Articles

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; [email protected].

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; [email protected].

Each year, more than one in every 100 infants are born at less than 32 weeks postmenstrual age.¹ In industrialized countries, many of these infants are discharged from the neonatal intensive care unit (NICU) with home apnea monitors,¹ which alert caregivers to episodes of apnea and bradycardia, while also capturing and storing data surrounding significant events for later analysis.²

Evidence supporting the use of home apnea monitoring is sparse, and recommendations highlight the need to use this technology sparingly and to discontinue use once it is no longer necessary (TABLE).³ Counseling parents is critical. It’s important to explain that home apnea monitoring can be used to help reduce the likelihood that a child will die in his or her sleep, but it affords users no “guarantees.” In addition, home apnea monitoring can adversely affect parents. Parents who use home apnea monitoring for their infants have been shown to have higher stress scores, greater levels of fatigue, and poorer health than parents of infants without home apnea monitors.^4-8

As a family physician, you are likely to encounter home apnea monitoring in one of 3 scenarios: at the first visit after discharge by a premature infant who experienced apnea while hospitalized, at a follow-up visit after discharge from the hospital by an infant who experienced an apparent life-threatening event (ALTE), and at a follow-up visit by an infant whose sibling had died from sudden infant death syndrome (SIDS). This article presents case studies that illustrate each of these scenarios, and explains what to tell parents who ask about how long they should continue home apnea monitoring.

CASE 1 › Apnea of prematurity

Jacob is a newborn who is brought in to your clinic by his parents for an initial visit. The infant was born prematurely at 32 weeks and required a prolonged NICU stay. His mother says that Jacob spent 4 weeks there and was discharged home with home apnea monitoring. On exam, the infant has a monitor attached via a chest band. Jacob appears healthy and his exam is normal. The mother asks you how long her son should use the home monitor.

Pathologic apnea is a respiratory pause that lasts at least 20 seconds or is associated with cyanosis; abrupt, marked pallor or hypotonia; or bradycardia.² Apnea of prematurity is present in almost all infants born at <29 weeks postmenstrual age or who weigh <1000 g.⁹ It is found in 54% of infants born at 30 to 31 weeks, 15% born at 32 to 33 weeks, and 7% of infants born at 34 to 35 weeks.¹⁰

Apnea of prematurity is primarily due to an immature respiratory control system, which results in impaired breathing regulation, immature respiratory responses to hypercapnia and hypoxia, and an exaggerated inhibitory response to stimulation of airway receptors.^11-13 Although apnea of prematurity usually resolves by 36 to 40 weeks postmenstrual age, it often persists beyond 38 to 40 weeks in infants born before 28 weeks.¹⁰ In these infants, by 43 to 44 weeks postmenstrual age, the frequency of apneic episodes decreases to that of full-term infants.¹⁴

Apnea of prematurity is not associated with an increased risk of sudden infant death syndrome.

The differences in long-term outcomes of infants with apnea of prematurity vs infants without it are subtle, if present at all.^14,15 There does seem to be a correlation between the number of days with apnea and poor outcomes. Neurodevelopmental impairment and death are more likely in neonates who experience a greater number of days with apnea episodes.^16,17 However, apnea of prematurity is not associated with an increased risk of SIDS.¹⁸

According to the American Academy of Pediatrics (AAP), home apnea monitoring may be warranted for premature infants who are at high risk of recurrent episodes of apnea, bradycardia, and hypoxemia after hospital discharge.³ While there is general consensus that all infants born prior to 29 weeks meet this criterion, the use of home apnea monitors in older preterm infants varies significantly, and the decision to initiate monitoring in these patients is made by the discharging physician.³ Once initiated, the AAP recommends that the use of home apnea monitoring in this population be discontinued after approximately 43 weeks postmenstrual age or after the cessation of extreme episodes, whichever comes last.³

In Jacob’s case, the monitoring should be discontinued at approximately week 12 of life, or about age 3 months.

CASE 2 › Apparent life-threatening event

Sarah is brought to your office after being hospitalized for an ALTE. Her mother reports that she had witnessed her 13-day-old daughter not breathing for “about a minute.” Upon realizing what was happening, she “blew into the baby’s face,” whereupon Sarah awakened. The mother then called 911 and they went by ambulance to the emergency room. The newborn was admitted for observation overnight and received a thorough evaluation. She was discharged with a home apnea monitor.

You review the work-up and find nothing worrisome. Sarah is in a car seat attached to the apnea monitor with a chest strap. An examination of the child is normal. The mother asks you when they should stop using the home monitor.

An ALTE is “an event that is frightening to the observer and ... is characterized by some combination of apnea (central or occasionally obstructive), color change (usually cyanotic or pallid but occasionally erythematous or plethoric), marked change in muscle tone (usually marked limpness), choking, or gagging.”² ALTE is a descriptive term, and not a definitive diagnosis.

The true incidence of ALTE is unknown, but is reported to be 0.5% to 6%; most events occur in children younger than age 1.^19,20 The risk for ALTE is increased for premature infants, particularly those with respiratory syncytial virus or who had undergone general anesthesia; infants who feed rapidly, cough frequently, or choke during feeding; and male infants.^19,21

The most common causes of ALTE (in descending order) are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.²² The etiology is unknown for about half of patients with ALTE.²³

Tell parents that if their infant experiences an ALTE, they should seek medical attention without delay. The fear is that failing to respond to this concern will ultimately result in a sudden unexpected infant death, specifically as a result of SIDS.²⁴

SIDS is very rare, occurring in only 40 per 100,000 births. One analysis found that children who die from SIDS and those who experience ALTE have very similar histories and clinical factors.²⁵ Approximately 7% of infants who die from SIDS have had an ALTE.² Overall, the long-term prognosis for infants who have had an ALTE is very good, although it depends on seriousness of the underlying etiology.^8,26-28

Guidance on the effective use of home apnea monitors in infants who experience an ALTE is sparse. Despite this, the National Institutes of Health (NIH) Consensus Statement on Infantile Apnea and Home Monitoring² and the American Academy of Pediatrics policy statement on apnea, sudden infant death syndrome, and home monitoring³ recommend the use of home apnea monitoring for certain infants who’ve had an ALTE. The NIH Consensus Statement specifies home monitoring for infants with one or more severe episodes of ALTEs that require mouth-to-mouth resuscitation or vigorous stimulation.² There are no specific guidelines regarding the duration of monitoring.^2,3

In Sarah’s case, home monitoring should be discontinued as soon as the mother is comfortable with the decision.

CASE 3 › Sudden infant death syndrome

The parents of a 2-month-old boy, Stephen, come to your office to establish care. They recently relocated and their previous care provider had prescribed a home apnea monitor because a child they’d had 3 years ago had died of SIDS. Stephen is in a car seat attached to the apnea monitor with a chest strap. Your examination of him is normal. Stephen’s parents would like to stop using the home monitor, and ask you if it’s safe to do so.

The most common causes of an apparent life-threatening event in an infant are gastroesophageal reflux, seizure disorder, and lower respiratory tract infection.

SIDS is the death of an infant or young child that is unexplained by history and in which postmortem examination fails to find an adequate explanation of cause of death.² Since the introduction of the Back to Sleep campaign in the early 1990s, the incidence of SIDS has decreased by more than 50%.⁸ In 2013, approximately 1500 infant deaths were attributed to SIDS.²⁴ Three-quarters of deaths due to SIDS occur between 2 to 4 months of age, and 95% of deaths occur before 9 months of age.²⁹ Risk factors for SIDS include sleep environment (prone and side sleeping, bed sharing, soft bedding), prenatal and postnatal maternal tobacco use, exposure to tobacco smoke, maternal mental illness or substance abuse, male sex, poverty, prematurity, low birth weight (less than 2500 g), and no or poor prenatal care.³⁰

The etiology of SIDS is unclear.³¹ The leading hypothesis is the “triple-risk model,” which proposes that death from SIDS is due to 3 overlapping factors: a vulnerable infant, a critical developmental period in homeostatic control, and an exogenous stressor.³²

Although the NIH Consensus Statement suggests home apnea monitoring is indicated for infants who are siblings of 2 or more SIDS victims,² more recent policy statements from the AAP recommend against using home apnea monitors to reduce the incidence of SIDS due to a lack of evidence.^3,8

With this in mind, Stephen’s monitor should be discontinued and his parents should be educated on proven methods of preventing SIDS, including placing him on his back to sleep, breastfeeding him, letting him use a pacifier during sleep, and not sleeping in the same bed with him or overdressing him when putting him to sleep.^3,8

CORRESPONDENCE
Allen Perkins, MD, MPH, Department of Family Medicine, University of South Alabama, 1504 Springhill Avenue, Suite 3414, Mobile, AL 36604; [email protected].

