Pulmonary Health Hub

Despite advances in the treatment of acute myocardial infarction, 30-day rehospitalization rates remained fairly constant from 1987 to 2010.

Rehospitalizations ranged from a high of 23% in 1987 to a low of 19% in 2010 – but that difference was not statistically significant, Dr. Shannon Dunlay and her colleagues reported in the July 3 issue of Annals of Internal Medicine

During that period, treatment advances were obvious. There was a significant decrease in fibrinolysis and significant increases in angiography, reperfusion, and percutaneous coronary intervention (PCI). But those improvements didn’t affect 30-day readmission rates, and in fact, seem to be a driver of them, the researchers, led by Dr. Dunlay, a cardiology fellow at the Mayo Clinic, Rochester, Minn., wrote.

"Angiography, reperfusion, and revascularization are mainstays of therapy in acute MI, and complications are associated with a high risk for rehospitalization," they wrote.

They also noted that "as the prevalence of such comorbid conditions as diabetes and COPD [chronic obstructive pulmonary disease] increases over time, rehospitalizations after acute MI may continue to shift toward noncardiovascular causes." Other medical comorbidities, including hypertension, hyperlipidemia, and obesity, were also significantly associated with readmission rates (Ann. Intern. Med. 2012; 157:11-18).

The authors found that 43% of the readmissions were related to the incident heart attack or its treatment, 30% were unrelated, and a relationship was unclear in 27%.

The review encompassed 3,010 cases extracted from the Rochester Epidemiology Project, a database that links patient records from three facilities in Olmstead County, Minn. The patients’ mean age was 67 years and did not change over the study period.

In-hospital survival improved over time (89% in 1987 and 96% in 2010).

There were significant changes in comorbid conditions from 1987 to 2010, including hypertension (61%-69%), hyperlipidemia (50%-68%), diabetes (22%-24%), and obesity [a body mass index of at least 30 kg/m²] (33%-38%).

Treatment changes included a significant decrease in fibrinolysis (28%-1%), and significant increases in reperfusion/revascularization (64%-69%), PCI (51%-63%), and angiography (76%-85%). The median length of stay dropped from 5 days to 3 days – also a significant change.

Increasing rates of complications were associated with these changes in treatment, the records showed. Ten percent of patients who underwent PCI had a complication. These included vascular or bleeding complications (6%), stroke (0.3%), and renal failure (5%). Of the vascular or bleeding complications, 63% were access site complications, most of which were groin hematomas.

The complication rate was low among patient receiving fibrinolysis (2%). Two percent of patients who had a coronary artery bypass graft (CABG) procedure had an associated stroke. The complication rate was 8% among patients who had angiography, with or without reperfusion. Most of those (5%) had acute renal failure, with three patients requiring dialysis. The other patients had vascular or bleeding complications.

Thirty-day rehospitalizations were required in 561 patients (19%), who were admitted a total of 643 times – 484 patients were admitted once, 72 twice, and 5 three times. Three percent (87) of the patients died within 30 days; among these, 19 were in a readmission when they died.

Readmission rates were 23% from 1987 to 1992; 22% from 1993 to 1998; 22% from 1999 to 2004; and 19% from 2005 to 2010.

The most common reasons for rehospitalization were ischemic heart disease (15%), respiratory or other chest symptoms (10%), heart failure (9%), and cardiac arrhythmias (6%). Other reasons included procedural complications (92%); fluid/electrolyte problems (2%); and hypotension, pneumonia, embolism/thrombosis, and stroke or transient ischemic attack (about 1%) each.

Angiography was performed in 24% of readmissions and PCI in 9%. Of these, 25% were repeat PCIs of the same vessel.

There were 44 CABG procedures among the readmitted group (28 planned). Forty-five percent of those undergoing a revascularization had been treated medically during their initial hospitalization.

Some treatments significantly increased the risk of 30-day readmission; most of that association was driven by procedural complications:

• Angiography with complications: hazard ratio, 2.40.

• Reperfusions with revascularization, with complications: HR, 2.12.

Some medical comorbidities also showed significant associations with readmission:

• Diabetes: HR, 1.34.

• Chronic obstructive pulmonary disease: HR, 1.43.

• Heart failure: HR, 1.12.

"Compared with our previous report on rehospitalizations after incident heart failure diagnosis in Olmsted County, COPD, diabetes, and anemia were common risk factors for rehospitalization among patients with incident MI and heart failure," the authors said. These risk factors "may be of particular importance as future targets in preventing rehospitalizations in patients hospitalized with cardiovascular disease."

The National Institutes of Health sponsored the study. The researchers reported having no relevant financial conflicts of interests.

Despite advances in the treatment of acute myocardial infarction, 30-day rehospitalization rates remained fairly constant from 1987 to 2010.

Rehospitalizations ranged from a high of 23% in 1987 to a low of 19% in 2010 – but that difference was not statistically significant, Dr. Shannon Dunlay and her colleagues reported in the July 3 issue of Annals of Internal Medicine

During that period, treatment advances were obvious. There was a significant decrease in fibrinolysis and significant increases in angiography, reperfusion, and percutaneous coronary intervention (PCI). But those improvements didn’t affect 30-day readmission rates, and in fact, seem to be a driver of them, the researchers, led by Dr. Dunlay, a cardiology fellow at the Mayo Clinic, Rochester, Minn., wrote.

"Angiography, reperfusion, and revascularization are mainstays of therapy in acute MI, and complications are associated with a high risk for rehospitalization," they wrote.

They also noted that "as the prevalence of such comorbid conditions as diabetes and COPD [chronic obstructive pulmonary disease] increases over time, rehospitalizations after acute MI may continue to shift toward noncardiovascular causes." Other medical comorbidities, including hypertension, hyperlipidemia, and obesity, were also significantly associated with readmission rates (Ann. Intern. Med. 2012; 157:11-18).

The authors found that 43% of the readmissions were related to the incident heart attack or its treatment, 30% were unrelated, and a relationship was unclear in 27%.

The review encompassed 3,010 cases extracted from the Rochester Epidemiology Project, a database that links patient records from three facilities in Olmstead County, Minn. The patients’ mean age was 67 years and did not change over the study period.

In-hospital survival improved over time (89% in 1987 and 96% in 2010).

There were significant changes in comorbid conditions from 1987 to 2010, including hypertension (61%-69%), hyperlipidemia (50%-68%), diabetes (22%-24%), and obesity [a body mass index of at least 30 kg/m²] (33%-38%).

Treatment changes included a significant decrease in fibrinolysis (28%-1%), and significant increases in reperfusion/revascularization (64%-69%), PCI (51%-63%), and angiography (76%-85%). The median length of stay dropped from 5 days to 3 days – also a significant change.

Increasing rates of complications were associated with these changes in treatment, the records showed. Ten percent of patients who underwent PCI had a complication. These included vascular or bleeding complications (6%), stroke (0.3%), and renal failure (5%). Of the vascular or bleeding complications, 63% were access site complications, most of which were groin hematomas.

The complication rate was low among patient receiving fibrinolysis (2%). Two percent of patients who had a coronary artery bypass graft (CABG) procedure had an associated stroke. The complication rate was 8% among patients who had angiography, with or without reperfusion. Most of those (5%) had acute renal failure, with three patients requiring dialysis. The other patients had vascular or bleeding complications.

Thirty-day rehospitalizations were required in 561 patients (19%), who were admitted a total of 643 times – 484 patients were admitted once, 72 twice, and 5 three times. Three percent (87) of the patients died within 30 days; among these, 19 were in a readmission when they died.

Readmission rates were 23% from 1987 to 1992; 22% from 1993 to 1998; 22% from 1999 to 2004; and 19% from 2005 to 2010.

The most common reasons for rehospitalization were ischemic heart disease (15%), respiratory or other chest symptoms (10%), heart failure (9%), and cardiac arrhythmias (6%). Other reasons included procedural complications (92%); fluid/electrolyte problems (2%); and hypotension, pneumonia, embolism/thrombosis, and stroke or transient ischemic attack (about 1%) each.

Angiography was performed in 24% of readmissions and PCI in 9%. Of these, 25% were repeat PCIs of the same vessel.

There were 44 CABG procedures among the readmitted group (28 planned). Forty-five percent of those undergoing a revascularization had been treated medically during their initial hospitalization.

Some treatments significantly increased the risk of 30-day readmission; most of that association was driven by procedural complications:

• Angiography with complications: hazard ratio, 2.40.

• Reperfusions with revascularization, with complications: HR, 2.12.

Some medical comorbidities also showed significant associations with readmission:

• Diabetes: HR, 1.34.

• Chronic obstructive pulmonary disease: HR, 1.43.

• Heart failure: HR, 1.12.

"Compared with our previous report on rehospitalizations after incident heart failure diagnosis in Olmsted County, COPD, diabetes, and anemia were common risk factors for rehospitalization among patients with incident MI and heart failure," the authors said. These risk factors "may be of particular importance as future targets in preventing rehospitalizations in patients hospitalized with cardiovascular disease."

The National Institutes of Health sponsored the study. The researchers reported having no relevant financial conflicts of interests.

Despite advances in the treatment of acute myocardial infarction, 30-day rehospitalization rates remained fairly constant from 1987 to 2010.

Rehospitalizations ranged from a high of 23% in 1987 to a low of 19% in 2010 – but that difference was not statistically significant, Dr. Shannon Dunlay and her colleagues reported in the July 3 issue of Annals of Internal Medicine

During that period, treatment advances were obvious. There was a significant decrease in fibrinolysis and significant increases in angiography, reperfusion, and percutaneous coronary intervention (PCI). But those improvements didn’t affect 30-day readmission rates, and in fact, seem to be a driver of them, the researchers, led by Dr. Dunlay, a cardiology fellow at the Mayo Clinic, Rochester, Minn., wrote.

"Angiography, reperfusion, and revascularization are mainstays of therapy in acute MI, and complications are associated with a high risk for rehospitalization," they wrote.

They also noted that "as the prevalence of such comorbid conditions as diabetes and COPD [chronic obstructive pulmonary disease] increases over time, rehospitalizations after acute MI may continue to shift toward noncardiovascular causes." Other medical comorbidities, including hypertension, hyperlipidemia, and obesity, were also significantly associated with readmission rates (Ann. Intern. Med. 2012; 157:11-18).

The authors found that 43% of the readmissions were related to the incident heart attack or its treatment, 30% were unrelated, and a relationship was unclear in 27%.

The review encompassed 3,010 cases extracted from the Rochester Epidemiology Project, a database that links patient records from three facilities in Olmstead County, Minn. The patients’ mean age was 67 years and did not change over the study period.

In-hospital survival improved over time (89% in 1987 and 96% in 2010).

There were significant changes in comorbid conditions from 1987 to 2010, including hypertension (61%-69%), hyperlipidemia (50%-68%), diabetes (22%-24%), and obesity [a body mass index of at least 30 kg/m²] (33%-38%).

Treatment changes included a significant decrease in fibrinolysis (28%-1%), and significant increases in reperfusion/revascularization (64%-69%), PCI (51%-63%), and angiography (76%-85%). The median length of stay dropped from 5 days to 3 days – also a significant change.

Increasing rates of complications were associated with these changes in treatment, the records showed. Ten percent of patients who underwent PCI had a complication. These included vascular or bleeding complications (6%), stroke (0.3%), and renal failure (5%). Of the vascular or bleeding complications, 63% were access site complications, most of which were groin hematomas.

The complication rate was low among patient receiving fibrinolysis (2%). Two percent of patients who had a coronary artery bypass graft (CABG) procedure had an associated stroke. The complication rate was 8% among patients who had angiography, with or without reperfusion. Most of those (5%) had acute renal failure, with three patients requiring dialysis. The other patients had vascular or bleeding complications.

Thirty-day rehospitalizations were required in 561 patients (19%), who were admitted a total of 643 times – 484 patients were admitted once, 72 twice, and 5 three times. Three percent (87) of the patients died within 30 days; among these, 19 were in a readmission when they died.

Readmission rates were 23% from 1987 to 1992; 22% from 1993 to 1998; 22% from 1999 to 2004; and 19% from 2005 to 2010.

The most common reasons for rehospitalization were ischemic heart disease (15%), respiratory or other chest symptoms (10%), heart failure (9%), and cardiac arrhythmias (6%). Other reasons included procedural complications (92%); fluid/electrolyte problems (2%); and hypotension, pneumonia, embolism/thrombosis, and stroke or transient ischemic attack (about 1%) each.

Angiography was performed in 24% of readmissions and PCI in 9%. Of these, 25% were repeat PCIs of the same vessel.

There were 44 CABG procedures among the readmitted group (28 planned). Forty-five percent of those undergoing a revascularization had been treated medically during their initial hospitalization.

Some treatments significantly increased the risk of 30-day readmission; most of that association was driven by procedural complications:

• Angiography with complications: hazard ratio, 2.40.

• Reperfusions with revascularization, with complications: HR, 2.12.

Some medical comorbidities also showed significant associations with readmission:

• Diabetes: HR, 1.34.

• Chronic obstructive pulmonary disease: HR, 1.43.

• Heart failure: HR, 1.12.

"Compared with our previous report on rehospitalizations after incident heart failure diagnosis in Olmsted County, COPD, diabetes, and anemia were common risk factors for rehospitalization among patients with incident MI and heart failure," the authors said. These risk factors "may be of particular importance as future targets in preventing rehospitalizations in patients hospitalized with cardiovascular disease."

The National Institutes of Health sponsored the study. The researchers reported having no relevant financial conflicts of interests.

ILLUSTRATIVE CASE

A 65-year-old man with a history of moderate to severe COPD schedules an appointment soon after discharge from the hospital—his second hospitalization for COPD exacerbations in 4 months. The patient uses inhaled glucocorticoids, a long-acting beta-agonist (LABA), and a long-acting anticholinergic. Should you add a macrolide to his medication regimen?

Acute exacerbations of COPD—the third highest cause of death in the United States²—have a major effect on quality of life, often resulting in repeat trips to the emergency department (ED) and numerous hospitalizations, office visits, and days lost from work. According to a new study that used 2006 data, there were 1.25 million hospitalizations for COPD exacerbations that year, with health care costs of $11.9 billion.³ Preventing exacerbations and the associated morbidity and mortality is a major challenge that primary care physicians face.

Can a macrolide help?
Corticosteroids, long-acting beta-agonists (LABAs), and the anticholinergic tiotropium are known to reduce COPD exacerbations,^4,5 but what about antibiotics? A Cochrane meta-analysis of 9 RCTs that assessed antibiotic use for COPD found that it did not decrease the number of exacerbations. Notably, however, macrolides were not used in any of the studies.⁶

Macrolides are known to have anti-inflammatory, antibacterial, and immunomodulatory properties that reduce pulmonary exacerbations in other chronic lung diseases. A recent meta-analysis found that patients with cystic fibrosis have fewer pulmonary exacerbations when they take azithromycin 3 times a week.⁷

Small studies of the effect of macrolides on the frequency of COPD exacerbations have had conflicting results.^8,9 The larger study detailed here evaluated the ability of daily azithromycin therapy to reduce COPD exacerbations.

