403291 Ortega HG, Liu MC, Pavord ID, et al; MENSA Investigators. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-207. [PMID: 25199059] doi:10.1056/NEJMoa1403290
Background: Recently, interest in better classifying asthma phenotypes and endotypes (subtypes of a condition with distinct pathophysiologic mechanisms) has increased. Researchers hope to identify targeted therapies that may be effective in specific groups of patients despite less impressive results when applied to a group with undifferentiated asthma. One such severe asthma phenotype is eosinophilic asthma, characterized by eosinophilia and either a requirement for longterm systemic corticosteroid therapy or frequent symptoms and exacerbations with conventional therapies (3). Findings: These 2 randomized, placebo-controlled trials examined the effect of the anti–interleukin-5 monoclonal antibody mepolizumab, administered parenterally every 4 weeks, in patients with eosinophilic asthma. The first study, which included 135 patients, documented a median 50% reduction in corticosteroid dose in the mepolizumab group at 24 weeks, accompanied by a reduced rate of exacerbations and improvement in Asthma Control Questionnaire scores. The second trial, which enrolled 576 patients, showed a roughly 50% decrease in exacerbations in mepolizumab-treated individuals, accompanied by improvements in FEV1 and several symptom scores. Cautions: Benefits of mepolizumab occurred in populations carefully selected for disease severity and eosinophilic phenotype. Some previous trials of anti– interleukin-5 therapies in patients with less severe asthma who had less stringent phenotyping have not found efficacy across multiple outcome measures. Regulatory submissions for mepolizumab have been made, and, if approved, the drug is anticipated to be expensive. Its manufacturer has not released price data at the time of publication. Implications: These studies suggest that the use of monoclonal antibody– based therapies may substantially benefit some patients with severe asthma that is refractory to traditional, less expensive therapies. However, patient selection for these newer therapies is critical, particularly because they cost far more than standard asthma treatments.
COPD Inhaled Glucocorticoids Can Be Withdrawn in Patients With Well-Controlled COPD Magnussen H, Disse B, Rodriguez-Roisin R, et al; WISDOM Investigators. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371:1285-94. [PMID: 25196117] doi:10.1056/NEJMoa1407154 2 Annals of Internal Medicine
Downloaded From: http://annals.org/ by a Oakland University User on 05/03/2015
Update in Pulmonary Medicine
Background: Despite limited evidence that inhaled glucocorticoids benefit unselected patients with COPD, many individuals are prescribed these medications. In contrast to the approach to managing patients with asthma, therapy for COPD is rarely “stepped down,” and all medications are continued even in clinically stable patients. Findings: A total of 2485 patients with severe or very severe COPD (postbronchodilator FEV1