PRACTICE CHANGER 
Prescribe oral prednisone 50 mg/d to hospitalized patients with mild-to-moderate community-acquired pneumonia. It decreases time to clinical stability and length of hospital stay.¹

STRENGTH OF RECOMMENDATION 
A: Based on a single good-­quality randomized controlled trial (RCT) and meta-analysis.¹

ILLUSTRATIVE CASE
A 75-year-old woman with hypertension and diabetes presents to the emergency department with shortness of breath, cough, and fever that she’s had for four days. On examination, her temperature is 38.2°C; heart rate, 110 beats/min; respiratory rate, 28 breaths/min; and O₂ saturation, 91%. Rhonchi are heard in her right lower lung field; chest x-ray reveals infiltrate in her right lower lobe. The patient is admitted and started on IV antibiotics, IV fluids, acetaminophen for fever, and oxygen. Can anything else be done to speed her recovery?

Community-acquired pneumonia (CAP) is responsible for more than 1 million hospitalizations annually in the United States and is the eighth leading cause of death.^2,3 Treatment of CAP typically consists of antibiotics and supportive measures (eg, IV fluids and antipyretics). Because the disease process involves extensive inflammation, adjunct treatment with corticosteroids may be beneficial.

Multiple studies have shown that treatment with corticosteroids can help patients with severe CAP, but the potential benefit in patients with less severe CAP has been uncertain.^4,5 A Coch­rane systematic review published in 2011 identified six small RCTs that evaluated the impact of corticosteroids on CAP recovery.⁴ It suggested that corticosteroids may decrease time to recovery, but the studies that included patients with less severe CAP had a relatively high risk for bias.

Subsequently, a 2012 meta-analysis of nine RCTs explored whether corticosteroids affected mortality in CAP; no benefit was observed in patients with less severe CAP.⁵ Most recently, a 2013 meta-analysis of eight moderate-quality RCTs showed that corticosteroid use was associated with shorter hospital stays but no change in mortality.⁶

The synthesis of small or moderate-quality studies suggests some potential benefit in treating less severe CAP with corticosteroids, but there has been a need for a large, definitive, high-quality RCT. This study investigated the impact of a short course of oral steroids on inpatients with less severe CAP.

STUDY SUMMARY
Prednisone hastens clinical stabilization, cuts hospital stay
In a multicenter, double-blind RCT, Blum et al¹ enrolled 785 patients with CAP who were admitted to one of seven tertiary care hospitals in Switzerland from 2009 to 2014. Patients were eligible if they were 18 or older, had a new infiltrate on chest x-ray, and had at least one additional sign or symptom of respiratory illness (eg, cough, dyspnea, fever, abnormal breathing signs or rales, or elevated or decreased white blood cell count). Patients were excluded if they had a contraindication to corticosteroids, cystic fibrosis, or active tuberculosis.

Patients were randomized to receive either prednisone 50 mg/d or placebo for seven days. They were treated with antibiotics according to accepted local guidelines; most patients received either amoxicillin/clavulanic acid or ceftriaxone. Antibiotic treatment was adjusted according to susceptibility whenever a specific pathogen was identified. Nurses assessed all patients every 12 hours during hospitalization, and laboratory tests were obtained on hospital days 1, 3, 5, and 7, and before discharge. Follow-up telephone interviews were conducted on day 30.

The primary outcome was length of time to clinical stability (eg, at least 24 hours of stable vital signs). This composite endpoint required all of the following: temperature ≤ 37.8°C; heart rate ≤ 100 beats/min; spontaneous respiratory rate ≤ 24 breaths/min; systolic blood pressure ≥ 90 mm Hg (≥ 100 mm Hg for patients diagnosed with hypertension) without vasopressor support; mental status back to baseline; ability to take food by mouth; and adequate oxygenation on room air.

Secondary outcomes included length of hospital stay, pneumonia recurrence, hospital readmission, intensive care unit (ICU) admission, all-cause mortality, and duration of antibiotic treatment. Researchers also explored whether the rates of complications from pneumonia or corticosteroid use differed between the prednisone and placebo groups.

In an intention-to-treat analysis, the median time to clinical stability was shorter for the prednisone group at 3 days (interquartile range [IQR], 2.5 to 3.4) compared to the placebo group at 4.4 days (IQR, 4 - 5; hazard ratio [HR], 1.33). Median time to hospital discharge was also shorter for the prednisone group (6 d vs 7 d; HR, 1.19), as was duration of IV antibiotic treatment (4 d vs 5 d; difference, –0.89 d).

There were no statistically significant differences in pneumonia recurrence, hospital readmission, ICU admission, or all-cause mortality. Patients treated with prednisone were more likely to experience hyperglycemia that required insulin treatment during admission (19% vs 11%; odds ratio, 1.96).

WHAT’S NEW 
This large, good-quality study reinforces previous evidence
This is the first rigorous study to show a clear decrease in both time to clinical stability and length of hospital stay. It also used an easy-to-administer dose of oral steroids, instead of the several-day course of IV steroids used in most other studies. The findings from this study were incorporated into a 2015 meta-analysis that confirmed that corticosteroid treatment in patients with less severe CAP results in a shorter length of hospital stay and decreased time to clinical stability.⁷

CAVEATS
It’s unclear if steroids benefit nonhospitalized patients
Because this study included hospitalized patients only, it’s not clear whether corticosteroids have a role in outpatient treatment of CAP. Additionally, although this was a large, well-designed study, it did not have a sufficient number of patients to examine whether corticosteroids impact mortality among patients with CAP.

Finally, the average length of hospital stay reported in this study was approximately 1.5 days longer than the typical length of stay in the US.² The average length of stay has varied widely in studies examining corticosteroids in CAP, but good-quality studies have consistently shown a median reduction in length of stay of one day.⁷

CHALLENGES TO IMPLEMENTATION
Risk for adverse events
Treatment with prednisone increases risk for corticosteroid-related adverse events, primarily hyperglycemia and the need for insulin. This may not be well received by patients or providers. However, these effects appear to resolve quickly after treatment and do not impact the overall time to clinical stability.

REFERENCES 
1. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomized, placebo-controlled trial. Lancet. 2015;385:1511-1518.
2. CDC. FastStats: Pneumonia. www.cdc.gov/nchs/fastats/pneumonia.htm. Accessed September 29, 2015.
3. CDC/National Center for Health Statistics. Top 10 leading causes of death: United States, 1999–2013. http://blogs.cdc.gov/nchs-data-visualization/2015/06/01/leading-causes-of-death. Accessed September 29, 2015.
4. Chen Y, Li K, Pu H, et al. Corticosteroids for pneumonia. Cochrane Database Syst Rev. 2011;3:CD007720.
5. Nie W, Zhang Y, Cheng J, et al. Corticosteroids in the treatment of community-acquired pneumonia in adults: a meta-analysis. PLoS One. 2012;7:e47926.
6. Shafiq M, Mansoor MS, Khan AA, et al. Adjuvant steroid therapy in community-acquired pneumonia: a systematic review and meta-analysis. J Hosp Med. 2013;8:68-75.
7. Siemieniuk RA, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med. 2015;163:519-528.

ACKNOWLEDGEMENT
The PURLs Surveillance System was 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.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(10):648-650.

PRACTICE CHANGER 
Prescribe oral prednisone 50 mg/d to hospitalized patients with mild-to-moderate community-acquired pneumonia. It decreases time to clinical stability and length of hospital stay.¹

STRENGTH OF RECOMMENDATION 
A: Based on a single good-­quality randomized controlled trial (RCT) and meta-analysis.¹

ILLUSTRATIVE CASE
A 75-year-old woman with hypertension and diabetes presents to the emergency department with shortness of breath, cough, and fever that she’s had for four days. On examination, her temperature is 38.2°C; heart rate, 110 beats/min; respiratory rate, 28 breaths/min; and O₂ saturation, 91%. Rhonchi are heard in her right lower lung field; chest x-ray reveals infiltrate in her right lower lobe. The patient is admitted and started on IV antibiotics, IV fluids, acetaminophen for fever, and oxygen. Can anything else be done to speed her recovery?

Community-acquired pneumonia (CAP) is responsible for more than 1 million hospitalizations annually in the United States and is the eighth leading cause of death.^2,3 Treatment of CAP typically consists of antibiotics and supportive measures (eg, IV fluids and antipyretics). Because the disease process involves extensive inflammation, adjunct treatment with corticosteroids may be beneficial.