STUDY SUMMARY: Daily dose led to fewer exacerbations

This double-blind RCT included close to 1150 participants from 12 US academic health centers, randomly assigned to receive azithromycin 250 mg daily or placebo, in addition to their usual care. (About 10% of patients in both groups died, withdrew, or were lost to follow-up.)

To be included, patients had to be ≥40 years old and have a clinical diagnosis of COPD, defined as a smoking history of 10 pack-years or more, a decreased forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio, and a decreased FEV1 after bronchodilation. In addition, participants had to be on long-term oxygen or have used systemic steroids within the previous year or have had an ED visit or hospital admission for COPD during that time frame. Exclusion criteria included a history of asthma, a resting heart rate >100 beats per minute, a prolonged corrected QT interval (QTc) on electrocardiogram or the use of a medication that might prolong QTc, and a documented hearing impairment.

At baseline, participants were similar in basic demographics, COPD severity, smoking history, and medication use: 49% of those in the azithromycin group and 46% of the placebo group were taking a combination of inhaled corticosteroids, LABAs, and a long-acting anticholinergic medication.

The primary outcome was the time to the first COPD exacerbation. This was defined as ≥3 days with 2 or more COPD symptoms—new onset or worsening cough, dyspnea, sputum production, chest tightness, or wheezing—for which antibiotics or steroids were required. Secondary outcomes were quality-of-life measurements on the St. George’s Respiratory Questionnaire (SGRQ) and the Medical Outcomes 36-item Short Form Health Survey (SF-36). Nasopharyngeal swabs were done every 3 months to check for colonization and resistance. Hearing was assessed with audiometry at the time of enrollment, and again at 3 and 12 months. All patients were followed for a year, with monthly telephone calls or clinic visits, to determine if an exacerbation had occurred in the previous month.

The median time to the first exacerbation in the azithromycin group was 266 days (95% confidence interval [CI], 227-313) vs 174 days (95% CI, 143-215) in the placebo group; P<.001. Frequency of acute exacerbations was 1.48 per patient-year for the azithromycin group compared with 1.83 for the placebo group (relative risk=0.83; 95% CI, 0.72–0.95; P=.01). The number needed to treat to prevent one acute exacerbation in a one-year period was 2.86.

There was no significant difference in the SGRQ and SF-36 scores for the azithromycin vs the placebo group. There was a small reduction in unscheduled office visits (0.11 per patient-year; P=.048) in the azithromycin group, and a decrease in hospitalization that was not statistically significant.

Azithromycin group had higher rates of adverse effects
Nasopharyngeal cultures from participants who became colonized during the course of the study found macrolide resistance in 81% of those in the azithromycin group vs 41% of the placebo group (P<.001). Twenty-five percent of patients in the azithromycin group developed measurable hearing loss, compared with 20% of those on placebo (P=0.04; number needed to harm=20).

WHAT’S NEW?: A better understanding of benefits and risks

This study shows that the addition of azithromycin (250 mg/d) to standard COPD treatment decreases the number of exacerbations, but does little to reduce hospital admissions. It also highlights the adverse effect profile of azithromycin and the importance of using the antibiotic only for carefully selected patients.

CAVEATS: Macrolide resistance is a key concern

Twenty-five percent of the azithromycin group had documented hearing loss—an additional one in 20 compared with patients in the placebo group. More importantly, there was an increase in the prevalence of macrolide-resistant respiratory pathogens in patients on daily azithromycin. The long-term impact of daily azithromycin on antibiotic resistance is unknown, both for patients themselves and the community at large.

Physicians will have to assess the benefit of a decrease in COPD exacerbations (approximately one every 3 years) vs the risk of an increase in hearing problems and macrolide resistance. A sensible approach would be to reserve daily use of azithromycin for patients with a history of multiple exacerbations, who potentially have more to gain.

CHALLENGES TO IMPLEMENTATION: There are none

There are no major challenges to implementation aside from the cost, which would be approximately $1200 per year (azithromycin 250 mg [30 tablets] at $98.99 per month).¹⁰

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 65-year-old man with a history of moderate to severe COPD schedules an appointment soon after discharge from the hospital—his second hospitalization for COPD exacerbations in 4 months. The patient uses inhaled glucocorticoids, a long-acting beta-agonist (LABA), and a long-acting anticholinergic. Should you add a macrolide to his medication regimen?

Acute exacerbations of COPD—the third highest cause of death in the United States²—have a major effect on quality of life, often resulting in repeat trips to the emergency department (ED) and numerous hospitalizations, office visits, and days lost from work. According to a new study that used 2006 data, there were 1.25 million hospitalizations for COPD exacerbations that year, with health care costs of $11.9 billion.³ Preventing exacerbations and the associated morbidity and mortality is a major challenge that primary care physicians face.

Can a macrolide help?
Corticosteroids, long-acting beta-agonists (LABAs), and the anticholinergic tiotropium are known to reduce COPD exacerbations,^4,5 but what about antibiotics? A Cochrane meta-analysis of 9 RCTs that assessed antibiotic use for COPD found that it did not decrease the number of exacerbations. Notably, however, macrolides were not used in any of the studies.⁶

Macrolides are known to have anti-inflammatory, antibacterial, and immunomodulatory properties that reduce pulmonary exacerbations in other chronic lung diseases. A recent meta-analysis found that patients with cystic fibrosis have fewer pulmonary exacerbations when they take azithromycin 3 times a week.⁷

Small studies of the effect of macrolides on the frequency of COPD exacerbations have had conflicting results.^8,9 The larger study detailed here evaluated the ability of daily azithromycin therapy to reduce COPD exacerbations.

STUDY SUMMARY: Daily dose led to fewer exacerbations

This double-blind RCT included close to 1150 participants from 12 US academic health centers, randomly assigned to receive azithromycin 250 mg daily or placebo, in addition to their usual care. (About 10% of patients in both groups died, withdrew, or were lost to follow-up.)

To be included, patients had to be ≥40 years old and have a clinical diagnosis of COPD, defined as a smoking history of 10 pack-years or more, a decreased forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio, and a decreased FEV1 after bronchodilation. In addition, participants had to be on long-term oxygen or have used systemic steroids within the previous year or have had an ED visit or hospital admission for COPD during that time frame. Exclusion criteria included a history of asthma, a resting heart rate >100 beats per minute, a prolonged corrected QT interval (QTc) on electrocardiogram or the use of a medication that might prolong QTc, and a documented hearing impairment.

At baseline, participants were similar in basic demographics, COPD severity, smoking history, and medication use: 49% of those in the azithromycin group and 46% of the placebo group were taking a combination of inhaled corticosteroids, LABAs, and a long-acting anticholinergic medication.

The primary outcome was the time to the first COPD exacerbation. This was defined as ≥3 days with 2 or more COPD symptoms—new onset or worsening cough, dyspnea, sputum production, chest tightness, or wheezing—for which antibiotics or steroids were required. Secondary outcomes were quality-of-life measurements on the St. George’s Respiratory Questionnaire (SGRQ) and the Medical Outcomes 36-item Short Form Health Survey (SF-36). Nasopharyngeal swabs were done every 3 months to check for colonization and resistance. Hearing was assessed with audiometry at the time of enrollment, and again at 3 and 12 months. All patients were followed for a year, with monthly telephone calls or clinic visits, to determine if an exacerbation had occurred in the previous month.

The median time to the first exacerbation in the azithromycin group was 266 days (95% confidence interval [CI], 227-313) vs 174 days (95% CI, 143-215) in the placebo group; P<.001. Frequency of acute exacerbations was 1.48 per patient-year for the azithromycin group compared with 1.83 for the placebo group (relative risk=0.83; 95% CI, 0.72–0.95; P=.01). The number needed to treat to prevent one acute exacerbation in a one-year period was 2.86.

There was no significant difference in the SGRQ and SF-36 scores for the azithromycin vs the placebo group. There was a small reduction in unscheduled office visits (0.11 per patient-year; P=.048) in the azithromycin group, and a decrease in hospitalization that was not statistically significant.

Azithromycin group had higher rates of adverse effects
Nasopharyngeal cultures from participants who became colonized during the course of the study found macrolide resistance in 81% of those in the azithromycin group vs 41% of the placebo group (P<.001). Twenty-five percent of patients in the azithromycin group developed measurable hearing loss, compared with 20% of those on placebo (P=0.04; number needed to harm=20).

WHAT’S NEW?: A better understanding of benefits and risks

This study shows that the addition of azithromycin (250 mg/d) to standard COPD treatment decreases the number of exacerbations, but does little to reduce hospital admissions. It also highlights the adverse effect profile of azithromycin and the importance of using the antibiotic only for carefully selected patients.

CAVEATS: Macrolide resistance is a key concern

Twenty-five percent of the azithromycin group had documented hearing loss—an additional one in 20 compared with patients in the placebo group. More importantly, there was an increase in the prevalence of macrolide-resistant respiratory pathogens in patients on daily azithromycin. The long-term impact of daily azithromycin on antibiotic resistance is unknown, both for patients themselves and the community at large.

Physicians will have to assess the benefit of a decrease in COPD exacerbations (approximately one every 3 years) vs the risk of an increase in hearing problems and macrolide resistance. A sensible approach would be to reserve daily use of azithromycin for patients with a history of multiple exacerbations, who potentially have more to gain.

CHALLENGES TO IMPLEMENTATION: There are none

There are no major challenges to implementation aside from the cost, which would be approximately $1200 per year (azithromycin 250 mg [30 tablets] at $98.99 per month).¹⁰

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 65-year-old man with a history of moderate to severe COPD schedules an appointment soon after discharge from the hospital—his second hospitalization for COPD exacerbations in 4 months. The patient uses inhaled glucocorticoids, a long-acting beta-agonist (LABA), and a long-acting anticholinergic. Should you add a macrolide to his medication regimen?

Acute exacerbations of COPD—the third highest cause of death in the United States²—have a major effect on quality of life, often resulting in repeat trips to the emergency department (ED) and numerous hospitalizations, office visits, and days lost from work. According to a new study that used 2006 data, there were 1.25 million hospitalizations for COPD exacerbations that year, with health care costs of $11.9 billion.³ Preventing exacerbations and the associated morbidity and mortality is a major challenge that primary care physicians face.

Can a macrolide help?
Corticosteroids, long-acting beta-agonists (LABAs), and the anticholinergic tiotropium are known to reduce COPD exacerbations,^4,5 but what about antibiotics? A Cochrane meta-analysis of 9 RCTs that assessed antibiotic use for COPD found that it did not decrease the number of exacerbations. Notably, however, macrolides were not used in any of the studies.⁶

Macrolides are known to have anti-inflammatory, antibacterial, and immunomodulatory properties that reduce pulmonary exacerbations in other chronic lung diseases. A recent meta-analysis found that patients with cystic fibrosis have fewer pulmonary exacerbations when they take azithromycin 3 times a week.⁷

Small studies of the effect of macrolides on the frequency of COPD exacerbations have had conflicting results.^8,9 The larger study detailed here evaluated the ability of daily azithromycin therapy to reduce COPD exacerbations.

STUDY SUMMARY: Daily dose led to fewer exacerbations

This double-blind RCT included close to 1150 participants from 12 US academic health centers, randomly assigned to receive azithromycin 250 mg daily or placebo, in addition to their usual care. (About 10% of patients in both groups died, withdrew, or were lost to follow-up.)

To be included, patients had to be ≥40 years old and have a clinical diagnosis of COPD, defined as a smoking history of 10 pack-years or more, a decreased forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio, and a decreased FEV1 after bronchodilation. In addition, participants had to be on long-term oxygen or have used systemic steroids within the previous year or have had an ED visit or hospital admission for COPD during that time frame. Exclusion criteria included a history of asthma, a resting heart rate >100 beats per minute, a prolonged corrected QT interval (QTc) on electrocardiogram or the use of a medication that might prolong QTc, and a documented hearing impairment.

At baseline, participants were similar in basic demographics, COPD severity, smoking history, and medication use: 49% of those in the azithromycin group and 46% of the placebo group were taking a combination of inhaled corticosteroids, LABAs, and a long-acting anticholinergic medication.

The primary outcome was the time to the first COPD exacerbation. This was defined as ≥3 days with 2 or more COPD symptoms—new onset or worsening cough, dyspnea, sputum production, chest tightness, or wheezing—for which antibiotics or steroids were required. Secondary outcomes were quality-of-life measurements on the St. George’s Respiratory Questionnaire (SGRQ) and the Medical Outcomes 36-item Short Form Health Survey (SF-36). Nasopharyngeal swabs were done every 3 months to check for colonization and resistance. Hearing was assessed with audiometry at the time of enrollment, and again at 3 and 12 months. All patients were followed for a year, with monthly telephone calls or clinic visits, to determine if an exacerbation had occurred in the previous month.

The median time to the first exacerbation in the azithromycin group was 266 days (95% confidence interval [CI], 227-313) vs 174 days (95% CI, 143-215) in the placebo group; P<.001. Frequency of acute exacerbations was 1.48 per patient-year for the azithromycin group compared with 1.83 for the placebo group (relative risk=0.83; 95% CI, 0.72–0.95; P=.01). The number needed to treat to prevent one acute exacerbation in a one-year period was 2.86.

There was no significant difference in the SGRQ and SF-36 scores for the azithromycin vs the placebo group. There was a small reduction in unscheduled office visits (0.11 per patient-year; P=.048) in the azithromycin group, and a decrease in hospitalization that was not statistically significant.

Azithromycin group had higher rates of adverse effects
Nasopharyngeal cultures from participants who became colonized during the course of the study found macrolide resistance in 81% of those in the azithromycin group vs 41% of the placebo group (P<.001). Twenty-five percent of patients in the azithromycin group developed measurable hearing loss, compared with 20% of those on placebo (P=0.04; number needed to harm=20).

WHAT’S NEW?: A better understanding of benefits and risks

This study shows that the addition of azithromycin (250 mg/d) to standard COPD treatment decreases the number of exacerbations, but does little to reduce hospital admissions. It also highlights the adverse effect profile of azithromycin and the importance of using the antibiotic only for carefully selected patients.

CAVEATS: Macrolide resistance is a key concern

Twenty-five percent of the azithromycin group had documented hearing loss—an additional one in 20 compared with patients in the placebo group. More importantly, there was an increase in the prevalence of macrolide-resistant respiratory pathogens in patients on daily azithromycin. The long-term impact of daily azithromycin on antibiotic resistance is unknown, both for patients themselves and the community at large.

Physicians will have to assess the benefit of a decrease in COPD exacerbations (approximately one every 3 years) vs the risk of an increase in hearing problems and macrolide resistance. A sensible approach would be to reserve daily use of azithromycin for patients with a history of multiple exacerbations, who potentially have more to gain.

CHALLENGES TO IMPLEMENTATION: There are none

There are no major challenges to implementation aside from the cost, which would be approximately $1200 per year (azithromycin 250 mg [30 tablets] at $98.99 per month).¹⁰

Acknowledgement

The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Evidence summary

The most commonly measured outcomes in allergic rhinitis and conjunctivitis trials are symptom scales, which are neither standardized nor clinically validated. Almost all the studies discussed here calculated outcomes as a percentage change from baseline symptom scores but didn’t provide absolute values, so it isn’t clear whether statistical differences are clinically relevant.

Steroids provide more relief of nasal symptoms
A meta-analysis of 21 randomized placebo-controlled trials (total 2821 patients, average age mid-30s) that compared changes in TNSS with intranasal steroids and oral antihistamines among adults with seasonal allergic rhinitis found that steroids reduced TNSS more than antihistamines.¹ Most of the patients had had moderate to severe symptoms for several years.

Investigators calculated percent changes from baseline in mean TNSS, which typically included sneezing, itching, congestion, and rhinorrhea, each usually scored on a scale of 0 to 3.¹ Individual RCTs compared one of 3 intranasal steroids (fluticasone, triamcinolone, or budesonide) and one of 3 oral antihistamines (cetirizine, loratadine, or fexofenadine) with placebo; no studies compared medications within classes against each other.¹

On individual symptom scores, intranasal steroids reduced sneezing, itching, congestion, and rhinorrhea more than placebo by more than 20%. Both intranasal steroids and oral antihistamines decreased itching and rhinorrhea a similar amount, but antihistamines reduced congestion by only 5% to 10% more than placebo.¹

This meta-analysis included only studies reporting TNSS as an outcome, and individual studies used varying TNSS scales. Investigators attributed heterogeneity in the studies to intraclass differences between medications.¹

Two drug company-sponsored RCTs (1616 patients combined, average age 30s, moderate to severe allergic rhinitis) published before the meta-analysis also demonstrated that the intranasal steroid fluticasone propionate modestly reduced TNSS compared with the oral antihistamine fexofenadine (1 point vs 1.3 on a scale of 0 to 12).² TABLE 1 summarizes the results of studies comparing intranasal steroids and oral antihistamines to reduce nasal symptoms.

TABLE 1
Intranasal steroids vs oral antihistamines for nasal symptom relief

Results for eye symptoms are mixed
A meta-analysis of 11 RCTs (1317 patients, average age 32) showed no significant difference in relief of eye symptoms between oral antihistamines (dexchlorpheniramine, terfenadine, and loratadine) and intranasal steroids (budesonide, beclomethasone, fluticasone, and triamcinolone) in patients with seasonal allergies, as measured by various symptom scores.³

Three other studies indicated that intranasal steroids (triamcinolone, fluticasone) relieved eye symptoms more effectively than oral antihistamines (loratadine, fexofenadine) based on mean reductions in TNSS, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), and Total Ocular Symptom Score (TOSS).^4-6 Of these scoring systems, only the RQLQ has been clinically validated.⁷

One additional study (including 2 RCTs) showed conflicting results.² TABLE 2 summarizes the results of studies comparing intranasal steroids and oral antihistamines to relieve eye symptoms.

TABLE 2
How intranasal steroids compare with oral antihistamines for reducing eye symptoms

Antihistamines cost less than steroids and are available OTC
Oral antihistamines are less expensive than intranasal steroids and are available over the counter. The cost of antihistamines ranges from $5.70 to $21.99 for a month of treatment, whereas the cost of intranasal steroids for the same period varies from $60.99 to $149.99.⁸

In the studies reviewed here, the 2 interventions showed similar harms, including sore throat, epistaxis, and headache.^2,4-6

Recommendations

The American Academy of Allergy, Asthma and Immunology’s 2010 guidelines conclude that intranasal steroids are first-line treatment for allergic rhinitis. If the patient prefers, use oral antihistamines.⁹

The Joint Task Force on Practice Parameters for Allergy and Immunology also recommends intranasal steroids as the most effective medication class for treating allergic rhinitis; no drug within the class is preferable to another. Daily administration is more effective than administration as needed, although the latter is an option. For treating ocular symptoms, intranasal corticosteroids and oral antihistamines work equally well.¹⁰

Evidence summary

The most commonly measured outcomes in allergic rhinitis and conjunctivitis trials are symptom scales, which are neither standardized nor clinically validated. Almost all the studies discussed here calculated outcomes as a percentage change from baseline symptom scores but didn’t provide absolute values, so it isn’t clear whether statistical differences are clinically relevant.

Steroids provide more relief of nasal symptoms
A meta-analysis of 21 randomized placebo-controlled trials (total 2821 patients, average age mid-30s) that compared changes in TNSS with intranasal steroids and oral antihistamines among adults with seasonal allergic rhinitis found that steroids reduced TNSS more than antihistamines.¹ Most of the patients had had moderate to severe symptoms for several years.

Investigators calculated percent changes from baseline in mean TNSS, which typically included sneezing, itching, congestion, and rhinorrhea, each usually scored on a scale of 0 to 3.¹ Individual RCTs compared one of 3 intranasal steroids (fluticasone, triamcinolone, or budesonide) and one of 3 oral antihistamines (cetirizine, loratadine, or fexofenadine) with placebo; no studies compared medications within classes against each other.¹

On individual symptom scores, intranasal steroids reduced sneezing, itching, congestion, and rhinorrhea more than placebo by more than 20%. Both intranasal steroids and oral antihistamines decreased itching and rhinorrhea a similar amount, but antihistamines reduced congestion by only 5% to 10% more than placebo.¹

This meta-analysis included only studies reporting TNSS as an outcome, and individual studies used varying TNSS scales. Investigators attributed heterogeneity in the studies to intraclass differences between medications.¹

Two drug company-sponsored RCTs (1616 patients combined, average age 30s, moderate to severe allergic rhinitis) published before the meta-analysis also demonstrated that the intranasal steroid fluticasone propionate modestly reduced TNSS compared with the oral antihistamine fexofenadine (1 point vs 1.3 on a scale of 0 to 12).² TABLE 1 summarizes the results of studies comparing intranasal steroids and oral antihistamines to reduce nasal symptoms.

TABLE 1
Intranasal steroids vs oral antihistamines for nasal symptom relief

Results for eye symptoms are mixed
A meta-analysis of 11 RCTs (1317 patients, average age 32) showed no significant difference in relief of eye symptoms between oral antihistamines (dexchlorpheniramine, terfenadine, and loratadine) and intranasal steroids (budesonide, beclomethasone, fluticasone, and triamcinolone) in patients with seasonal allergies, as measured by various symptom scores.³

Three other studies indicated that intranasal steroids (triamcinolone, fluticasone) relieved eye symptoms more effectively than oral antihistamines (loratadine, fexofenadine) based on mean reductions in TNSS, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), and Total Ocular Symptom Score (TOSS).^4-6 Of these scoring systems, only the RQLQ has been clinically validated.⁷

One additional study (including 2 RCTs) showed conflicting results.² TABLE 2 summarizes the results of studies comparing intranasal steroids and oral antihistamines to relieve eye symptoms.

TABLE 2
How intranasal steroids compare with oral antihistamines for reducing eye symptoms

Antihistamines cost less than steroids and are available OTC
Oral antihistamines are less expensive than intranasal steroids and are available over the counter. The cost of antihistamines ranges from $5.70 to $21.99 for a month of treatment, whereas the cost of intranasal steroids for the same period varies from $60.99 to $149.99.⁸

In the studies reviewed here, the 2 interventions showed similar harms, including sore throat, epistaxis, and headache.^2,4-6

Recommendations

The American Academy of Allergy, Asthma and Immunology’s 2010 guidelines conclude that intranasal steroids are first-line treatment for allergic rhinitis. If the patient prefers, use oral antihistamines.⁹

The Joint Task Force on Practice Parameters for Allergy and Immunology also recommends intranasal steroids as the most effective medication class for treating allergic rhinitis; no drug within the class is preferable to another. Daily administration is more effective than administration as needed, although the latter is an option. For treating ocular symptoms, intranasal corticosteroids and oral antihistamines work equally well.¹⁰

Evidence summary

The most commonly measured outcomes in allergic rhinitis and conjunctivitis trials are symptom scales, which are neither standardized nor clinically validated. Almost all the studies discussed here calculated outcomes as a percentage change from baseline symptom scores but didn’t provide absolute values, so it isn’t clear whether statistical differences are clinically relevant.

Steroids provide more relief of nasal symptoms
A meta-analysis of 21 randomized placebo-controlled trials (total 2821 patients, average age mid-30s) that compared changes in TNSS with intranasal steroids and oral antihistamines among adults with seasonal allergic rhinitis found that steroids reduced TNSS more than antihistamines.¹ Most of the patients had had moderate to severe symptoms for several years.

Investigators calculated percent changes from baseline in mean TNSS, which typically included sneezing, itching, congestion, and rhinorrhea, each usually scored on a scale of 0 to 3.¹ Individual RCTs compared one of 3 intranasal steroids (fluticasone, triamcinolone, or budesonide) and one of 3 oral antihistamines (cetirizine, loratadine, or fexofenadine) with placebo; no studies compared medications within classes against each other.¹

On individual symptom scores, intranasal steroids reduced sneezing, itching, congestion, and rhinorrhea more than placebo by more than 20%. Both intranasal steroids and oral antihistamines decreased itching and rhinorrhea a similar amount, but antihistamines reduced congestion by only 5% to 10% more than placebo.¹

This meta-analysis included only studies reporting TNSS as an outcome, and individual studies used varying TNSS scales. Investigators attributed heterogeneity in the studies to intraclass differences between medications.¹

Two drug company-sponsored RCTs (1616 patients combined, average age 30s, moderate to severe allergic rhinitis) published before the meta-analysis also demonstrated that the intranasal steroid fluticasone propionate modestly reduced TNSS compared with the oral antihistamine fexofenadine (1 point vs 1.3 on a scale of 0 to 12).² TABLE 1 summarizes the results of studies comparing intranasal steroids and oral antihistamines to reduce nasal symptoms.

TABLE 1
Intranasal steroids vs oral antihistamines for nasal symptom relief

Results for eye symptoms are mixed
A meta-analysis of 11 RCTs (1317 patients, average age 32) showed no significant difference in relief of eye symptoms between oral antihistamines (dexchlorpheniramine, terfenadine, and loratadine) and intranasal steroids (budesonide, beclomethasone, fluticasone, and triamcinolone) in patients with seasonal allergies, as measured by various symptom scores.³

Three other studies indicated that intranasal steroids (triamcinolone, fluticasone) relieved eye symptoms more effectively than oral antihistamines (loratadine, fexofenadine) based on mean reductions in TNSS, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), and Total Ocular Symptom Score (TOSS).^4-6 Of these scoring systems, only the RQLQ has been clinically validated.⁷

One additional study (including 2 RCTs) showed conflicting results.² TABLE 2 summarizes the results of studies comparing intranasal steroids and oral antihistamines to relieve eye symptoms.

TABLE 2
How intranasal steroids compare with oral antihistamines for reducing eye symptoms

Antihistamines cost less than steroids and are available OTC
Oral antihistamines are less expensive than intranasal steroids and are available over the counter. The cost of antihistamines ranges from $5.70 to $21.99 for a month of treatment, whereas the cost of intranasal steroids for the same period varies from $60.99 to $149.99.⁸

In the studies reviewed here, the 2 interventions showed similar harms, including sore throat, epistaxis, and headache.^2,4-6

Recommendations

The American Academy of Allergy, Asthma and Immunology’s 2010 guidelines conclude that intranasal steroids are first-line treatment for allergic rhinitis. If the patient prefers, use oral antihistamines.⁹

The Joint Task Force on Practice Parameters for Allergy and Immunology also recommends intranasal steroids as the most effective medication class for treating allergic rhinitis; no drug within the class is preferable to another. Daily administration is more effective than administration as needed, although the latter is an option. For treating ocular symptoms, intranasal corticosteroids and oral antihistamines work equally well.¹⁰

BOSTON – Adaptive servoventilation is more reliably effective than continuous positive airway pressure is for the prolonged treatment of complex sleep apnea, a study has shown.

Prior studies have shown that the adaptive ventilatory support method, which continuously monitors and analyzes a patient’s breathing pattern and adds variable amounts of inspiratory pressure support to low levels of background expiratory positive airway pressure as needed, is initially more effective than is continuous positive airway pressure (CPAP) in complex sleep apnea patients. But sustained efficacy over time has not been established, according to Dr. Timothy I. Morgenthaler of the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minn.

"The concern is that residual central breathing events may resolve over time with CPAP therapy, which is less expensive than adaptive servoventilation [ASV] and therefore may be a better option," he said at the annual meeting of the Associated Professional Sleep Societies.

To evaluate the longer-term efficacy of ASV relative to CPAP in individuals with complex sleep apnea syndrome (CSAS), Dr. Morgenthaler and his colleagues conducted a multicenter, prospective trial of 66 patients with CSAS, defined as those meeting the criteria for obstructive sleep apnea on diagnostic polysomnography who also had a central apnea index (CAI) score of 10 or higher while on optimal CPAP. The participants were randomized to treatment with either CPAP (n = 33) or ASV (n = 33), both titrated to optimal settings. Clinical and polysomnographic measures were collected at baseline and after 90 days of therapy, he said.

In addition to having a diagnosis of CSAS, eligible patients were older than 18 years and were naive to positive airway pressure treatment. The mean age of the study participants was 59.2 years, and the mean body mass index was 35.0 kg/m², with no between-group differences. Additionally, about 9% of the patients had congestive heart failure and 13.6% reported chronic opiate use, Dr. Morgenthaler reported.

At baseline, the mean apnea-hypopnea index (AHI) and CAI scores were 37.7 and 3.2, respectively. After second-night treatment titration, the AHI scores were 4.7 in the ASV group vs. 14.1 in the CPAP group, and the respective CAI scores were 1.1 and 8.8, said Dr. Morgenthaler. At 90 days, the AHI for the ASV group was 4.4, compared with 9.9 for CPAP, and the respective CAI scores were 0.7 and 4.8, he said.

"In the intention-to-treat analysis, treatment was successful [defined as an AHI of less than 10] in 89.7% of the adaptive servoventilation group," while only 64.5% of the CPAP patients attained similar success, Dr. Morgenthaler stated, noting that there were no significant differences between the groups with respect to compliance, Epworth Sleepiness Scale (ESS) changes, or sleep apnea quality of life index (SAQLI) scores.