Multiple studies have shown that treatment with corticosteroids can help patients with severe CAP, but the potential benefit in patients with less severe CAP has been uncertain.^4,5 A Coch­rane systematic review published in 2011 identified six small RCTs that evaluated the impact of corticosteroids on CAP recovery.⁴ It suggested that corticosteroids may decrease time to recovery, but the studies that included patients with less severe CAP had a relatively high risk for bias.

Subsequently, a 2012 meta-analysis of nine RCTs explored whether corticosteroids affected mortality in CAP; no benefit was observed in patients with less severe CAP.⁵ Most recently, a 2013 meta-analysis of eight moderate-quality RCTs showed that corticosteroid use was associated with shorter hospital stays but no change in mortality.⁶

The synthesis of small or moderate-quality studies suggests some potential benefit in treating less severe CAP with corticosteroids, but there has been a need for a large, definitive, high-quality RCT. This study investigated the impact of a short course of oral steroids on inpatients with less severe CAP.

STUDY SUMMARY
Prednisone hastens clinical stabilization, cuts hospital stay
In a multicenter, double-blind RCT, Blum et al¹ enrolled 785 patients with CAP who were admitted to one of seven tertiary care hospitals in Switzerland from 2009 to 2014. Patients were eligible if they were 18 or older, had a new infiltrate on chest x-ray, and had at least one additional sign or symptom of respiratory illness (eg, cough, dyspnea, fever, abnormal breathing signs or rales, or elevated or decreased white blood cell count). Patients were excluded if they had a contraindication to corticosteroids, cystic fibrosis, or active tuberculosis.

Patients were randomized to receive either prednisone 50 mg/d or placebo for seven days. They were treated with antibiotics according to accepted local guidelines; most patients received either amoxicillin/clavulanic acid or ceftriaxone. Antibiotic treatment was adjusted according to susceptibility whenever a specific pathogen was identified. Nurses assessed all patients every 12 hours during hospitalization, and laboratory tests were obtained on hospital days 1, 3, 5, and 7, and before discharge. Follow-up telephone interviews were conducted on day 30.

The primary outcome was length of time to clinical stability (eg, at least 24 hours of stable vital signs). This composite endpoint required all of the following: temperature ≤ 37.8°C; heart rate ≤ 100 beats/min; spontaneous respiratory rate ≤ 24 breaths/min; systolic blood pressure ≥ 90 mm Hg (≥ 100 mm Hg for patients diagnosed with hypertension) without vasopressor support; mental status back to baseline; ability to take food by mouth; and adequate oxygenation on room air.

Secondary outcomes included length of hospital stay, pneumonia recurrence, hospital readmission, intensive care unit (ICU) admission, all-cause mortality, and duration of antibiotic treatment. Researchers also explored whether the rates of complications from pneumonia or corticosteroid use differed between the prednisone and placebo groups.

In an intention-to-treat analysis, the median time to clinical stability was shorter for the prednisone group at 3 days (interquartile range [IQR], 2.5 to 3.4) compared to the placebo group at 4.4 days (IQR, 4 - 5; hazard ratio [HR], 1.33). Median time to hospital discharge was also shorter for the prednisone group (6 d vs 7 d; HR, 1.19), as was duration of IV antibiotic treatment (4 d vs 5 d; difference, –0.89 d).

There were no statistically significant differences in pneumonia recurrence, hospital readmission, ICU admission, or all-cause mortality. Patients treated with prednisone were more likely to experience hyperglycemia that required insulin treatment during admission (19% vs 11%; odds ratio, 1.96).

WHAT’S NEW 
This large, good-quality study reinforces previous evidence
This is the first rigorous study to show a clear decrease in both time to clinical stability and length of hospital stay. It also used an easy-to-administer dose of oral steroids, instead of the several-day course of IV steroids used in most other studies. The findings from this study were incorporated into a 2015 meta-analysis that confirmed that corticosteroid treatment in patients with less severe CAP results in a shorter length of hospital stay and decreased time to clinical stability.⁷

CAVEATS
It’s unclear if steroids benefit nonhospitalized patients
Because this study included hospitalized patients only, it’s not clear whether corticosteroids have a role in outpatient treatment of CAP. Additionally, although this was a large, well-designed study, it did not have a sufficient number of patients to examine whether corticosteroids impact mortality among patients with CAP.

Finally, the average length of hospital stay reported in this study was approximately 1.5 days longer than the typical length of stay in the US.² The average length of stay has varied widely in studies examining corticosteroids in CAP, but good-quality studies have consistently shown a median reduction in length of stay of one day.⁷

CHALLENGES TO IMPLEMENTATION
Risk for adverse events
Treatment with prednisone increases risk for corticosteroid-related adverse events, primarily hyperglycemia and the need for insulin. This may not be well received by patients or providers. However, these effects appear to resolve quickly after treatment and do not impact the overall time to clinical stability.

REFERENCES 
1. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomized, placebo-controlled trial. Lancet. 2015;385:1511-1518.
2. CDC. FastStats: Pneumonia. www.cdc.gov/nchs/fastats/pneumonia.htm. Accessed September 29, 2015.
3. CDC/National Center for Health Statistics. Top 10 leading causes of death: United States, 1999–2013. http://blogs.cdc.gov/nchs-data-visualization/2015/06/01/leading-causes-of-death. Accessed September 29, 2015.
4. Chen Y, Li K, Pu H, et al. Corticosteroids for pneumonia. Cochrane Database Syst Rev. 2011;3:CD007720.
5. Nie W, Zhang Y, Cheng J, et al. Corticosteroids in the treatment of community-acquired pneumonia in adults: a meta-analysis. PLoS One. 2012;7:e47926.
6. Shafiq M, Mansoor MS, Khan AA, et al. Adjuvant steroid therapy in community-acquired pneumonia: a systematic review and meta-analysis. J Hosp Med. 2013;8:68-75.
7. Siemieniuk RA, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med. 2015;163:519-528.

ACKNOWLEDGEMENT
The PURLs Surveillance System was 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.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(10):648-650.

PRACTICE CHANGER 
Prescribe oral prednisone 50 mg/d to hospitalized patients with mild-to-moderate community-acquired pneumonia. It decreases time to clinical stability and length of hospital stay.¹

STRENGTH OF RECOMMENDATION 
A: Based on a single good-­quality randomized controlled trial (RCT) and meta-analysis.¹

ILLUSTRATIVE CASE
A 75-year-old woman with hypertension and diabetes presents to the emergency department with shortness of breath, cough, and fever that she’s had for four days. On examination, her temperature is 38.2°C; heart rate, 110 beats/min; respiratory rate, 28 breaths/min; and O₂ saturation, 91%. Rhonchi are heard in her right lower lung field; chest x-ray reveals infiltrate in her right lower lobe. The patient is admitted and started on IV antibiotics, IV fluids, acetaminophen for fever, and oxygen. Can anything else be done to speed her recovery?

Community-acquired pneumonia (CAP) is responsible for more than 1 million hospitalizations annually in the United States and is the eighth leading cause of death.^2,3 Treatment of CAP typically consists of antibiotics and supportive measures (eg, IV fluids and antipyretics). Because the disease process involves extensive inflammation, adjunct treatment with corticosteroids may be beneficial.

Multiple studies have shown that treatment with corticosteroids can help patients with severe CAP, but the potential benefit in patients with less severe CAP has been uncertain.^4,5 A Coch­rane systematic review published in 2011 identified six small RCTs that evaluated the impact of corticosteroids on CAP recovery.⁴ It suggested that corticosteroids may decrease time to recovery, but the studies that included patients with less severe CAP had a relatively high risk for bias.

Subsequently, a 2012 meta-analysis of nine RCTs explored whether corticosteroids affected mortality in CAP; no benefit was observed in patients with less severe CAP.⁵ Most recently, a 2013 meta-analysis of eight moderate-quality RCTs showed that corticosteroid use was associated with shorter hospital stays but no change in mortality.⁶

The synthesis of small or moderate-quality studies suggests some potential benefit in treating less severe CAP with corticosteroids, but there has been a need for a large, definitive, high-quality RCT. This study investigated the impact of a short course of oral steroids on inpatients with less severe CAP.

STUDY SUMMARY
Prednisone hastens clinical stabilization, cuts hospital stay
In a multicenter, double-blind RCT, Blum et al¹ enrolled 785 patients with CAP who were admitted to one of seven tertiary care hospitals in Switzerland from 2009 to 2014. Patients were eligible if they were 18 or older, had a new infiltrate on chest x-ray, and had at least one additional sign or symptom of respiratory illness (eg, cough, dyspnea, fever, abnormal breathing signs or rales, or elevated or decreased white blood cell count). Patients were excluded if they had a contraindication to corticosteroids, cystic fibrosis, or active tuberculosis.