Although significantly more ASV patients showed evidence of treatment efficacy based on polysomnographic measures than did CPAP patients, "there were no similar symptomatic differences between the groups," Dr. Morgenthaler acknowledged. It is possible, but yet to be determined, that ASV-induced improvements on polysomnography will translate into other positive health outcomes, such as maximal suppression of Cheyne-Stokes respiration and central sleep apnea (CSR-CSA), as well as improvement in brain natriuretic peptide, in patients with heart failure, he said.

Dr. Morgenthaler disclosed that this study was supported by a grant from ResMed, the manufacturer of the ASV device used in the investigation.

BOSTON – Adaptive servoventilation is more reliably effective than continuous positive airway pressure is for the prolonged treatment of complex sleep apnea, a study has shown.

Prior studies have shown that the adaptive ventilatory support method, which continuously monitors and analyzes a patient’s breathing pattern and adds variable amounts of inspiratory pressure support to low levels of background expiratory positive airway pressure as needed, is initially more effective than is continuous positive airway pressure (CPAP) in complex sleep apnea patients. But sustained efficacy over time has not been established, according to Dr. Timothy I. Morgenthaler of the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minn.

"The concern is that residual central breathing events may resolve over time with CPAP therapy, which is less expensive than adaptive servoventilation [ASV] and therefore may be a better option," he said at the annual meeting of the Associated Professional Sleep Societies.

To evaluate the longer-term efficacy of ASV relative to CPAP in individuals with complex sleep apnea syndrome (CSAS), Dr. Morgenthaler and his colleagues conducted a multicenter, prospective trial of 66 patients with CSAS, defined as those meeting the criteria for obstructive sleep apnea on diagnostic polysomnography who also had a central apnea index (CAI) score of 10 or higher while on optimal CPAP. The participants were randomized to treatment with either CPAP (n = 33) or ASV (n = 33), both titrated to optimal settings. Clinical and polysomnographic measures were collected at baseline and after 90 days of therapy, he said.

In addition to having a diagnosis of CSAS, eligible patients were older than 18 years and were naive to positive airway pressure treatment. The mean age of the study participants was 59.2 years, and the mean body mass index was 35.0 kg/m², with no between-group differences. Additionally, about 9% of the patients had congestive heart failure and 13.6% reported chronic opiate use, Dr. Morgenthaler reported.

At baseline, the mean apnea-hypopnea index (AHI) and CAI scores were 37.7 and 3.2, respectively. After second-night treatment titration, the AHI scores were 4.7 in the ASV group vs. 14.1 in the CPAP group, and the respective CAI scores were 1.1 and 8.8, said Dr. Morgenthaler. At 90 days, the AHI for the ASV group was 4.4, compared with 9.9 for CPAP, and the respective CAI scores were 0.7 and 4.8, he said.

"In the intention-to-treat analysis, treatment was successful [defined as an AHI of less than 10] in 89.7% of the adaptive servoventilation group," while only 64.5% of the CPAP patients attained similar success, Dr. Morgenthaler stated, noting that there were no significant differences between the groups with respect to compliance, Epworth Sleepiness Scale (ESS) changes, or sleep apnea quality of life index (SAQLI) scores.

Although significantly more ASV patients showed evidence of treatment efficacy based on polysomnographic measures than did CPAP patients, "there were no similar symptomatic differences between the groups," Dr. Morgenthaler acknowledged. It is possible, but yet to be determined, that ASV-induced improvements on polysomnography will translate into other positive health outcomes, such as maximal suppression of Cheyne-Stokes respiration and central sleep apnea (CSR-CSA), as well as improvement in brain natriuretic peptide, in patients with heart failure, he said.

Dr. Morgenthaler disclosed that this study was supported by a grant from ResMed, the manufacturer of the ASV device used in the investigation.

BOSTON – Adaptive servoventilation is more reliably effective than continuous positive airway pressure is for the prolonged treatment of complex sleep apnea, a study has shown.

Prior studies have shown that the adaptive ventilatory support method, which continuously monitors and analyzes a patient’s breathing pattern and adds variable amounts of inspiratory pressure support to low levels of background expiratory positive airway pressure as needed, is initially more effective than is continuous positive airway pressure (CPAP) in complex sleep apnea patients. But sustained efficacy over time has not been established, according to Dr. Timothy I. Morgenthaler of the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minn.

"The concern is that residual central breathing events may resolve over time with CPAP therapy, which is less expensive than adaptive servoventilation [ASV] and therefore may be a better option," he said at the annual meeting of the Associated Professional Sleep Societies.

To evaluate the longer-term efficacy of ASV relative to CPAP in individuals with complex sleep apnea syndrome (CSAS), Dr. Morgenthaler and his colleagues conducted a multicenter, prospective trial of 66 patients with CSAS, defined as those meeting the criteria for obstructive sleep apnea on diagnostic polysomnography who also had a central apnea index (CAI) score of 10 or higher while on optimal CPAP. The participants were randomized to treatment with either CPAP (n = 33) or ASV (n = 33), both titrated to optimal settings. Clinical and polysomnographic measures were collected at baseline and after 90 days of therapy, he said.

In addition to having a diagnosis of CSAS, eligible patients were older than 18 years and were naive to positive airway pressure treatment. The mean age of the study participants was 59.2 years, and the mean body mass index was 35.0 kg/m², with no between-group differences. Additionally, about 9% of the patients had congestive heart failure and 13.6% reported chronic opiate use, Dr. Morgenthaler reported.

At baseline, the mean apnea-hypopnea index (AHI) and CAI scores were 37.7 and 3.2, respectively. After second-night treatment titration, the AHI scores were 4.7 in the ASV group vs. 14.1 in the CPAP group, and the respective CAI scores were 1.1 and 8.8, said Dr. Morgenthaler. At 90 days, the AHI for the ASV group was 4.4, compared with 9.9 for CPAP, and the respective CAI scores were 0.7 and 4.8, he said.

"In the intention-to-treat analysis, treatment was successful [defined as an AHI of less than 10] in 89.7% of the adaptive servoventilation group," while only 64.5% of the CPAP patients attained similar success, Dr. Morgenthaler stated, noting that there were no significant differences between the groups with respect to compliance, Epworth Sleepiness Scale (ESS) changes, or sleep apnea quality of life index (SAQLI) scores.

Although significantly more ASV patients showed evidence of treatment efficacy based on polysomnographic measures than did CPAP patients, "there were no similar symptomatic differences between the groups," Dr. Morgenthaler acknowledged. It is possible, but yet to be determined, that ASV-induced improvements on polysomnography will translate into other positive health outcomes, such as maximal suppression of Cheyne-Stokes respiration and central sleep apnea (CSR-CSA), as well as improvement in brain natriuretic peptide, in patients with heart failure, he said.

Dr. Morgenthaler disclosed that this study was supported by a grant from ResMed, the manufacturer of the ASV device used in the investigation.

SAN FRANCISCO – Underlying pulmonary fungal colonization or infection may be the reason that some children with severe asthma don’t respond fully to conventional treatments.

Severe asthma with fungal sensitization (SAFS) has been recognized only recently. In adults, SAFS has been found to respond to oral itraconazole (Am. J. Respir. Crit. Care Med. 2009;179:11-8).

CDC/Dr. Lucille K. Georg

SAFS also occurs in children, according to Dr. Alfin G. Vicencio, chief of pediatric pulmonology and cystic fibrosis at Cohen Children’s Medical Center in New Hyde Park, N.Y., and his colleagues.

The researchers looked at 41 children, teens, and young adults (aged 2-21 years) with severe asthma who were failing level 4 or greater combination asthma therapy, and found that 17 (41.5%) had serum fungal IgE levels above 100 IU/mL and evidence of fungal sensitization on radioallergosorbent or skin-prick tests, indicating SAFS.

Eleven (65%) of those patients were sensitive to more than one fungal species. Aspergillus was the most commonly implicated species, followed by Alternaria, Candida, Cladosporium, Setomelanomma, Mucor, and Penicillium, Dr. Vicencio said at an international conference of the American Thoracic Society.

Boys and girls were affected equally, but SAFS patients tended to be older and have worse results on pulmonary function tests (PFTs) than their peers did, with forced expiratory volume in 1 second (FEV₁) at 73.33% of predicted, for instance, compared with 91.60% in those without SAFS. Some of the children who didn’t meet the criteria for SAFS diagnosis had high IgE levels but no evidence of fungal sensitization, or evidence of fungal sensitivity but normal IgE levels.

"The contribution of fungi to poorly controlled asthma in children is likely to be underestimated, as is the number of patients who might benefit from antifungal therapy," Dr. Vicencio said.

So far, he’s treated about a dozen pediatric SAFS patients with itraconazole. "About half of them have done very well. Their asthma is better controlled. We have documented some PFT improvements. Their IgE levels are variable; some of them are dropping dramatically, and some are not," he said.

Overall, "what it looks like is that fungal sensitization is a risk factor for severe persistent disease. We do believe that there is going to be a role for antifungal agents in certain select populations," he said.

The ongoing series now includes about 60 children with severe, poorly controlled asthma. "Something on the order of 60% actually have fungal sensitization," Dr. Vicencio said.

Sputum testing or bronchoalveolar lavage is planned to see if young SAFS patients actually have fungus in their lungs.

Genotyping is also underway to see if these patients have a mutation in the CHIT1 gene, which encodes for chitotriosidase, a kind of natural antifungal found in mammals. Dr. Vicencio has published a case series in which the mutation was present in six pediatric SAFS patients tested for it. Of the three treated with itraconazole, two responded well and one responded "dramatically" (Pediatrics 2010;126:e982-5).

About a third of the general population has the mutation, and it doesn’t cause disease in most. However, in someone with asthma and fungal exposure, "we believe the mutation" might cause "a perfect storm for asthma," he said.

Dr. Vicencio said he has no relevant disclosures.

SAN FRANCISCO – Underlying pulmonary fungal colonization or infection may be the reason that some children with severe asthma don’t respond fully to conventional treatments.

Severe asthma with fungal sensitization (SAFS) has been recognized only recently. In adults, SAFS has been found to respond to oral itraconazole (Am. J. Respir. Crit. Care Med. 2009;179:11-8).

CDC/Dr. Lucille K. Georg

SAFS also occurs in children, according to Dr. Alfin G. Vicencio, chief of pediatric pulmonology and cystic fibrosis at Cohen Children’s Medical Center in New Hyde Park, N.Y., and his colleagues.

The researchers looked at 41 children, teens, and young adults (aged 2-21 years) with severe asthma who were failing level 4 or greater combination asthma therapy, and found that 17 (41.5%) had serum fungal IgE levels above 100 IU/mL and evidence of fungal sensitization on radioallergosorbent or skin-prick tests, indicating SAFS.

Eleven (65%) of those patients were sensitive to more than one fungal species. Aspergillus was the most commonly implicated species, followed by Alternaria, Candida, Cladosporium, Setomelanomma, Mucor, and Penicillium, Dr. Vicencio said at an international conference of the American Thoracic Society.

Boys and girls were affected equally, but SAFS patients tended to be older and have worse results on pulmonary function tests (PFTs) than their peers did, with forced expiratory volume in 1 second (FEV₁) at 73.33% of predicted, for instance, compared with 91.60% in those without SAFS. Some of the children who didn’t meet the criteria for SAFS diagnosis had high IgE levels but no evidence of fungal sensitization, or evidence of fungal sensitivity but normal IgE levels.

"The contribution of fungi to poorly controlled asthma in children is likely to be underestimated, as is the number of patients who might benefit from antifungal therapy," Dr. Vicencio said.

So far, he’s treated about a dozen pediatric SAFS patients with itraconazole. "About half of them have done very well. Their asthma is better controlled. We have documented some PFT improvements. Their IgE levels are variable; some of them are dropping dramatically, and some are not," he said.

Overall, "what it looks like is that fungal sensitization is a risk factor for severe persistent disease. We do believe that there is going to be a role for antifungal agents in certain select populations," he said.

The ongoing series now includes about 60 children with severe, poorly controlled asthma. "Something on the order of 60% actually have fungal sensitization," Dr. Vicencio said.

Sputum testing or bronchoalveolar lavage is planned to see if young SAFS patients actually have fungus in their lungs.

Genotyping is also underway to see if these patients have a mutation in the CHIT1 gene, which encodes for chitotriosidase, a kind of natural antifungal found in mammals. Dr. Vicencio has published a case series in which the mutation was present in six pediatric SAFS patients tested for it. Of the three treated with itraconazole, two responded well and one responded "dramatically" (Pediatrics 2010;126:e982-5).

About a third of the general population has the mutation, and it doesn’t cause disease in most. However, in someone with asthma and fungal exposure, "we believe the mutation" might cause "a perfect storm for asthma," he said.

Dr. Vicencio said he has no relevant disclosures.

SAN FRANCISCO – Underlying pulmonary fungal colonization or infection may be the reason that some children with severe asthma don’t respond fully to conventional treatments.

Severe asthma with fungal sensitization (SAFS) has been recognized only recently. In adults, SAFS has been found to respond to oral itraconazole (Am. J. Respir. Crit. Care Med. 2009;179:11-8).

CDC/Dr. Lucille K. Georg

SAFS also occurs in children, according to Dr. Alfin G. Vicencio, chief of pediatric pulmonology and cystic fibrosis at Cohen Children’s Medical Center in New Hyde Park, N.Y., and his colleagues.

The researchers looked at 41 children, teens, and young adults (aged 2-21 years) with severe asthma who were failing level 4 or greater combination asthma therapy, and found that 17 (41.5%) had serum fungal IgE levels above 100 IU/mL and evidence of fungal sensitization on radioallergosorbent or skin-prick tests, indicating SAFS.

Eleven (65%) of those patients were sensitive to more than one fungal species. Aspergillus was the most commonly implicated species, followed by Alternaria, Candida, Cladosporium, Setomelanomma, Mucor, and Penicillium, Dr. Vicencio said at an international conference of the American Thoracic Society.

Boys and girls were affected equally, but SAFS patients tended to be older and have worse results on pulmonary function tests (PFTs) than their peers did, with forced expiratory volume in 1 second (FEV₁) at 73.33% of predicted, for instance, compared with 91.60% in those without SAFS. Some of the children who didn’t meet the criteria for SAFS diagnosis had high IgE levels but no evidence of fungal sensitization, or evidence of fungal sensitivity but normal IgE levels.

"The contribution of fungi to poorly controlled asthma in children is likely to be underestimated, as is the number of patients who might benefit from antifungal therapy," Dr. Vicencio said.

So far, he’s treated about a dozen pediatric SAFS patients with itraconazole. "About half of them have done very well. Their asthma is better controlled. We have documented some PFT improvements. Their IgE levels are variable; some of them are dropping dramatically, and some are not," he said.

Overall, "what it looks like is that fungal sensitization is a risk factor for severe persistent disease. We do believe that there is going to be a role for antifungal agents in certain select populations," he said.

The ongoing series now includes about 60 children with severe, poorly controlled asthma. "Something on the order of 60% actually have fungal sensitization," Dr. Vicencio said.

Sputum testing or bronchoalveolar lavage is planned to see if young SAFS patients actually have fungus in their lungs.

Genotyping is also underway to see if these patients have a mutation in the CHIT1 gene, which encodes for chitotriosidase, a kind of natural antifungal found in mammals. Dr. Vicencio has published a case series in which the mutation was present in six pediatric SAFS patients tested for it. Of the three treated with itraconazole, two responded well and one responded "dramatically" (Pediatrics 2010;126:e982-5).

About a third of the general population has the mutation, and it doesn’t cause disease in most. However, in someone with asthma and fungal exposure, "we believe the mutation" might cause "a perfect storm for asthma," he said.

Dr. Vicencio said he has no relevant disclosures.

SAN FRANCISCO – The recent findings of significantly increased risk for cancer incidence and mortality in people with sleep apnea echo previous in vitro and animal studies that found repeated episodes of hypoxia were associated with accelerated cancer progression.

In one of two new studies, people with obstructive sleep apnea were 10%-480% more likely to die of cancer, depending on apnea severity, compared with people without OSA, in a 20-year follow-up study of 1,522 participants in the Wisconsin Sleep Cohort.

Both the number of dips in oxygen level during sleep and the severity of hypoxia during those episodes were associated with increased risk of cancer mortality, but the association was stronger with hypoxia severity. Patients who spent much of their sleep time getting less than 90% oxyhemoglobin saturation were nearly nine times more likely to die of cancer during the study, compared with controls, said Dr. F. Javier Nieto and his associates reported in a press briefing at the annual meeting of the American Thoracic Society.

In a separate prospective 5-year study of 5,618 patients who were referred to seven sleep clinics in Spain, severe hypoxemia during sleep was associated with significantly increased incidence of cancer. Patients with OSA who spent more than 30% of their sleep time getting less than 90% oxyhemoglobin saturation had more than twice the risk for a new diagnosis of cancer during 5 years of follow-up, compared with patients without sleep apnea, Dr. Miguel A. Martinez-Garcia and his associates reported at the briefing.

"In both studies, when they looked at the amount of low oxygen that they were getting, that’s when the incidence and mortality from cancer went up," said Mary J. Morrell, Ph.D., who moderated the press briefing. "What it suggests is that there’s something associated with low oxygen that’s triggering the cancer, which would fit with the initial animal work that caused them to look into the two large cohorts" of people, added Dr. Morrell, professor of sleep and respiratory physiology at Imperial College, London.

The U.S. study analyzed mortality data for participants in the Wisconsin Sleep Cohort, a prospective, community-based study of the predictors and natural history of sleep disorders. All underwent polysomnography at the start of the study. Sleep-disordered breathing was defined as an apnea-hypopnea index (AHI) score of 5 or greater, representing the mean number of apnea and hypopnea events per hour of sleep.

The mortality risks were associated with the presence and severity of sleep apnea in a dose-response fashion, said Dr. Nieto, chair of the department of population health sciences at the University of Wisconsin, Madison.

Compared with participants who did not have sleep apnea, those with mild sleep apnea (defined as an AHI of 5-14.9) were 10% more likely to die of cancer during the follow-up years. People with moderate sleep apnea (an AHI of 15-29.9) were twice as likely and those with severe apnea (an AHI of 30 or greater) were nearly five times as likely to die of cancer, compared with the control group without sleep apnea. The results were adjusted for the confounding effects of age, sex, body mass index, and smoking, Dr. Nieto said.

"The key thing is that it’s the amount of low oxygen that the patients are getting, not essentially how many times it occurs, which is the apnea-hypopnea index. It’s the amount that they’re getting" that matters most, Dr. Morrell noted.

When the results of the Spanish study were analyzed according to scores on the AHI, which includes both hypopnea and hypoxemia, the increased incidence of cancer in patients with sleep apnea became statistically nonsignificant after adjusting for the confounding effects of age, gender, and body mass index, said Dr. Martinez-Garcia of Le Fe University and Polytechnic Hospital, Valencia, Spain. Subset analyses suggest that the association between the hypoxemia index and cancer incidence may be limited to males and younger patients, Dr. Martinez-Garcia said.

Dr. Nieto, Dr. Martinez-Garcia, and Dr. Morrell reported having no financial disclosures.

SAN FRANCISCO – The recent findings of significantly increased risk for cancer incidence and mortality in people with sleep apnea echo previous in vitro and animal studies that found repeated episodes of hypoxia were associated with accelerated cancer progression.

In one of two new studies, people with obstructive sleep apnea were 10%-480% more likely to die of cancer, depending on apnea severity, compared with people without OSA, in a 20-year follow-up study of 1,522 participants in the Wisconsin Sleep Cohort.

Both the number of dips in oxygen level during sleep and the severity of hypoxia during those episodes were associated with increased risk of cancer mortality, but the association was stronger with hypoxia severity. Patients who spent much of their sleep time getting less than 90% oxyhemoglobin saturation were nearly nine times more likely to die of cancer during the study, compared with controls, said Dr. F. Javier Nieto and his associates reported in a press briefing at the annual meeting of the American Thoracic Society.

In a separate prospective 5-year study of 5,618 patients who were referred to seven sleep clinics in Spain, severe hypoxemia during sleep was associated with significantly increased incidence of cancer. Patients with OSA who spent more than 30% of their sleep time getting less than 90% oxyhemoglobin saturation had more than twice the risk for a new diagnosis of cancer during 5 years of follow-up, compared with patients without sleep apnea, Dr. Miguel A. Martinez-Garcia and his associates reported at the briefing.

"In both studies, when they looked at the amount of low oxygen that they were getting, that’s when the incidence and mortality from cancer went up," said Mary J. Morrell, Ph.D., who moderated the press briefing. "What it suggests is that there’s something associated with low oxygen that’s triggering the cancer, which would fit with the initial animal work that caused them to look into the two large cohorts" of people, added Dr. Morrell, professor of sleep and respiratory physiology at Imperial College, London.

The U.S. study analyzed mortality data for participants in the Wisconsin Sleep Cohort, a prospective, community-based study of the predictors and natural history of sleep disorders. All underwent polysomnography at the start of the study. Sleep-disordered breathing was defined as an apnea-hypopnea index (AHI) score of 5 or greater, representing the mean number of apnea and hypopnea events per hour of sleep.

The mortality risks were associated with the presence and severity of sleep apnea in a dose-response fashion, said Dr. Nieto, chair of the department of population health sciences at the University of Wisconsin, Madison.

Compared with participants who did not have sleep apnea, those with mild sleep apnea (defined as an AHI of 5-14.9) were 10% more likely to die of cancer during the follow-up years. People with moderate sleep apnea (an AHI of 15-29.9) were twice as likely and those with severe apnea (an AHI of 30 or greater) were nearly five times as likely to die of cancer, compared with the control group without sleep apnea. The results were adjusted for the confounding effects of age, sex, body mass index, and smoking, Dr. Nieto said.

"The key thing is that it’s the amount of low oxygen that the patients are getting, not essentially how many times it occurs, which is the apnea-hypopnea index. It’s the amount that they’re getting" that matters most, Dr. Morrell noted.

When the results of the Spanish study were analyzed according to scores on the AHI, which includes both hypopnea and hypoxemia, the increased incidence of cancer in patients with sleep apnea became statistically nonsignificant after adjusting for the confounding effects of age, gender, and body mass index, said Dr. Martinez-Garcia of Le Fe University and Polytechnic Hospital, Valencia, Spain. Subset analyses suggest that the association between the hypoxemia index and cancer incidence may be limited to males and younger patients, Dr. Martinez-Garcia said.

Dr. Nieto, Dr. Martinez-Garcia, and Dr. Morrell reported having no financial disclosures.

SAN FRANCISCO – The recent findings of significantly increased risk for cancer incidence and mortality in people with sleep apnea echo previous in vitro and animal studies that found repeated episodes of hypoxia were associated with accelerated cancer progression.

In one of two new studies, people with obstructive sleep apnea were 10%-480% more likely to die of cancer, depending on apnea severity, compared with people without OSA, in a 20-year follow-up study of 1,522 participants in the Wisconsin Sleep Cohort.

Both the number of dips in oxygen level during sleep and the severity of hypoxia during those episodes were associated with increased risk of cancer mortality, but the association was stronger with hypoxia severity. Patients who spent much of their sleep time getting less than 90% oxyhemoglobin saturation were nearly nine times more likely to die of cancer during the study, compared with controls, said Dr. F. Javier Nieto and his associates reported in a press briefing at the annual meeting of the American Thoracic Society.

In a separate prospective 5-year study of 5,618 patients who were referred to seven sleep clinics in Spain, severe hypoxemia during sleep was associated with significantly increased incidence of cancer. Patients with OSA who spent more than 30% of their sleep time getting less than 90% oxyhemoglobin saturation had more than twice the risk for a new diagnosis of cancer during 5 years of follow-up, compared with patients without sleep apnea, Dr. Miguel A. Martinez-Garcia and his associates reported at the briefing.

"In both studies, when they looked at the amount of low oxygen that they were getting, that’s when the incidence and mortality from cancer went up," said Mary J. Morrell, Ph.D., who moderated the press briefing. "What it suggests is that there’s something associated with low oxygen that’s triggering the cancer, which would fit with the initial animal work that caused them to look into the two large cohorts" of people, added Dr. Morrell, professor of sleep and respiratory physiology at Imperial College, London.

The U.S. study analyzed mortality data for participants in the Wisconsin Sleep Cohort, a prospective, community-based study of the predictors and natural history of sleep disorders. All underwent polysomnography at the start of the study. Sleep-disordered breathing was defined as an apnea-hypopnea index (AHI) score of 5 or greater, representing the mean number of apnea and hypopnea events per hour of sleep.

The mortality risks were associated with the presence and severity of sleep apnea in a dose-response fashion, said Dr. Nieto, chair of the department of population health sciences at the University of Wisconsin, Madison.

Compared with participants who did not have sleep apnea, those with mild sleep apnea (defined as an AHI of 5-14.9) were 10% more likely to die of cancer during the follow-up years. People with moderate sleep apnea (an AHI of 15-29.9) were twice as likely and those with severe apnea (an AHI of 30 or greater) were nearly five times as likely to die of cancer, compared with the control group without sleep apnea. The results were adjusted for the confounding effects of age, sex, body mass index, and smoking, Dr. Nieto said.

"The key thing is that it’s the amount of low oxygen that the patients are getting, not essentially how many times it occurs, which is the apnea-hypopnea index. It’s the amount that they’re getting" that matters most, Dr. Morrell noted.

When the results of the Spanish study were analyzed according to scores on the AHI, which includes both hypopnea and hypoxemia, the increased incidence of cancer in patients with sleep apnea became statistically nonsignificant after adjusting for the confounding effects of age, gender, and body mass index, said Dr. Martinez-Garcia of Le Fe University and Polytechnic Hospital, Valencia, Spain. Subset analyses suggest that the association between the hypoxemia index and cancer incidence may be limited to males and younger patients, Dr. Martinez-Garcia said.

Dr. Nieto, Dr. Martinez-Garcia, and Dr. Morrell reported having no financial disclosures.

It is best to avoid any new drug in women of childbearing potential or during pregnancy if an older agent with human pregnancy experience exists. However, this is not always possible, because the new drug may be a major breakthrough or is the only or most efficacious drug for the indication. So, how do you counsel the patient about a drug’s risk to the embryo or fetus when there is little or no human pregnancy data?

Fortunately, the package insert provides data for three factors that can be used to give some estimate of risk: pharmacologic class, potential to cross the placenta, and animal reproduction data. Although all of the factors are important, the animal data are often the best source for estimating human risk. The book "Drugs in Pregnancy and Lactation," which I coauthored, defines the levels of risk (low-moderate-high) that I use to evaluate the animal data.

In 2011, the Food and Drug Administration approved 30 new drugs and biologics. Because they are unlikely to be used during pregnancy or lactation, the following 10 new drugs will not be reviewed here: abiraterone (Zytiga; pregnancy risk category X) for prostate cancer; adenovirus type 4 and type 7 live virus vaccine (X), for prevention of febrile acute respiratory disease; azficel-T (LaViv; C), for nasolabial fold wrinkles; centruroides (Anascorp; C), for scorpion envenomation; Coccidioides immitis skin test antigen (Spherusol; C); gabapentin enacarbil (Horizant; C), prodrug of the antiepileptic gabapentin for restless legs syndrome; gadobutrol (Gadavist; C), a contrast agent for MRI of the central nervous system; ioflupane I¹²³ (DaTscan; B), for single-photon emission computed tomography (SPECT) brain imaging; and two drugs for chronic obstructive pulmonary disease: indacaterol (Arcapta Neohaler; C) and roflumilast (Daliresp; C).

Of the remaining 20 drugs, only one has human pregnancy data: factor XIII concentrate human (Corifact; C). The new drugs can be categorized into 10 pharmacologic classes: 2 anticoagulants, 1 anticonvulsant, 1 antidepressant, 1 antidiabetic, 1 antihypertensive, 4 anti-infectives, 5 antineoplastics, 1 dermatologic, 2 hematologics, and 2 immunologic agents.

Rivaroxaban (Xarelto; C), a factor Xa inhibitor, is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and to prevent deep vein thrombosis in patients undergoing knee or hip replacement surgery. The drug crosses the human placenta, and the animal data suggest risk. Ticagrelor (Brilinta; C) is a platelet inhibitor indicated for reducing the rate of thrombotic events in patients with acute coronary syndrome. The animal data suggest risk, and the drug probably crosses the placenta. Although both of these agents are best avoided in pregnancy, the maternal benefit in some cases may outweigh the unknown embryo-fetal risk.

The animal data suggest risk if ezogabine (Potiga; C), an oral anticonvulsant indicated as adjunctive treatment of partial-onset seizures, is used in pregnancy. If used in pregnancy, the woman should be advised of the absence of human data. Pregnant women taking ezogabine are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.

The new antidepressant is vilazodone (Viibryd; C), a selective serotonin reuptake inhibitor. As with other SSRIs, the potential developmental toxicity includes spontaneous abortion, low birth weight, preterm delivery, neonatal serotonin syndrome, neonatal withdrawal, abnormal behavior beyond the neonatal period, and persistent pulmonary hypertension of the newborn. However, the benefits of vilazodone may outweigh the risks and must be evaluated on a case by case basis.

Linagliptin (Tradjenta; B), a dipeptidyl peptidase-4 inhibitor taken orally, is indicated for type 2 diabetes. Although the animal data suggest low risk, the lack of human pregnancy data prevents an assessment of its effect in a condition requiring tight control of glucose. Insulin remains the gold standard, but other oral agents, such as glipizide, glyburide, and metformin, have been effective in selected cases.