Patients were randomized to receive either prednisone 50 mg/d or placebo for seven days. They were treated with antibiotics according to accepted local guidelines; most patients received either amoxicillin/clavulanic acid or ceftriaxone. Antibiotic treatment was adjusted according to susceptibility whenever a specific pathogen was identified. Nurses assessed all patients every 12 hours during hospitalization, and laboratory tests were obtained on hospital days 1, 3, 5, and 7, and before discharge. Follow-up telephone interviews were conducted on day 30.

The primary outcome was length of time to clinical stability (eg, at least 24 hours of stable vital signs). This composite endpoint required all of the following: temperature ≤ 37.8°C; heart rate ≤ 100 beats/min; spontaneous respiratory rate ≤ 24 breaths/min; systolic blood pressure ≥ 90 mm Hg (≥ 100 mm Hg for patients diagnosed with hypertension) without vasopressor support; mental status back to baseline; ability to take food by mouth; and adequate oxygenation on room air.

Secondary outcomes included length of hospital stay, pneumonia recurrence, hospital readmission, intensive care unit (ICU) admission, all-cause mortality, and duration of antibiotic treatment. Researchers also explored whether the rates of complications from pneumonia or corticosteroid use differed between the prednisone and placebo groups.

In an intention-to-treat analysis, the median time to clinical stability was shorter for the prednisone group at 3 days (interquartile range [IQR], 2.5 to 3.4) compared to the placebo group at 4.4 days (IQR, 4 - 5; hazard ratio [HR], 1.33). Median time to hospital discharge was also shorter for the prednisone group (6 d vs 7 d; HR, 1.19), as was duration of IV antibiotic treatment (4 d vs 5 d; difference, –0.89 d).

There were no statistically significant differences in pneumonia recurrence, hospital readmission, ICU admission, or all-cause mortality. Patients treated with prednisone were more likely to experience hyperglycemia that required insulin treatment during admission (19% vs 11%; odds ratio, 1.96).

WHAT’S NEW 
This large, good-quality study reinforces previous evidence
This is the first rigorous study to show a clear decrease in both time to clinical stability and length of hospital stay. It also used an easy-to-administer dose of oral steroids, instead of the several-day course of IV steroids used in most other studies. The findings from this study were incorporated into a 2015 meta-analysis that confirmed that corticosteroid treatment in patients with less severe CAP results in a shorter length of hospital stay and decreased time to clinical stability.⁷

CAVEATS
It’s unclear if steroids benefit nonhospitalized patients
Because this study included hospitalized patients only, it’s not clear whether corticosteroids have a role in outpatient treatment of CAP. Additionally, although this was a large, well-designed study, it did not have a sufficient number of patients to examine whether corticosteroids impact mortality among patients with CAP.

Finally, the average length of hospital stay reported in this study was approximately 1.5 days longer than the typical length of stay in the US.² The average length of stay has varied widely in studies examining corticosteroids in CAP, but good-quality studies have consistently shown a median reduction in length of stay of one day.⁷

CHALLENGES TO IMPLEMENTATION
Risk for adverse events
Treatment with prednisone increases risk for corticosteroid-related adverse events, primarily hyperglycemia and the need for insulin. This may not be well received by patients or providers. However, these effects appear to resolve quickly after treatment and do not impact the overall time to clinical stability.

REFERENCES 
1. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomized, placebo-controlled trial. Lancet. 2015;385:1511-1518.
2. CDC. FastStats: Pneumonia. www.cdc.gov/nchs/fastats/pneumonia.htm. Accessed September 29, 2015.
3. CDC/National Center for Health Statistics. Top 10 leading causes of death: United States, 1999–2013. http://blogs.cdc.gov/nchs-data-visualization/2015/06/01/leading-causes-of-death. Accessed September 29, 2015.
4. Chen Y, Li K, Pu H, et al. Corticosteroids for pneumonia. Cochrane Database Syst Rev. 2011;3:CD007720.
5. Nie W, Zhang Y, Cheng J, et al. Corticosteroids in the treatment of community-acquired pneumonia in adults: a meta-analysis. PLoS One. 2012;7:e47926.
6. Shafiq M, Mansoor MS, Khan AA, et al. Adjuvant steroid therapy in community-acquired pneumonia: a systematic review and meta-analysis. J Hosp Med. 2013;8:68-75.
7. Siemieniuk RA, Meade MO, Alonso-Coello P, et al. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis. Ann Intern Med. 2015;163:519-528.

ACKNOWLEDGEMENT
The PURLs Surveillance System was 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.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(10):648-650.

Chronic obstructive pulmonary disease (COPD) carries a high disease burden. In 2012, it was the 4th leading cause of death worldwide.^1,2 In 2015, the World Health Organization updated its Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, classifying patients with COPD based on disease burden as determined by symptoms, airflow obstruction, and exacerbation history.³ These revisions, coupled with expanded therapeutic options within established classes of medications and new combination drugs to treat COPD (TABLE 1),^3-6 have led to questions about interclass differences and the best treatment regimen for particular patients.

Comparisons of various agents within a therapeutic class and their impact on lung function and rate of exacerbations address many of these concerns. In the text and tables that follow, we present the latest evidence highlighting differences in dosing, safety, and efficacy. We also include the updated GOLD classifications, evidence of efficacy for pulmonary rehabilitation, and practical implications of these findings for the optimal management of patients with COPD.

But first, a word about terminology.

Understanding COPD

COPD is a chronic lung disease characterized by progressive airflow limitation, usually measured by spirometry (TABLE 2),³ and chronic airway inflammation. Emphysema and chronic bronchitis are often used synonymously with COPD. In fact, there are important differences.

Individuals with chronic bronchitis do not necessarily have the airflow limitations found in those with COPD. And patients with COPD develop pathologic lung changes beyond the alveolar damage characteristic of emphysema, including airway fibrosis and inflammation, luminal plugging, and loss of elastic recoil.³

The medications included in this review aim to reduce both the morbidity and mortality associated with COPD. These drugs can also help relieve the symptoms of patients with chronic bronchitis and emphysema, but have limited effect on patient mortality.

Short- and long-acting beta₂-agonists

Bronchodilator therapy with beta₂-agonists improves forced expiratory volume in one second (FEV₁) through relaxation of airway smooth muscle. Beta₂-agonists have proven to be safe and effective when used as needed or scheduled for patients with COPD.⁷

Inhaled short-acting beta₂-agonists (SABAs) improve FEV₁ and symptoms within 10 minutes, with effects lasting up to 4 to 6 hours; long-acting beta₂-agonists (LABAs) have a variable onset, with effects lasting 12 to 24 hours.⁸ Inhaled levalbuterol, the last SABA to receive US Food and Drug Administration approval, has not proven to be superior to conventional bronchodilators in ambulatory patients with stable COPD.³ In clinical trials, however, the slightly longer half-life of the nebulized formulation of levalbuterol was found to reduce both the frequency of administration and the overall cost of therapy in patients hospitalized with acute exacerbations of COPD.^9,10

Recently approved LABAs

Clinical trials have studied the safety and efficacy of newer agents vs older LABAs in patients with moderate to severe COPD. Compared with theophylline, for example, formoterol 12 mcg inhaled every 12 hours for a 12-month period provided a clinically significant increase of >120 ml in FEV₁ (P=.026).¹¹ Higher doses of formoterol did not provide any additional improvement.

In a trial comparing indacaterol and tiotropium, an inhaled anticholinergic, both treatment groups had a clinically significant increase in FEV₁, but patients receiving indacaterol achieved an additional increase of 40 to 50 mL at 12 weeks.¹²

Exacerbation rates for all LABAs range from 22% to 44%.^5,12,13 In a study of patients receiving formoterol 12 mcg compared with 15-mcg and 25-mcg doses of arformoterol, those taking formoterol had a lower exacerbation rate than those on either strength of arformoterol (22% vs 32% and 31%, respectively).¹⁰ In various studies, doses greater than the FDA-approved regimens for indacaterol, arformoterol, and olodaterol did not result in a significant improvement in either FEV₁ or exacerbation rates compared with placebo.^5,12,14

Exacerbation rates for all long-acting beta₂-agonists range from 22% to 44%.

Studies that assessed the use of rescue medication as well as exacerbation rates in patients taking LABAs reported reductions in the use of the rescue drugs ranging from 0.46 to 1.32 actuations per day, but the findings had limited clinical relevance.^5,13 With the exception of indacaterol and olodaterol—both of which may be preferable because of their once-daily dosing regimen—no significant differences in safety and efficacy among LABAs have been found.^5,12,13

Long-acting inhaled anticholinergics

Inhaled anticholinergic agents (IACs) can be used in place of, or in conjunction with, LABAs to provide bronchodilation for up to 24 hours.³ The introduction of long-acting IACs dosed once or twice daily has the potential to improve medication adherence over traditional short-acting ipratropium, which requires multiple daily doses for symptom control. Over 4 years, tiotropium has been shown to increase time to first exacerbation by approximately 4 months. It did not, however, significantly reduce the number of exacerbations compared with placebo.¹⁵

Long-term use of tiotropium appears to have the potential to preserve lung function. In one trial, it slowed the rate of decline in FEV₁ by 5 mL per year, but this finding lacked clinical significance.¹³ In clinical trials of patients with moderate to severe COPD, however, once-daily tiotropium and umeclidinium provided clinically significant improvements in FEV₁ (>120 mL; P<.01), regardless of the dose administered.^6,16 In another trial, patients taking aclidinium 200 mcg or 400 mcg every 12 hours did not achieve a clinically significant improvement in FEV₁ compared with placebo.¹⁷

In patients with moderate to severe COPD, the combination of umeclidinium/vilanterol, a LABA, administered once daily resulted in a clinically significant improvement in FEV₁ (167 mL; P<.001) vs placebo—but was not significantly better than treatment with either agent alone.¹⁸

Long-acting inhaled anticholinergic agents—when used in combination with LABAS—have a positive effect on FEV₁, but their effect on exacerbation rates has not been established.

Few studies have evaluated time to exacerbation in patients receiving aclidinium or umeclidinium. In comparison to salmeterol, tiotropium reduced the time to first exacerbation by 42 days at one year (hazard ratio=0.83; 95% confidence interval [CI], 0.77-0.9; P<.001).¹⁹ The evidence suggests that when used in combination with LABAs, long-acting IACs have a positive impact on FEV₁, but their effect on exacerbation rates has not been established.

Combination therapy with steroids and LABAs

The combination of inhaled corticosteroids (ICS) and LABAs has been found to improve FEV₁ and symptoms in patients with moderate to severe COPD more than monotherapy with either drug class.^20,21 In fact, ICS alone have not been proven to slow the progression of the disease or to lower mortality rates in patients with COPD.²²

Fluticasone/salmeterol demonstrated a 25% reduction in exacerbation rates compared with placebo (P<.0001), a greater reduction than that of either drug alone.²⁰ A retrospective observational study comparing fixed dose fluticasone/salmeterol with budesonide/formoterol reported a similar reduction in exacerbation rates, but the number of patients requiring the addition of an IAC was 16% lower in the latter group.²³

The combination of fluticasone/vilanterol has the potential to improve adherence, given that it is dosed once daily, unlike other COPD combination drugs. Its clinical efficacy is comparable to that of fluticasone/salmeterol after 12 weeks of therapy, with similar improvements in FEV₁,²⁴ but fluticasone/vilanterol is associated with an increased risk of pneumonia.³

Chronic use of oral corticosteroids

Oral corticosteroids (OCS) are clinically indicated in individuals whose symptoms continue despite optimal therapy with inhaled agents that have demonstrated efficacy. Such patients are often referred to as “steroid dependent.”

While OCS are prescribed for both their anti-inflammatory activity and their ability to slow the progression of COPD,^25,26 no well-designed studies have investigated their benefits for this patient population. One study concluded that patients who were slowly withdrawn from their OCS regimen had no more frequent exacerbations than those who maintained chronic usage. The withdrawal group did, however, lose weight.²⁷

GOLD guidelines do not recommend OCS for chronic management of COPD due to the risk of toxicity.³ The well-established adverse effects of chronic OCS include hyperglycemia, hypertension, osteoporosis, and myopathy.^28,29 A study of muscle function in 21 COPD patients receiving corticosteroids revealed decreases in quadriceps muscle strength and pulmonary function.³⁰ Daily use of OCS will likely result in additional therapies to control drug-induced conditions, as well—another antihypertensive secondary to fluid retention caused by chronic use of OCS in patients with high blood pressure, for example, or additional medication to control elevated blood glucose levels in patients with diabetes.

Phosphodiesterase-4 inhibitors

In one study, patients slowly withdrawn from oral corticosteroids had no more frequent exacerbations than those who maintained chronic usage.

The recommendation for roflumilast in patients with GOLD Class 2 to 4 symptoms remains unchanged since the introduction of this agent as a treatment option for COPD.³ Phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce inflammation in the lungs and have no activity as a bronchodilator.^31,32

Roflumilast has been shown to improve FEV₁ in patients concurrently receiving a long-acting bronchodilator and to reduce exacerbations in steroid-dependent patients, a recent systematic review of 29 PDE-4 trials found.³³ Patients taking roflumilast, however, suffered from more adverse events (nausea, appetite reduction, diarrhea, weight loss, sleep disturbances, and headache) than those on placebo.³³

Antibiotics

GOLD guidelines do not recommend the use of antibiotics for patients with COPD, except to treat acute exacerbations.¹ However, recent studies suggest that routine or pulsed dosing of prophylactic antibiotics can reduce the number of exacerbations.^34-36 A 2013 review of 7 studies determined that continuous antibiotics, particularly macrolides, reduced the number of COPD exacerbations in patients with a mean age of 66 years (odds ratio [OR]=0.55; 95% CI, 0.39-0.77).³⁷

Patients with limited mobility can benefit from non-exercise components of pulmonary rehabilitation.

A more recent trial randomized 92 patients with a history of ≥3 exacerbations in the previous year to receive either prophylactic azithromycin or placebo daily for 12 months. The treatment group experienced a significant decrease in the number of exacerbations (OR=0.58; 95% CI, 0.42-0.79; P=.001).³⁸ This benefit must be weighed against the potential development of antibiotic resistance and adverse effects, so careful patient selection is important.

Pulmonary rehabilitation has proven benefits

GOLD, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society all recommend pulmonary rehabilitation for patients with COPD.^39-41 In addition to reducing morbidity and mortality rates—including a reduction in number of hospitalizations and length of stay and improved post-discharge recovery—pulmonary rehabilitation has been shown to have other physical and psychological benefits.⁴² Specific benefits include improved exercise capacity, greater arm strength and endurance, reduced perception of intensity of breathlessness, and improved overall health-related quality of life.

Key features of rehab programs

Important components of pulmonary rehabilitation include counseling on tobacco cessation, nutrition, education—including correct inhalation technique—and exercise training. There are few contraindications to participation, and patients can derive benefit from both its non-exercise components and upper extremity training regardless of their mobility level.

A 2006 Cochrane review concluded that an effective pulmonary rehabilitation program should be at least 4 weeks in duration,⁴³ and longer programs have been shown to produce greater benefits.⁴⁴ However, there is no agreement on an optimal time frame. Studies are inconclusive on other specific aspects of pulmonary rehab programs, as well, such as the number of sessions per week, number of hours per session, duration and intensity of exercise regimens, and staff-to-patient ratios.

An effective pulmonary rehabilitation program should be at least 4 weeks long.

Home-based exercise training may produce many of the same benefits as a formal pulmonary rehabilitation program. A systematic review found improved quality of life and exercise capacity associated with patient care that lacked formal pulmonary rehabilitation, with no differences between results from home-based training and hospital-based outpatient pulmonary rehabilitation programs.⁴⁵

Given the lack of availability of formal rehab programs in many communities, homebased training for patients with COPD is important to consider.

Implications for practice

What is the takeaway from this evidence-based review? Overall, it is clear that, with the possible exception of the effect of once-daily dosing on adherence, there is little difference among the therapeutic agents within a particular class of medications—and that more is not necessarily better. Indeed, evidence suggests that higher doses of LABAs may reduce their effectiveness, rendering them no better than placebo. In addition, there is no significant difference in the rate of exacerbations in patients taking ICS/LABA combinations and those receiving IACs alone.

Determining the optimal treatment for a particular patient requires an assessment of comorbidities, including potential adverse drug effects.

Pulmonary rehabilitation should be recommended for all newly diagnosed patients, while appropriate drug therapies should be individualized based on the GOLD symptoms/risk evaluation categories (TABLE 3).³ While daily OCS and daily antibiotics have the potential to reduce exacerbation rates, for example, the risks of adverse effects and toxicities outweigh the benefits for patients whose condition is stable.