Azilsartan (Edarbi; D) is an angiotensin II receptor blocker used for hypertension. As with all agents in this class, severe fetal toxicity, including death, is a potential complication if it is used in the second half of pregnancy.

Two of the new anti-infectives are protease inhibitors used for chronic hepatitis C infection: boceprevir (Victrelis; B) and telaprevir (Incivek; B). Although both drugs carry an FDA rating of B, they must be used in combination with ribavirin (contraindicated in pregnancy) and peginterferon alfa. Thus, they should not be used in pregnancy.

Fidaxomicin (Dificid; B) is an oral macrolide used for Clostridium difficile–associated diarrhea. Only minimal amounts are absorbed and, like other macrolides, such as erythromycin, the drug is probably compatible with pregnancy. Rilpivirine (Edurant; B) is a non-nucleoside reverse transcriptase inhibitor used in combination with other agents for HIV-1 infections. Animal data suggest low risk, but there are no human pregnancy data. However, the maternal benefit appears to outweigh embryo-fetal risk.

The five antineoplastics are: brentuximab (Adcetris; D), approved for Hodgkin’s disease and systemic anaplastic large cell lymphoma; crizotinib (Xalkori; D), for metastatic non–small cell lung cancer; ipilimumab (Yervoy; C), for metastatic melanoma; vandetanib (Caprelsa; D), for metastatic medullary thyroid cancer; and vemurafenib (Zelboraf; D) for metastatic melanoma. The properties (molecular weight, plasma elimination half-life) of these agents suggest that they will probably cross the placenta. The combination of these properties, their mechanisms of action, and/or their animal reproduction data suggests that all should be avoided in pregnancy.

Spinosad (Natroba; B) is an insecticide used for head lice infection. The pediculicide is not absorbed systemically, so it is compatible with pregnancy.

Factor XIII Concentrate (Human) (Corifact; C) is a hematologic agent used for the prophylactic treatment of congenital factor XIII deficiency. The product is made from pooled human plasma that has been checked for hepatitis B surface antigen and antibodies to HIV-1/2 and HCV. The limited human data suggest that it is low risk in pregnancy. In contrast, the animal data for icatibant (Firazyr; C), the other hematologic agent that is indicated for the treatment of acute attacks of hereditary angioedema, suggest risk. Currently, plasma-derived human C1 inhibitor concentrate is preferred for acute treatment and short- or long-term prophylaxis of hereditary angioedema (J. Allergy Clin. Immunol. 2012;129:308-20). Until human data are available, icatibant is best avoided in pregnancy.

The first of the two immunologic agents is the immunosuppressant belatacept (Nulojix; C), indicated to prevent rejection of a kidney transplant. Although the animal data suggest low risk, it is given in combination with basiliximab induction and two agents known to be teratogenic, mycophenolate and corticosteroids. The absolute risk for major defects with corticosteroids is low, but the risk magnitude is thought to be much higher for mycophenolate. If possible, belatacept should be avoided in pregnancy. The other agent is the immunomodulator belimumab (Benlysta; C), which is indicated for the treatment of systemic lupus erythematosus. The animal data for this monoclonal antibody are reassuring, and the agent is probably compatible with pregnancy.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; a clinical professor of pharmacy at the University of California, San Francisco; and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He said he had no relevant financial disclosures.

It is best to avoid any new drug in women of childbearing potential or during pregnancy if an older agent with human pregnancy experience exists. However, this is not always possible, because the new drug may be a major breakthrough or is the only or most efficacious drug for the indication. So, how do you counsel the patient about a drug’s risk to the embryo or fetus when there is little or no human pregnancy data?

Fortunately, the package insert provides data for three factors that can be used to give some estimate of risk: pharmacologic class, potential to cross the placenta, and animal reproduction data. Although all of the factors are important, the animal data are often the best source for estimating human risk. The book "Drugs in Pregnancy and Lactation," which I coauthored, defines the levels of risk (low-moderate-high) that I use to evaluate the animal data.

In 2011, the Food and Drug Administration approved 30 new drugs and biologics. Because they are unlikely to be used during pregnancy or lactation, the following 10 new drugs will not be reviewed here: abiraterone (Zytiga; pregnancy risk category X) for prostate cancer; adenovirus type 4 and type 7 live virus vaccine (X), for prevention of febrile acute respiratory disease; azficel-T (LaViv; C), for nasolabial fold wrinkles; centruroides (Anascorp; C), for scorpion envenomation; Coccidioides immitis skin test antigen (Spherusol; C); gabapentin enacarbil (Horizant; C), prodrug of the antiepileptic gabapentin for restless legs syndrome; gadobutrol (Gadavist; C), a contrast agent for MRI of the central nervous system; ioflupane I¹²³ (DaTscan; B), for single-photon emission computed tomography (SPECT) brain imaging; and two drugs for chronic obstructive pulmonary disease: indacaterol (Arcapta Neohaler; C) and roflumilast (Daliresp; C).

Of the remaining 20 drugs, only one has human pregnancy data: factor XIII concentrate human (Corifact; C). The new drugs can be categorized into 10 pharmacologic classes: 2 anticoagulants, 1 anticonvulsant, 1 antidepressant, 1 antidiabetic, 1 antihypertensive, 4 anti-infectives, 5 antineoplastics, 1 dermatologic, 2 hematologics, and 2 immunologic agents.

Rivaroxaban (Xarelto; C), a factor Xa inhibitor, is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and to prevent deep vein thrombosis in patients undergoing knee or hip replacement surgery. The drug crosses the human placenta, and the animal data suggest risk. Ticagrelor (Brilinta; C) is a platelet inhibitor indicated for reducing the rate of thrombotic events in patients with acute coronary syndrome. The animal data suggest risk, and the drug probably crosses the placenta. Although both of these agents are best avoided in pregnancy, the maternal benefit in some cases may outweigh the unknown embryo-fetal risk.

The animal data suggest risk if ezogabine (Potiga; C), an oral anticonvulsant indicated as adjunctive treatment of partial-onset seizures, is used in pregnancy. If used in pregnancy, the woman should be advised of the absence of human data. Pregnant women taking ezogabine are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.

The new antidepressant is vilazodone (Viibryd; C), a selective serotonin reuptake inhibitor. As with other SSRIs, the potential developmental toxicity includes spontaneous abortion, low birth weight, preterm delivery, neonatal serotonin syndrome, neonatal withdrawal, abnormal behavior beyond the neonatal period, and persistent pulmonary hypertension of the newborn. However, the benefits of vilazodone may outweigh the risks and must be evaluated on a case by case basis.

Linagliptin (Tradjenta; B), a dipeptidyl peptidase-4 inhibitor taken orally, is indicated for type 2 diabetes. Although the animal data suggest low risk, the lack of human pregnancy data prevents an assessment of its effect in a condition requiring tight control of glucose. Insulin remains the gold standard, but other oral agents, such as glipizide, glyburide, and metformin, have been effective in selected cases.

Azilsartan (Edarbi; D) is an angiotensin II receptor blocker used for hypertension. As with all agents in this class, severe fetal toxicity, including death, is a potential complication if it is used in the second half of pregnancy.

Two of the new anti-infectives are protease inhibitors used for chronic hepatitis C infection: boceprevir (Victrelis; B) and telaprevir (Incivek; B). Although both drugs carry an FDA rating of B, they must be used in combination with ribavirin (contraindicated in pregnancy) and peginterferon alfa. Thus, they should not be used in pregnancy.

Fidaxomicin (Dificid; B) is an oral macrolide used for Clostridium difficile–associated diarrhea. Only minimal amounts are absorbed and, like other macrolides, such as erythromycin, the drug is probably compatible with pregnancy. Rilpivirine (Edurant; B) is a non-nucleoside reverse transcriptase inhibitor used in combination with other agents for HIV-1 infections. Animal data suggest low risk, but there are no human pregnancy data. However, the maternal benefit appears to outweigh embryo-fetal risk.

The five antineoplastics are: brentuximab (Adcetris; D), approved for Hodgkin’s disease and systemic anaplastic large cell lymphoma; crizotinib (Xalkori; D), for metastatic non–small cell lung cancer; ipilimumab (Yervoy; C), for metastatic melanoma; vandetanib (Caprelsa; D), for metastatic medullary thyroid cancer; and vemurafenib (Zelboraf; D) for metastatic melanoma. The properties (molecular weight, plasma elimination half-life) of these agents suggest that they will probably cross the placenta. The combination of these properties, their mechanisms of action, and/or their animal reproduction data suggests that all should be avoided in pregnancy.

Spinosad (Natroba; B) is an insecticide used for head lice infection. The pediculicide is not absorbed systemically, so it is compatible with pregnancy.

Factor XIII Concentrate (Human) (Corifact; C) is a hematologic agent used for the prophylactic treatment of congenital factor XIII deficiency. The product is made from pooled human plasma that has been checked for hepatitis B surface antigen and antibodies to HIV-1/2 and HCV. The limited human data suggest that it is low risk in pregnancy. In contrast, the animal data for icatibant (Firazyr; C), the other hematologic agent that is indicated for the treatment of acute attacks of hereditary angioedema, suggest risk. Currently, plasma-derived human C1 inhibitor concentrate is preferred for acute treatment and short- or long-term prophylaxis of hereditary angioedema (J. Allergy Clin. Immunol. 2012;129:308-20). Until human data are available, icatibant is best avoided in pregnancy.

The first of the two immunologic agents is the immunosuppressant belatacept (Nulojix; C), indicated to prevent rejection of a kidney transplant. Although the animal data suggest low risk, it is given in combination with basiliximab induction and two agents known to be teratogenic, mycophenolate and corticosteroids. The absolute risk for major defects with corticosteroids is low, but the risk magnitude is thought to be much higher for mycophenolate. If possible, belatacept should be avoided in pregnancy. The other agent is the immunomodulator belimumab (Benlysta; C), which is indicated for the treatment of systemic lupus erythematosus. The animal data for this monoclonal antibody are reassuring, and the agent is probably compatible with pregnancy.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; a clinical professor of pharmacy at the University of California, San Francisco; and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He said he had no relevant financial disclosures.

It is best to avoid any new drug in women of childbearing potential or during pregnancy if an older agent with human pregnancy experience exists. However, this is not always possible, because the new drug may be a major breakthrough or is the only or most efficacious drug for the indication. So, how do you counsel the patient about a drug’s risk to the embryo or fetus when there is little or no human pregnancy data?

Fortunately, the package insert provides data for three factors that can be used to give some estimate of risk: pharmacologic class, potential to cross the placenta, and animal reproduction data. Although all of the factors are important, the animal data are often the best source for estimating human risk. The book "Drugs in Pregnancy and Lactation," which I coauthored, defines the levels of risk (low-moderate-high) that I use to evaluate the animal data.

In 2011, the Food and Drug Administration approved 30 new drugs and biologics. Because they are unlikely to be used during pregnancy or lactation, the following 10 new drugs will not be reviewed here: abiraterone (Zytiga; pregnancy risk category X) for prostate cancer; adenovirus type 4 and type 7 live virus vaccine (X), for prevention of febrile acute respiratory disease; azficel-T (LaViv; C), for nasolabial fold wrinkles; centruroides (Anascorp; C), for scorpion envenomation; Coccidioides immitis skin test antigen (Spherusol; C); gabapentin enacarbil (Horizant; C), prodrug of the antiepileptic gabapentin for restless legs syndrome; gadobutrol (Gadavist; C), a contrast agent for MRI of the central nervous system; ioflupane I¹²³ (DaTscan; B), for single-photon emission computed tomography (SPECT) brain imaging; and two drugs for chronic obstructive pulmonary disease: indacaterol (Arcapta Neohaler; C) and roflumilast (Daliresp; C).

Of the remaining 20 drugs, only one has human pregnancy data: factor XIII concentrate human (Corifact; C). The new drugs can be categorized into 10 pharmacologic classes: 2 anticoagulants, 1 anticonvulsant, 1 antidepressant, 1 antidiabetic, 1 antihypertensive, 4 anti-infectives, 5 antineoplastics, 1 dermatologic, 2 hematologics, and 2 immunologic agents.

Rivaroxaban (Xarelto; C), a factor Xa inhibitor, is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and to prevent deep vein thrombosis in patients undergoing knee or hip replacement surgery. The drug crosses the human placenta, and the animal data suggest risk. Ticagrelor (Brilinta; C) is a platelet inhibitor indicated for reducing the rate of thrombotic events in patients with acute coronary syndrome. The animal data suggest risk, and the drug probably crosses the placenta. Although both of these agents are best avoided in pregnancy, the maternal benefit in some cases may outweigh the unknown embryo-fetal risk.

The animal data suggest risk if ezogabine (Potiga; C), an oral anticonvulsant indicated as adjunctive treatment of partial-onset seizures, is used in pregnancy. If used in pregnancy, the woman should be advised of the absence of human data. Pregnant women taking ezogabine are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 888-233-2334.

The new antidepressant is vilazodone (Viibryd; C), a selective serotonin reuptake inhibitor. As with other SSRIs, the potential developmental toxicity includes spontaneous abortion, low birth weight, preterm delivery, neonatal serotonin syndrome, neonatal withdrawal, abnormal behavior beyond the neonatal period, and persistent pulmonary hypertension of the newborn. However, the benefits of vilazodone may outweigh the risks and must be evaluated on a case by case basis.

Linagliptin (Tradjenta; B), a dipeptidyl peptidase-4 inhibitor taken orally, is indicated for type 2 diabetes. Although the animal data suggest low risk, the lack of human pregnancy data prevents an assessment of its effect in a condition requiring tight control of glucose. Insulin remains the gold standard, but other oral agents, such as glipizide, glyburide, and metformin, have been effective in selected cases.

Azilsartan (Edarbi; D) is an angiotensin II receptor blocker used for hypertension. As with all agents in this class, severe fetal toxicity, including death, is a potential complication if it is used in the second half of pregnancy.

Two of the new anti-infectives are protease inhibitors used for chronic hepatitis C infection: boceprevir (Victrelis; B) and telaprevir (Incivek; B). Although both drugs carry an FDA rating of B, they must be used in combination with ribavirin (contraindicated in pregnancy) and peginterferon alfa. Thus, they should not be used in pregnancy.

Fidaxomicin (Dificid; B) is an oral macrolide used for Clostridium difficile–associated diarrhea. Only minimal amounts are absorbed and, like other macrolides, such as erythromycin, the drug is probably compatible with pregnancy. Rilpivirine (Edurant; B) is a non-nucleoside reverse transcriptase inhibitor used in combination with other agents for HIV-1 infections. Animal data suggest low risk, but there are no human pregnancy data. However, the maternal benefit appears to outweigh embryo-fetal risk.