Determining the optimal treatment for a particular patient also requires an assessment of comorbidities, including potential adverse drug effects (TABLE 4).^{3,27-29,33,46-52} Selection of medication should be driven by patient and physician preference to optimize adherence and clinical outcomes, although cost and accessibility often play a significant role, as well.

CORRESPONDENCE
Nabila Ahmed-Sarwar, PharmD, BCPS, CDE, St. John Fisher College, Wegmans School of Pharmacy, 3690 East Avenue, Rochester, NY 14618; [email protected]

ACKNOWLEDGEMENTS
The authors thank the following people for their assistance in the preparation of this manuscript: Matthew Stryker, PharmD, Timothy Adler, PharmD, and Angela K. Nagel, PharmD, BCPS.

Chronic obstructive pulmonary disease (COPD) carries a high disease burden. In 2012, it was the 4th leading cause of death worldwide.^1,2 In 2015, the World Health Organization updated its Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, classifying patients with COPD based on disease burden as determined by symptoms, airflow obstruction, and exacerbation history.³ These revisions, coupled with expanded therapeutic options within established classes of medications and new combination drugs to treat COPD (TABLE 1),^3-6 have led to questions about interclass differences and the best treatment regimen for particular patients.

Comparisons of various agents within a therapeutic class and their impact on lung function and rate of exacerbations address many of these concerns. In the text and tables that follow, we present the latest evidence highlighting differences in dosing, safety, and efficacy. We also include the updated GOLD classifications, evidence of efficacy for pulmonary rehabilitation, and practical implications of these findings for the optimal management of patients with COPD.

But first, a word about terminology.

Understanding COPD

COPD is a chronic lung disease characterized by progressive airflow limitation, usually measured by spirometry (TABLE 2),³ and chronic airway inflammation. Emphysema and chronic bronchitis are often used synonymously with COPD. In fact, there are important differences.

Individuals with chronic bronchitis do not necessarily have the airflow limitations found in those with COPD. And patients with COPD develop pathologic lung changes beyond the alveolar damage characteristic of emphysema, including airway fibrosis and inflammation, luminal plugging, and loss of elastic recoil.³

The medications included in this review aim to reduce both the morbidity and mortality associated with COPD. These drugs can also help relieve the symptoms of patients with chronic bronchitis and emphysema, but have limited effect on patient mortality.

Short- and long-acting beta₂-agonists

Bronchodilator therapy with beta₂-agonists improves forced expiratory volume in one second (FEV₁) through relaxation of airway smooth muscle. Beta₂-agonists have proven to be safe and effective when used as needed or scheduled for patients with COPD.⁷

Inhaled short-acting beta₂-agonists (SABAs) improve FEV₁ and symptoms within 10 minutes, with effects lasting up to 4 to 6 hours; long-acting beta₂-agonists (LABAs) have a variable onset, with effects lasting 12 to 24 hours.⁸ Inhaled levalbuterol, the last SABA to receive US Food and Drug Administration approval, has not proven to be superior to conventional bronchodilators in ambulatory patients with stable COPD.³ In clinical trials, however, the slightly longer half-life of the nebulized formulation of levalbuterol was found to reduce both the frequency of administration and the overall cost of therapy in patients hospitalized with acute exacerbations of COPD.^9,10

Recently approved LABAs

Clinical trials have studied the safety and efficacy of newer agents vs older LABAs in patients with moderate to severe COPD. Compared with theophylline, for example, formoterol 12 mcg inhaled every 12 hours for a 12-month period provided a clinically significant increase of >120 ml in FEV₁ (P=.026).¹¹ Higher doses of formoterol did not provide any additional improvement.

In a trial comparing indacaterol and tiotropium, an inhaled anticholinergic, both treatment groups had a clinically significant increase in FEV₁, but patients receiving indacaterol achieved an additional increase of 40 to 50 mL at 12 weeks.¹²

Exacerbation rates for all LABAs range from 22% to 44%.^5,12,13 In a study of patients receiving formoterol 12 mcg compared with 15-mcg and 25-mcg doses of arformoterol, those taking formoterol had a lower exacerbation rate than those on either strength of arformoterol (22% vs 32% and 31%, respectively).¹⁰ In various studies, doses greater than the FDA-approved regimens for indacaterol, arformoterol, and olodaterol did not result in a significant improvement in either FEV₁ or exacerbation rates compared with placebo.^5,12,14

Exacerbation rates for all long-acting beta₂-agonists range from 22% to 44%.

Studies that assessed the use of rescue medication as well as exacerbation rates in patients taking LABAs reported reductions in the use of the rescue drugs ranging from 0.46 to 1.32 actuations per day, but the findings had limited clinical relevance.^5,13 With the exception of indacaterol and olodaterol—both of which may be preferable because of their once-daily dosing regimen—no significant differences in safety and efficacy among LABAs have been found.^5,12,13

Long-acting inhaled anticholinergics

Inhaled anticholinergic agents (IACs) can be used in place of, or in conjunction with, LABAs to provide bronchodilation for up to 24 hours.³ The introduction of long-acting IACs dosed once or twice daily has the potential to improve medication adherence over traditional short-acting ipratropium, which requires multiple daily doses for symptom control. Over 4 years, tiotropium has been shown to increase time to first exacerbation by approximately 4 months. It did not, however, significantly reduce the number of exacerbations compared with placebo.¹⁵

Long-term use of tiotropium appears to have the potential to preserve lung function. In one trial, it slowed the rate of decline in FEV₁ by 5 mL per year, but this finding lacked clinical significance.¹³ In clinical trials of patients with moderate to severe COPD, however, once-daily tiotropium and umeclidinium provided clinically significant improvements in FEV₁ (>120 mL; P<.01), regardless of the dose administered.^6,16 In another trial, patients taking aclidinium 200 mcg or 400 mcg every 12 hours did not achieve a clinically significant improvement in FEV₁ compared with placebo.¹⁷

In patients with moderate to severe COPD, the combination of umeclidinium/vilanterol, a LABA, administered once daily resulted in a clinically significant improvement in FEV₁ (167 mL; P<.001) vs placebo—but was not significantly better than treatment with either agent alone.¹⁸

Long-acting inhaled anticholinergic agents—when used in combination with LABAS—have a positive effect on FEV₁, but their effect on exacerbation rates has not been established.

Few studies have evaluated time to exacerbation in patients receiving aclidinium or umeclidinium. In comparison to salmeterol, tiotropium reduced the time to first exacerbation by 42 days at one year (hazard ratio=0.83; 95% confidence interval [CI], 0.77-0.9; P<.001).¹⁹ The evidence suggests that when used in combination with LABAs, long-acting IACs have a positive impact on FEV₁, but their effect on exacerbation rates has not been established.

Combination therapy with steroids and LABAs

The combination of inhaled corticosteroids (ICS) and LABAs has been found to improve FEV₁ and symptoms in patients with moderate to severe COPD more than monotherapy with either drug class.^20,21 In fact, ICS alone have not been proven to slow the progression of the disease or to lower mortality rates in patients with COPD.²²

Fluticasone/salmeterol demonstrated a 25% reduction in exacerbation rates compared with placebo (P<.0001), a greater reduction than that of either drug alone.²⁰ A retrospective observational study comparing fixed dose fluticasone/salmeterol with budesonide/formoterol reported a similar reduction in exacerbation rates, but the number of patients requiring the addition of an IAC was 16% lower in the latter group.²³

The combination of fluticasone/vilanterol has the potential to improve adherence, given that it is dosed once daily, unlike other COPD combination drugs. Its clinical efficacy is comparable to that of fluticasone/salmeterol after 12 weeks of therapy, with similar improvements in FEV₁,²⁴ but fluticasone/vilanterol is associated with an increased risk of pneumonia.³

Chronic use of oral corticosteroids

Oral corticosteroids (OCS) are clinically indicated in individuals whose symptoms continue despite optimal therapy with inhaled agents that have demonstrated efficacy. Such patients are often referred to as “steroid dependent.”

While OCS are prescribed for both their anti-inflammatory activity and their ability to slow the progression of COPD,^25,26 no well-designed studies have investigated their benefits for this patient population. One study concluded that patients who were slowly withdrawn from their OCS regimen had no more frequent exacerbations than those who maintained chronic usage. The withdrawal group did, however, lose weight.²⁷

GOLD guidelines do not recommend OCS for chronic management of COPD due to the risk of toxicity.³ The well-established adverse effects of chronic OCS include hyperglycemia, hypertension, osteoporosis, and myopathy.^28,29 A study of muscle function in 21 COPD patients receiving corticosteroids revealed decreases in quadriceps muscle strength and pulmonary function.³⁰ Daily use of OCS will likely result in additional therapies to control drug-induced conditions, as well—another antihypertensive secondary to fluid retention caused by chronic use of OCS in patients with high blood pressure, for example, or additional medication to control elevated blood glucose levels in patients with diabetes.

Phosphodiesterase-4 inhibitors

In one study, patients slowly withdrawn from oral corticosteroids had no more frequent exacerbations than those who maintained chronic usage.

The recommendation for roflumilast in patients with GOLD Class 2 to 4 symptoms remains unchanged since the introduction of this agent as a treatment option for COPD.³ Phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce inflammation in the lungs and have no activity as a bronchodilator.^31,32

Roflumilast has been shown to improve FEV₁ in patients concurrently receiving a long-acting bronchodilator and to reduce exacerbations in steroid-dependent patients, a recent systematic review of 29 PDE-4 trials found.³³ Patients taking roflumilast, however, suffered from more adverse events (nausea, appetite reduction, diarrhea, weight loss, sleep disturbances, and headache) than those on placebo.³³

Antibiotics

GOLD guidelines do not recommend the use of antibiotics for patients with COPD, except to treat acute exacerbations.¹ However, recent studies suggest that routine or pulsed dosing of prophylactic antibiotics can reduce the number of exacerbations.^34-36 A 2013 review of 7 studies determined that continuous antibiotics, particularly macrolides, reduced the number of COPD exacerbations in patients with a mean age of 66 years (odds ratio [OR]=0.55; 95% CI, 0.39-0.77).³⁷

Patients with limited mobility can benefit from non-exercise components of pulmonary rehabilitation.

A more recent trial randomized 92 patients with a history of ≥3 exacerbations in the previous year to receive either prophylactic azithromycin or placebo daily for 12 months. The treatment group experienced a significant decrease in the number of exacerbations (OR=0.58; 95% CI, 0.42-0.79; P=.001).³⁸ This benefit must be weighed against the potential development of antibiotic resistance and adverse effects, so careful patient selection is important.

Pulmonary rehabilitation has proven benefits

GOLD, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society all recommend pulmonary rehabilitation for patients with COPD.^39-41 In addition to reducing morbidity and mortality rates—including a reduction in number of hospitalizations and length of stay and improved post-discharge recovery—pulmonary rehabilitation has been shown to have other physical and psychological benefits.⁴² Specific benefits include improved exercise capacity, greater arm strength and endurance, reduced perception of intensity of breathlessness, and improved overall health-related quality of life.

Key features of rehab programs

Important components of pulmonary rehabilitation include counseling on tobacco cessation, nutrition, education—including correct inhalation technique—and exercise training. There are few contraindications to participation, and patients can derive benefit from both its non-exercise components and upper extremity training regardless of their mobility level.

A 2006 Cochrane review concluded that an effective pulmonary rehabilitation program should be at least 4 weeks in duration,⁴³ and longer programs have been shown to produce greater benefits.⁴⁴ However, there is no agreement on an optimal time frame. Studies are inconclusive on other specific aspects of pulmonary rehab programs, as well, such as the number of sessions per week, number of hours per session, duration and intensity of exercise regimens, and staff-to-patient ratios.

An effective pulmonary rehabilitation program should be at least 4 weeks long.

Home-based exercise training may produce many of the same benefits as a formal pulmonary rehabilitation program. A systematic review found improved quality of life and exercise capacity associated with patient care that lacked formal pulmonary rehabilitation, with no differences between results from home-based training and hospital-based outpatient pulmonary rehabilitation programs.⁴⁵

Given the lack of availability of formal rehab programs in many communities, homebased training for patients with COPD is important to consider.

Implications for practice

What is the takeaway from this evidence-based review? Overall, it is clear that, with the possible exception of the effect of once-daily dosing on adherence, there is little difference among the therapeutic agents within a particular class of medications—and that more is not necessarily better. Indeed, evidence suggests that higher doses of LABAs may reduce their effectiveness, rendering them no better than placebo. In addition, there is no significant difference in the rate of exacerbations in patients taking ICS/LABA combinations and those receiving IACs alone.

Determining the optimal treatment for a particular patient requires an assessment of comorbidities, including potential adverse drug effects.

Pulmonary rehabilitation should be recommended for all newly diagnosed patients, while appropriate drug therapies should be individualized based on the GOLD symptoms/risk evaluation categories (TABLE 3).³ While daily OCS and daily antibiotics have the potential to reduce exacerbation rates, for example, the risks of adverse effects and toxicities outweigh the benefits for patients whose condition is stable.

Determining the optimal treatment for a particular patient also requires an assessment of comorbidities, including potential adverse drug effects (TABLE 4).^{3,27-29,33,46-52} Selection of medication should be driven by patient and physician preference to optimize adherence and clinical outcomes, although cost and accessibility often play a significant role, as well.

CORRESPONDENCE
Nabila Ahmed-Sarwar, PharmD, BCPS, CDE, St. John Fisher College, Wegmans School of Pharmacy, 3690 East Avenue, Rochester, NY 14618; [email protected]

ACKNOWLEDGEMENTS
The authors thank the following people for their assistance in the preparation of this manuscript: Matthew Stryker, PharmD, Timothy Adler, PharmD, and Angela K. Nagel, PharmD, BCPS.

Chronic obstructive pulmonary disease (COPD) carries a high disease burden. In 2012, it was the 4th leading cause of death worldwide.^1,2 In 2015, the World Health Organization updated its Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, classifying patients with COPD based on disease burden as determined by symptoms, airflow obstruction, and exacerbation history.³ These revisions, coupled with expanded therapeutic options within established classes of medications and new combination drugs to treat COPD (TABLE 1),^3-6 have led to questions about interclass differences and the best treatment regimen for particular patients.

Comparisons of various agents within a therapeutic class and their impact on lung function and rate of exacerbations address many of these concerns. In the text and tables that follow, we present the latest evidence highlighting differences in dosing, safety, and efficacy. We also include the updated GOLD classifications, evidence of efficacy for pulmonary rehabilitation, and practical implications of these findings for the optimal management of patients with COPD.

But first, a word about terminology.

Understanding COPD

COPD is a chronic lung disease characterized by progressive airflow limitation, usually measured by spirometry (TABLE 2),³ and chronic airway inflammation. Emphysema and chronic bronchitis are often used synonymously with COPD. In fact, there are important differences.

Individuals with chronic bronchitis do not necessarily have the airflow limitations found in those with COPD. And patients with COPD develop pathologic lung changes beyond the alveolar damage characteristic of emphysema, including airway fibrosis and inflammation, luminal plugging, and loss of elastic recoil.³

The medications included in this review aim to reduce both the morbidity and mortality associated with COPD. These drugs can also help relieve the symptoms of patients with chronic bronchitis and emphysema, but have limited effect on patient mortality.

Short- and long-acting beta₂-agonists

Bronchodilator therapy with beta₂-agonists improves forced expiratory volume in one second (FEV₁) through relaxation of airway smooth muscle. Beta₂-agonists have proven to be safe and effective when used as needed or scheduled for patients with COPD.⁷

Inhaled short-acting beta₂-agonists (SABAs) improve FEV₁ and symptoms within 10 minutes, with effects lasting up to 4 to 6 hours; long-acting beta₂-agonists (LABAs) have a variable onset, with effects lasting 12 to 24 hours.⁸ Inhaled levalbuterol, the last SABA to receive US Food and Drug Administration approval, has not proven to be superior to conventional bronchodilators in ambulatory patients with stable COPD.³ In clinical trials, however, the slightly longer half-life of the nebulized formulation of levalbuterol was found to reduce both the frequency of administration and the overall cost of therapy in patients hospitalized with acute exacerbations of COPD.^9,10

Recently approved LABAs

Clinical trials have studied the safety and efficacy of newer agents vs older LABAs in patients with moderate to severe COPD. Compared with theophylline, for example, formoterol 12 mcg inhaled every 12 hours for a 12-month period provided a clinically significant increase of >120 ml in FEV₁ (P=.026).¹¹ Higher doses of formoterol did not provide any additional improvement.