The five antineoplastics are: brentuximab (Adcetris; D), approved for Hodgkin’s disease and systemic anaplastic large cell lymphoma; crizotinib (Xalkori; D), for metastatic non–small cell lung cancer; ipilimumab (Yervoy; C), for metastatic melanoma; vandetanib (Caprelsa; D), for metastatic medullary thyroid cancer; and vemurafenib (Zelboraf; D) for metastatic melanoma. The properties (molecular weight, plasma elimination half-life) of these agents suggest that they will probably cross the placenta. The combination of these properties, their mechanisms of action, and/or their animal reproduction data suggests that all should be avoided in pregnancy.

Spinosad (Natroba; B) is an insecticide used for head lice infection. The pediculicide is not absorbed systemically, so it is compatible with pregnancy.

Factor XIII Concentrate (Human) (Corifact; C) is a hematologic agent used for the prophylactic treatment of congenital factor XIII deficiency. The product is made from pooled human plasma that has been checked for hepatitis B surface antigen and antibodies to HIV-1/2 and HCV. The limited human data suggest that it is low risk in pregnancy. In contrast, the animal data for icatibant (Firazyr; C), the other hematologic agent that is indicated for the treatment of acute attacks of hereditary angioedema, suggest risk. Currently, plasma-derived human C1 inhibitor concentrate is preferred for acute treatment and short- or long-term prophylaxis of hereditary angioedema (J. Allergy Clin. Immunol. 2012;129:308-20). Until human data are available, icatibant is best avoided in pregnancy.

The first of the two immunologic agents is the immunosuppressant belatacept (Nulojix; C), indicated to prevent rejection of a kidney transplant. Although the animal data suggest low risk, it is given in combination with basiliximab induction and two agents known to be teratogenic, mycophenolate and corticosteroids. The absolute risk for major defects with corticosteroids is low, but the risk magnitude is thought to be much higher for mycophenolate. If possible, belatacept should be avoided in pregnancy. The other agent is the immunomodulator belimumab (Benlysta; C), which is indicated for the treatment of systemic lupus erythematosus. The animal data for this monoclonal antibody are reassuring, and the agent is probably compatible with pregnancy.

Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; a clinical professor of pharmacy at the University of California, San Francisco; and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of "Drugs in Pregnancy and Lactation," and coeditor of "Diseases, Complications, and Drug Therapy in Obstetrics." He said he had no relevant financial disclosures.

SAN FRANCISCO – Newborn lung function was significantly better in pregnant smokers who took vitamin C supplements, compared with smoking mothers on placebo, in a double-blind trial that randomized 179 women.

Among 159 infants who underwent pulmonary function tests at around 48 hours of age, results in the 76 newborns of smokers getting vitamin C were similar to results for 76 newborns of nonsmoking women in a nonrandomized comparison group. Both subgroups had better pulmonary function than did the 83 newborns of placebo-treated smokers, Dr. Cindy T. McEvoy and her associates reported at an international conference of the American Thoracic Society.

Photo Courtesy Dr. Cindy T. McEvoy

"We speculate that vitamin C supplementation in pregnant women who cannot quit smoking is helpful," said Dr. McEvoy of Oregon Health and Science University, Portland.

The current study randomized pregnant smokers aged 15 years and older, and prior to 22 weeks gestation of their singletons, to take 500 mg/day of vitamin C or placebo until delivery. The women were counseled throughout the trial to quit smoking but declined to do so.

Maternal plasma levels of ascorbic acid were significantly lower in the two smoking groups at randomization, compared with levels in nonsmokers. By mid-gestation, ascorbic acid levels in the vitamin C group were similar to levels in nonsmokers (59 and 58 micromol/L, respectively), but levels in the placebo group remained significantly lower (40 micromol/L).

Infant pulmonary flow volume, characterized as a ratio of the time to peak tidal expiratory flow to expiratory time, was significantly lower in the placebo group (0.345), compared with the vitamin C group (0.383) and the nonsmoking group (0.399), Dr. McEvoy said.

Investigators also measured the newborns’ passive respiratory mechanics, or compliance of the respiratory system (Crs/kg), and found significantly lower results in the placebo group (1.2 Crs/kg), compared with the vitamin C group (1.32 Crs/kg) or the nonsmoking group (1.36 Crs/kg).

Treatment did not significantly affect respiratory rate.

There were no significant differences between the randomized groups at the start of the study in characteristics including maternal age, insurance coverage, cotinine levels, medication adherence, history of asthma, or the proportion of women smoking 10 or more cigarettes per day.

Infant demographics were similar in the two groups of smokers and the reference group of nonsmokers, including birth weight, gestational age at delivery, sex, rate of delivery before 32 weeks’ gestation, and rate of vaginal delivery.

The investigators plan to perform infant pulmonary function tests again when the study babies are 1 year old and compare it with clinical outcomes such as episodes of wheezing. They have secured support from the National Heart, Lung, and Blood Institute to randomize a new cohort and measure newborn forced expiratory flows as the primary outcome, she said.

The investigators did not give vitamin C supplementation to infants, but that strategy may deserve study as well, Dr. McEvoy said.

The study excluded pregnancies with multiple gestation or fetal congenital anomalies and women who currently used illicit drugs or abused alcohol, had a history of kidney stones, had insulin-dependent diabetes, or who had been taking vitamin C daily since their last menstrual period. Before the treatment period began, participants were asked to take a daily placebo; those who complied with fewer than 75% of placebo doses were excluded from randomization.

Approximately 12% of U.S. women smoke during pregnancy and at least 500,000 newborns each year have been exposed to smoke in utero. Previous studies have shown that infants of smokers have worse lung function at birth and a higher risk of developing lung diseases, including asthma, bronchitis, and pneumonia, compared with infants of nonsmokers.

The current findings support evidence from nonhuman primates that daily vitamin C can block the in utero effects of nicotine on lung development and newborn pulmonary function (Am. J. Respir. Crit. Care Med. 2005;171:1032-9).

Dr. McEvoy reported having no financial disclosures. The National Heart, Lung, and Blood Institute funded the study.

SAN FRANCISCO – Newborn lung function was significantly better in pregnant smokers who took vitamin C supplements, compared with smoking mothers on placebo, in a double-blind trial that randomized 179 women.

Among 159 infants who underwent pulmonary function tests at around 48 hours of age, results in the 76 newborns of smokers getting vitamin C were similar to results for 76 newborns of nonsmoking women in a nonrandomized comparison group. Both subgroups had better pulmonary function than did the 83 newborns of placebo-treated smokers, Dr. Cindy T. McEvoy and her associates reported at an international conference of the American Thoracic Society.

Photo Courtesy Dr. Cindy T. McEvoy

"We speculate that vitamin C supplementation in pregnant women who cannot quit smoking is helpful," said Dr. McEvoy of Oregon Health and Science University, Portland.

The current study randomized pregnant smokers aged 15 years and older, and prior to 22 weeks gestation of their singletons, to take 500 mg/day of vitamin C or placebo until delivery. The women were counseled throughout the trial to quit smoking but declined to do so.

Maternal plasma levels of ascorbic acid were significantly lower in the two smoking groups at randomization, compared with levels in nonsmokers. By mid-gestation, ascorbic acid levels in the vitamin C group were similar to levels in nonsmokers (59 and 58 micromol/L, respectively), but levels in the placebo group remained significantly lower (40 micromol/L).

Infant pulmonary flow volume, characterized as a ratio of the time to peak tidal expiratory flow to expiratory time, was significantly lower in the placebo group (0.345), compared with the vitamin C group (0.383) and the nonsmoking group (0.399), Dr. McEvoy said.

Investigators also measured the newborns’ passive respiratory mechanics, or compliance of the respiratory system (Crs/kg), and found significantly lower results in the placebo group (1.2 Crs/kg), compared with the vitamin C group (1.32 Crs/kg) or the nonsmoking group (1.36 Crs/kg).

Treatment did not significantly affect respiratory rate.

There were no significant differences between the randomized groups at the start of the study in characteristics including maternal age, insurance coverage, cotinine levels, medication adherence, history of asthma, or the proportion of women smoking 10 or more cigarettes per day.

Infant demographics were similar in the two groups of smokers and the reference group of nonsmokers, including birth weight, gestational age at delivery, sex, rate of delivery before 32 weeks’ gestation, and rate of vaginal delivery.

The investigators plan to perform infant pulmonary function tests again when the study babies are 1 year old and compare it with clinical outcomes such as episodes of wheezing. They have secured support from the National Heart, Lung, and Blood Institute to randomize a new cohort and measure newborn forced expiratory flows as the primary outcome, she said.

The investigators did not give vitamin C supplementation to infants, but that strategy may deserve study as well, Dr. McEvoy said.

The study excluded pregnancies with multiple gestation or fetal congenital anomalies and women who currently used illicit drugs or abused alcohol, had a history of kidney stones, had insulin-dependent diabetes, or who had been taking vitamin C daily since their last menstrual period. Before the treatment period began, participants were asked to take a daily placebo; those who complied with fewer than 75% of placebo doses were excluded from randomization.

Approximately 12% of U.S. women smoke during pregnancy and at least 500,000 newborns each year have been exposed to smoke in utero. Previous studies have shown that infants of smokers have worse lung function at birth and a higher risk of developing lung diseases, including asthma, bronchitis, and pneumonia, compared with infants of nonsmokers.

The current findings support evidence from nonhuman primates that daily vitamin C can block the in utero effects of nicotine on lung development and newborn pulmonary function (Am. J. Respir. Crit. Care Med. 2005;171:1032-9).

Dr. McEvoy reported having no financial disclosures. The National Heart, Lung, and Blood Institute funded the study.

SAN FRANCISCO – Newborn lung function was significantly better in pregnant smokers who took vitamin C supplements, compared with smoking mothers on placebo, in a double-blind trial that randomized 179 women.

Among 159 infants who underwent pulmonary function tests at around 48 hours of age, results in the 76 newborns of smokers getting vitamin C were similar to results for 76 newborns of nonsmoking women in a nonrandomized comparison group. Both subgroups had better pulmonary function than did the 83 newborns of placebo-treated smokers, Dr. Cindy T. McEvoy and her associates reported at an international conference of the American Thoracic Society.

Photo Courtesy Dr. Cindy T. McEvoy

"We speculate that vitamin C supplementation in pregnant women who cannot quit smoking is helpful," said Dr. McEvoy of Oregon Health and Science University, Portland.

The current study randomized pregnant smokers aged 15 years and older, and prior to 22 weeks gestation of their singletons, to take 500 mg/day of vitamin C or placebo until delivery. The women were counseled throughout the trial to quit smoking but declined to do so.

Maternal plasma levels of ascorbic acid were significantly lower in the two smoking groups at randomization, compared with levels in nonsmokers. By mid-gestation, ascorbic acid levels in the vitamin C group were similar to levels in nonsmokers (59 and 58 micromol/L, respectively), but levels in the placebo group remained significantly lower (40 micromol/L).

Infant pulmonary flow volume, characterized as a ratio of the time to peak tidal expiratory flow to expiratory time, was significantly lower in the placebo group (0.345), compared with the vitamin C group (0.383) and the nonsmoking group (0.399), Dr. McEvoy said.

Investigators also measured the newborns’ passive respiratory mechanics, or compliance of the respiratory system (Crs/kg), and found significantly lower results in the placebo group (1.2 Crs/kg), compared with the vitamin C group (1.32 Crs/kg) or the nonsmoking group (1.36 Crs/kg).

Treatment did not significantly affect respiratory rate.

There were no significant differences between the randomized groups at the start of the study in characteristics including maternal age, insurance coverage, cotinine levels, medication adherence, history of asthma, or the proportion of women smoking 10 or more cigarettes per day.

Infant demographics were similar in the two groups of smokers and the reference group of nonsmokers, including birth weight, gestational age at delivery, sex, rate of delivery before 32 weeks’ gestation, and rate of vaginal delivery.

The investigators plan to perform infant pulmonary function tests again when the study babies are 1 year old and compare it with clinical outcomes such as episodes of wheezing. They have secured support from the National Heart, Lung, and Blood Institute to randomize a new cohort and measure newborn forced expiratory flows as the primary outcome, she said.

The investigators did not give vitamin C supplementation to infants, but that strategy may deserve study as well, Dr. McEvoy said.

The study excluded pregnancies with multiple gestation or fetal congenital anomalies and women who currently used illicit drugs or abused alcohol, had a history of kidney stones, had insulin-dependent diabetes, or who had been taking vitamin C daily since their last menstrual period. Before the treatment period began, participants were asked to take a daily placebo; those who complied with fewer than 75% of placebo doses were excluded from randomization.

Approximately 12% of U.S. women smoke during pregnancy and at least 500,000 newborns each year have been exposed to smoke in utero. Previous studies have shown that infants of smokers have worse lung function at birth and a higher risk of developing lung diseases, including asthma, bronchitis, and pneumonia, compared with infants of nonsmokers.

The current findings support evidence from nonhuman primates that daily vitamin C can block the in utero effects of nicotine on lung development and newborn pulmonary function (Am. J. Respir. Crit. Care Med. 2005;171:1032-9).

Dr. McEvoy reported having no financial disclosures. The National Heart, Lung, and Blood Institute funded the study.

Move over Lyme disease, there is a new tick borne illness in town - an allergic reaction to beef.

According to a new report from ABC News, a single bite from a lone star tick may trigger the allergy.

Photo ©James Gathany/CDC

Researchers at the University of Virginia began to look into the ticks after the allergy began to spread along the East Coast, where lone star ticks are prevalent. The researchers noted that they have seen 400 cases of the meat allergy, mostly in Virginia, with 90% of the patients reporting a history of tick bites.

Alpha-gal antibodies, found in red meat, increase after a bite from a long star tick. Several hours after eating beef, patients with the allergy will have a reaction and develop hives, and could even go into anaphylactic shock.

The news report noted that author John Grisham, who has a plantation in Virginia, is believed to have developed the allergy.

Watch the full ABC News report here.

Move over Lyme disease, there is a new tick borne illness in town - an allergic reaction to beef.

According to a new report from ABC News, a single bite from a lone star tick may trigger the allergy.

Photo ©James Gathany/CDC

Researchers at the University of Virginia began to look into the ticks after the allergy began to spread along the East Coast, where lone star ticks are prevalent. The researchers noted that they have seen 400 cases of the meat allergy, mostly in Virginia, with 90% of the patients reporting a history of tick bites.

Alpha-gal antibodies, found in red meat, increase after a bite from a long star tick. Several hours after eating beef, patients with the allergy will have a reaction and develop hives, and could even go into anaphylactic shock.

The news report noted that author John Grisham, who has a plantation in Virginia, is believed to have developed the allergy.

Watch the full ABC News report here.

Move over Lyme disease, there is a new tick borne illness in town - an allergic reaction to beef.

According to a new report from ABC News, a single bite from a lone star tick may trigger the allergy.

Photo ©James Gathany/CDC

Researchers at the University of Virginia began to look into the ticks after the allergy began to spread along the East Coast, where lone star ticks are prevalent. The researchers noted that they have seen 400 cases of the meat allergy, mostly in Virginia, with 90% of the patients reporting a history of tick bites.

Alpha-gal antibodies, found in red meat, increase after a bite from a long star tick. Several hours after eating beef, patients with the allergy will have a reaction and develop hives, and could even go into anaphylactic shock.

The news report noted that author John Grisham, who has a plantation in Virginia, is believed to have developed the allergy.

Watch the full ABC News report here.

BOSTON – The promise of shorter time to sleep, longer sleep duration, and fewer side effects associated with the experimental sleep drug suvorexant has sleep medicine clinicians and their patients eagerly anticipating the approval of the first-in-class agent.

Suvorexant’s mechanism of action in targeting the orexin system, which promotes wakefulness, sets it apart from some of the currently available sleep medications, according to Dr. Michael Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in New York. "The effects of the new drug are fairly localized because it targets a more specific receptor than the GABA agonists, which have a more generalized effect and thus more side effects." Importantly, suvorexant does not depress the central nervous system or respiratory function and thus may be a good option for patients with suspected sleep apnea, he noted.

Two pivotal phase III studies of the drug were presented at the meeting. Both randomized, double-blind, placebo-controlled trials were 3-month studies designed to confirm the safety and efficacy outcomes of an initial 4-week proof-of-concept study in patients with primary insomnia. Each trial evaluated two dose regimens: 40 mg for patients 18-64 years and 30 mg for those older than 65 years in the first trial; and 20 mg and 15 mg, respectively, in the second trial, explained Dr. Andrew D. Krystal, professor of psychiatry and behavioral sciences at Duke University Medical Center, Durham, N.C., and an investigator for both trials.*

Efficacy measures were patient self-reported time to sleep onset (sTSO), self-reported total sleep time (sTST), and self-reported wake after sleep onset (sWASO), as well as the polysomnographic end points of latency to onset of persistent sleep (LPS) and wake after persistent sleep onset (WASO), he said.

In the first trial, which randomized 1,021 patients, suvorexant at 40 mg and 30 mg was significantly better than placebo was in all end points at 1 and 3 months, Dr. Krystal reported. Specifically, at 3 months, the mean differences from placebo in change from baseline were an increase of 19.7 minutes for sTST, and decreases of 8.4 minutes for sTSO, 6.9 minutes for sWASO, 9.4 minutes for LPS, and 22.9 minutes for WASO.

Similarly, significant changes were observed in the second trial, with the exception of the drug’s effect on LPS at 3 months, which was not significant – a finding the investigators attributed to high placebo response, Dr. Krystal said. In this study, the mean differences from placebo in change from baseline at 3 months were an increase of 25.1 minutes for sTST and decreases of 13.2 minutes for sTSO, 8.9 minutes for sWASO, 3.6 minutes for LPS, and 29.4 minutes for WASO.

Both studies also measured the time it took patients to fall into continuous sleep and the time they spent awake during the first night of use, comparing the results with those reported before starting the drug, Dr. Krystal said. In the first trial, "patients [taking suvorexant] entered into continuous sleep 30.6 minutes faster and spent 58.0 fewer minutes awake during the night, compared to before they started taking the drug," he said. Similarly, in the second trial, the suvorexant patients entered into continuous sleep 34.7 minutes faster and spent 63.3 fewer minutes awake during the night, compared with before they started the drug. The respective placebo group improvements in the two trials were 13.0-20.3 minutes and 19.6-21.3 minutes, he said.

Both dose regimens of suvorexant in the trials were well tolerated with no evidence of clinically important rebound or withdrawal on discontinuation, Dr. Krystal reported. "Over the 3-month period, the overall incidence of adverse events in the higher-dose groups was 25.1%, compared with 13.8% for the placebo group in the first trial, and 22.2%, compared with 16.4%, in the second, and no serious drug-related adverse events were observed in either trial with the high dose of the drug," he said. The most common adverse events that occurred at least 5% more frequently in the high dose suvorexant group, compared with placebo, were sleepiness and headache, he noted.

There were no significant next-day objective residual effects associated with the study drug relative to placebo, as measured by the Digit Symbol Substitution Test, Dr. Krystal said. At 3 months, the incidence of next day sleepiness was about 10% in high-dose suvorexant patients and 3% among placebo patients.

While the drug was well tolerated in two short-term trials, "longer trials will be more telling," Dr. Thorpy said. "The orexin inhibitors were first investigated because of their effect on metabolism, so there is a possibility that, in the longer-term studies, we might see weight changes or other metabolic effects."

Although suvorexant, which has not yet been submitted to the Food and Drug Administration for approval, promises to be a valuable addition to the sleep therapy arsenal, "medications in the management of insomnia can only go so far," Dr. Thorpy stressed. "Some of the more important therapies are behavioral. No sleep pill will work with someone who has bad sleep hygiene or sleep/wake cycle issues. For optimal efficacy, all medications should be used in combination with behavioral interventions."

Dr. Krystal is a consultant to Merck, which funded both trials. Dr. Thorpy said that he had no relevant conflicts of interest.

* Correction, 6/21/12: An earlier version of this story implied that Dr. Andrew D. Krystal presented the results of the two trials described in the article. He was an investigator for the studies, but did not present them.

BOSTON – The promise of shorter time to sleep, longer sleep duration, and fewer side effects associated with the experimental sleep drug suvorexant has sleep medicine clinicians and their patients eagerly anticipating the approval of the first-in-class agent.

Suvorexant’s mechanism of action in targeting the orexin system, which promotes wakefulness, sets it apart from some of the currently available sleep medications, according to Dr. Michael Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in New York. "The effects of the new drug are fairly localized because it targets a more specific receptor than the GABA agonists, which have a more generalized effect and thus more side effects." Importantly, suvorexant does not depress the central nervous system or respiratory function and thus may be a good option for patients with suspected sleep apnea, he noted.

Two pivotal phase III studies of the drug were presented at the meeting. Both randomized, double-blind, placebo-controlled trials were 3-month studies designed to confirm the safety and efficacy outcomes of an initial 4-week proof-of-concept study in patients with primary insomnia. Each trial evaluated two dose regimens: 40 mg for patients 18-64 years and 30 mg for those older than 65 years in the first trial; and 20 mg and 15 mg, respectively, in the second trial, explained Dr. Andrew D. Krystal, professor of psychiatry and behavioral sciences at Duke University Medical Center, Durham, N.C., and an investigator for both trials.*

Efficacy measures were patient self-reported time to sleep onset (sTSO), self-reported total sleep time (sTST), and self-reported wake after sleep onset (sWASO), as well as the polysomnographic end points of latency to onset of persistent sleep (LPS) and wake after persistent sleep onset (WASO), he said.

In the first trial, which randomized 1,021 patients, suvorexant at 40 mg and 30 mg was significantly better than placebo was in all end points at 1 and 3 months, Dr. Krystal reported. Specifically, at 3 months, the mean differences from placebo in change from baseline were an increase of 19.7 minutes for sTST, and decreases of 8.4 minutes for sTSO, 6.9 minutes for sWASO, 9.4 minutes for LPS, and 22.9 minutes for WASO.

Similarly, significant changes were observed in the second trial, with the exception of the drug’s effect on LPS at 3 months, which was not significant – a finding the investigators attributed to high placebo response, Dr. Krystal said. In this study, the mean differences from placebo in change from baseline at 3 months were an increase of 25.1 minutes for sTST and decreases of 13.2 minutes for sTSO, 8.9 minutes for sWASO, 3.6 minutes for LPS, and 29.4 minutes for WASO.

Both studies also measured the time it took patients to fall into continuous sleep and the time they spent awake during the first night of use, comparing the results with those reported before starting the drug, Dr. Krystal said. In the first trial, "patients [taking suvorexant] entered into continuous sleep 30.6 minutes faster and spent 58.0 fewer minutes awake during the night, compared to before they started taking the drug," he said. Similarly, in the second trial, the suvorexant patients entered into continuous sleep 34.7 minutes faster and spent 63.3 fewer minutes awake during the night, compared with before they started the drug. The respective placebo group improvements in the two trials were 13.0-20.3 minutes and 19.6-21.3 minutes, he said.

Both dose regimens of suvorexant in the trials were well tolerated with no evidence of clinically important rebound or withdrawal on discontinuation, Dr. Krystal reported. "Over the 3-month period, the overall incidence of adverse events in the higher-dose groups was 25.1%, compared with 13.8% for the placebo group in the first trial, and 22.2%, compared with 16.4%, in the second, and no serious drug-related adverse events were observed in either trial with the high dose of the drug," he said. The most common adverse events that occurred at least 5% more frequently in the high dose suvorexant group, compared with placebo, were sleepiness and headache, he noted.

There were no significant next-day objective residual effects associated with the study drug relative to placebo, as measured by the Digit Symbol Substitution Test, Dr. Krystal said. At 3 months, the incidence of next day sleepiness was about 10% in high-dose suvorexant patients and 3% among placebo patients.

While the drug was well tolerated in two short-term trials, "longer trials will be more telling," Dr. Thorpy said. "The orexin inhibitors were first investigated because of their effect on metabolism, so there is a possibility that, in the longer-term studies, we might see weight changes or other metabolic effects."

Although suvorexant, which has not yet been submitted to the Food and Drug Administration for approval, promises to be a valuable addition to the sleep therapy arsenal, "medications in the management of insomnia can only go so far," Dr. Thorpy stressed. "Some of the more important therapies are behavioral. No sleep pill will work with someone who has bad sleep hygiene or sleep/wake cycle issues. For optimal efficacy, all medications should be used in combination with behavioral interventions."

Dr. Krystal is a consultant to Merck, which funded both trials. Dr. Thorpy said that he had no relevant conflicts of interest.

* Correction, 6/21/12: An earlier version of this story implied that Dr. Andrew D. Krystal presented the results of the two trials described in the article. He was an investigator for the studies, but did not present them.

BOSTON – The promise of shorter time to sleep, longer sleep duration, and fewer side effects associated with the experimental sleep drug suvorexant has sleep medicine clinicians and their patients eagerly anticipating the approval of the first-in-class agent.

Suvorexant’s mechanism of action in targeting the orexin system, which promotes wakefulness, sets it apart from some of the currently available sleep medications, according to Dr. Michael Thorpy, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center in New York. "The effects of the new drug are fairly localized because it targets a more specific receptor than the GABA agonists, which have a more generalized effect and thus more side effects." Importantly, suvorexant does not depress the central nervous system or respiratory function and thus may be a good option for patients with suspected sleep apnea, he noted.

Two pivotal phase III studies of the drug were presented at the meeting. Both randomized, double-blind, placebo-controlled trials were 3-month studies designed to confirm the safety and efficacy outcomes of an initial 4-week proof-of-concept study in patients with primary insomnia. Each trial evaluated two dose regimens: 40 mg for patients 18-64 years and 30 mg for those older than 65 years in the first trial; and 20 mg and 15 mg, respectively, in the second trial, explained Dr. Andrew D. Krystal, professor of psychiatry and behavioral sciences at Duke University Medical Center, Durham, N.C., and an investigator for both trials.*

Efficacy measures were patient self-reported time to sleep onset (sTSO), self-reported total sleep time (sTST), and self-reported wake after sleep onset (sWASO), as well as the polysomnographic end points of latency to onset of persistent sleep (LPS) and wake after persistent sleep onset (WASO), he said.

In the first trial, which randomized 1,021 patients, suvorexant at 40 mg and 30 mg was significantly better than placebo was in all end points at 1 and 3 months, Dr. Krystal reported. Specifically, at 3 months, the mean differences from placebo in change from baseline were an increase of 19.7 minutes for sTST, and decreases of 8.4 minutes for sTSO, 6.9 minutes for sWASO, 9.4 minutes for LPS, and 22.9 minutes for WASO.

Similarly, significant changes were observed in the second trial, with the exception of the drug’s effect on LPS at 3 months, which was not significant – a finding the investigators attributed to high placebo response, Dr. Krystal said. In this study, the mean differences from placebo in change from baseline at 3 months were an increase of 25.1 minutes for sTST and decreases of 13.2 minutes for sTSO, 8.9 minutes for sWASO, 3.6 minutes for LPS, and 29.4 minutes for WASO.

Both studies also measured the time it took patients to fall into continuous sleep and the time they spent awake during the first night of use, comparing the results with those reported before starting the drug, Dr. Krystal said. In the first trial, "patients [taking suvorexant] entered into continuous sleep 30.6 minutes faster and spent 58.0 fewer minutes awake during the night, compared to before they started taking the drug," he said. Similarly, in the second trial, the suvorexant patients entered into continuous sleep 34.7 minutes faster and spent 63.3 fewer minutes awake during the night, compared with before they started the drug. The respective placebo group improvements in the two trials were 13.0-20.3 minutes and 19.6-21.3 minutes, he said.

Both dose regimens of suvorexant in the trials were well tolerated with no evidence of clinically important rebound or withdrawal on discontinuation, Dr. Krystal reported. "Over the 3-month period, the overall incidence of adverse events in the higher-dose groups was 25.1%, compared with 13.8% for the placebo group in the first trial, and 22.2%, compared with 16.4%, in the second, and no serious drug-related adverse events were observed in either trial with the high dose of the drug," he said. The most common adverse events that occurred at least 5% more frequently in the high dose suvorexant group, compared with placebo, were sleepiness and headache, he noted.

There were no significant next-day objective residual effects associated with the study drug relative to placebo, as measured by the Digit Symbol Substitution Test, Dr. Krystal said. At 3 months, the incidence of next day sleepiness was about 10% in high-dose suvorexant patients and 3% among placebo patients.

While the drug was well tolerated in two short-term trials, "longer trials will be more telling," Dr. Thorpy said. "The orexin inhibitors were first investigated because of their effect on metabolism, so there is a possibility that, in the longer-term studies, we might see weight changes or other metabolic effects."

Although suvorexant, which has not yet been submitted to the Food and Drug Administration for approval, promises to be a valuable addition to the sleep therapy arsenal, "medications in the management of insomnia can only go so far," Dr. Thorpy stressed. "Some of the more important therapies are behavioral. No sleep pill will work with someone who has bad sleep hygiene or sleep/wake cycle issues. For optimal efficacy, all medications should be used in combination with behavioral interventions."

Dr. Krystal is a consultant to Merck, which funded both trials. Dr. Thorpy said that he had no relevant conflicts of interest.

* Correction, 6/21/12: An earlier version of this story implied that Dr. Andrew D. Krystal presented the results of the two trials described in the article. He was an investigator for the studies, but did not present them.