In a trial comparing indacaterol and tiotropium, an inhaled anticholinergic, both treatment groups had a clinically significant increase in FEV₁, but patients receiving indacaterol achieved an additional increase of 40 to 50 mL at 12 weeks.¹²

Exacerbation rates for all LABAs range from 22% to 44%.^5,12,13 In a study of patients receiving formoterol 12 mcg compared with 15-mcg and 25-mcg doses of arformoterol, those taking formoterol had a lower exacerbation rate than those on either strength of arformoterol (22% vs 32% and 31%, respectively).¹⁰ In various studies, doses greater than the FDA-approved regimens for indacaterol, arformoterol, and olodaterol did not result in a significant improvement in either FEV₁ or exacerbation rates compared with placebo.^5,12,14

Exacerbation rates for all long-acting beta₂-agonists range from 22% to 44%.

Studies that assessed the use of rescue medication as well as exacerbation rates in patients taking LABAs reported reductions in the use of the rescue drugs ranging from 0.46 to 1.32 actuations per day, but the findings had limited clinical relevance.^5,13 With the exception of indacaterol and olodaterol—both of which may be preferable because of their once-daily dosing regimen—no significant differences in safety and efficacy among LABAs have been found.^5,12,13

Long-acting inhaled anticholinergics

Inhaled anticholinergic agents (IACs) can be used in place of, or in conjunction with, LABAs to provide bronchodilation for up to 24 hours.³ The introduction of long-acting IACs dosed once or twice daily has the potential to improve medication adherence over traditional short-acting ipratropium, which requires multiple daily doses for symptom control. Over 4 years, tiotropium has been shown to increase time to first exacerbation by approximately 4 months. It did not, however, significantly reduce the number of exacerbations compared with placebo.¹⁵

Long-term use of tiotropium appears to have the potential to preserve lung function. In one trial, it slowed the rate of decline in FEV₁ by 5 mL per year, but this finding lacked clinical significance.¹³ In clinical trials of patients with moderate to severe COPD, however, once-daily tiotropium and umeclidinium provided clinically significant improvements in FEV₁ (>120 mL; P<.01), regardless of the dose administered.^6,16 In another trial, patients taking aclidinium 200 mcg or 400 mcg every 12 hours did not achieve a clinically significant improvement in FEV₁ compared with placebo.¹⁷

In patients with moderate to severe COPD, the combination of umeclidinium/vilanterol, a LABA, administered once daily resulted in a clinically significant improvement in FEV₁ (167 mL; P<.001) vs placebo—but was not significantly better than treatment with either agent alone.¹⁸

Long-acting inhaled anticholinergic agents—when used in combination with LABAS—have a positive effect on FEV₁, but their effect on exacerbation rates has not been established.

Few studies have evaluated time to exacerbation in patients receiving aclidinium or umeclidinium. In comparison to salmeterol, tiotropium reduced the time to first exacerbation by 42 days at one year (hazard ratio=0.83; 95% confidence interval [CI], 0.77-0.9; P<.001).¹⁹ The evidence suggests that when used in combination with LABAs, long-acting IACs have a positive impact on FEV₁, but their effect on exacerbation rates has not been established.

Combination therapy with steroids and LABAs

The combination of inhaled corticosteroids (ICS) and LABAs has been found to improve FEV₁ and symptoms in patients with moderate to severe COPD more than monotherapy with either drug class.^20,21 In fact, ICS alone have not been proven to slow the progression of the disease or to lower mortality rates in patients with COPD.²²

Fluticasone/salmeterol demonstrated a 25% reduction in exacerbation rates compared with placebo (P<.0001), a greater reduction than that of either drug alone.²⁰ A retrospective observational study comparing fixed dose fluticasone/salmeterol with budesonide/formoterol reported a similar reduction in exacerbation rates, but the number of patients requiring the addition of an IAC was 16% lower in the latter group.²³

The combination of fluticasone/vilanterol has the potential to improve adherence, given that it is dosed once daily, unlike other COPD combination drugs. Its clinical efficacy is comparable to that of fluticasone/salmeterol after 12 weeks of therapy, with similar improvements in FEV₁,²⁴ but fluticasone/vilanterol is associated with an increased risk of pneumonia.³

Chronic use of oral corticosteroids

Oral corticosteroids (OCS) are clinically indicated in individuals whose symptoms continue despite optimal therapy with inhaled agents that have demonstrated efficacy. Such patients are often referred to as “steroid dependent.”

While OCS are prescribed for both their anti-inflammatory activity and their ability to slow the progression of COPD,^25,26 no well-designed studies have investigated their benefits for this patient population. One study concluded that patients who were slowly withdrawn from their OCS regimen had no more frequent exacerbations than those who maintained chronic usage. The withdrawal group did, however, lose weight.²⁷

GOLD guidelines do not recommend OCS for chronic management of COPD due to the risk of toxicity.³ The well-established adverse effects of chronic OCS include hyperglycemia, hypertension, osteoporosis, and myopathy.^28,29 A study of muscle function in 21 COPD patients receiving corticosteroids revealed decreases in quadriceps muscle strength and pulmonary function.³⁰ Daily use of OCS will likely result in additional therapies to control drug-induced conditions, as well—another antihypertensive secondary to fluid retention caused by chronic use of OCS in patients with high blood pressure, for example, or additional medication to control elevated blood glucose levels in patients with diabetes.

Phosphodiesterase-4 inhibitors

In one study, patients slowly withdrawn from oral corticosteroids had no more frequent exacerbations than those who maintained chronic usage.

The recommendation for roflumilast in patients with GOLD Class 2 to 4 symptoms remains unchanged since the introduction of this agent as a treatment option for COPD.³ Phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce inflammation in the lungs and have no activity as a bronchodilator.^31,32

Roflumilast has been shown to improve FEV₁ in patients concurrently receiving a long-acting bronchodilator and to reduce exacerbations in steroid-dependent patients, a recent systematic review of 29 PDE-4 trials found.³³ Patients taking roflumilast, however, suffered from more adverse events (nausea, appetite reduction, diarrhea, weight loss, sleep disturbances, and headache) than those on placebo.³³

Antibiotics

GOLD guidelines do not recommend the use of antibiotics for patients with COPD, except to treat acute exacerbations.¹ However, recent studies suggest that routine or pulsed dosing of prophylactic antibiotics can reduce the number of exacerbations.^34-36 A 2013 review of 7 studies determined that continuous antibiotics, particularly macrolides, reduced the number of COPD exacerbations in patients with a mean age of 66 years (odds ratio [OR]=0.55; 95% CI, 0.39-0.77).³⁷

Patients with limited mobility can benefit from non-exercise components of pulmonary rehabilitation.

A more recent trial randomized 92 patients with a history of ≥3 exacerbations in the previous year to receive either prophylactic azithromycin or placebo daily for 12 months. The treatment group experienced a significant decrease in the number of exacerbations (OR=0.58; 95% CI, 0.42-0.79; P=.001).³⁸ This benefit must be weighed against the potential development of antibiotic resistance and adverse effects, so careful patient selection is important.

Pulmonary rehabilitation has proven benefits

GOLD, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society all recommend pulmonary rehabilitation for patients with COPD.^39-41 In addition to reducing morbidity and mortality rates—including a reduction in number of hospitalizations and length of stay and improved post-discharge recovery—pulmonary rehabilitation has been shown to have other physical and psychological benefits.⁴² Specific benefits include improved exercise capacity, greater arm strength and endurance, reduced perception of intensity of breathlessness, and improved overall health-related quality of life.

Key features of rehab programs

Important components of pulmonary rehabilitation include counseling on tobacco cessation, nutrition, education—including correct inhalation technique—and exercise training. There are few contraindications to participation, and patients can derive benefit from both its non-exercise components and upper extremity training regardless of their mobility level.

A 2006 Cochrane review concluded that an effective pulmonary rehabilitation program should be at least 4 weeks in duration,⁴³ and longer programs have been shown to produce greater benefits.⁴⁴ However, there is no agreement on an optimal time frame. Studies are inconclusive on other specific aspects of pulmonary rehab programs, as well, such as the number of sessions per week, number of hours per session, duration and intensity of exercise regimens, and staff-to-patient ratios.

An effective pulmonary rehabilitation program should be at least 4 weeks long.

Home-based exercise training may produce many of the same benefits as a formal pulmonary rehabilitation program. A systematic review found improved quality of life and exercise capacity associated with patient care that lacked formal pulmonary rehabilitation, with no differences between results from home-based training and hospital-based outpatient pulmonary rehabilitation programs.⁴⁵

Given the lack of availability of formal rehab programs in many communities, homebased training for patients with COPD is important to consider.

Implications for practice

What is the takeaway from this evidence-based review? Overall, it is clear that, with the possible exception of the effect of once-daily dosing on adherence, there is little difference among the therapeutic agents within a particular class of medications—and that more is not necessarily better. Indeed, evidence suggests that higher doses of LABAs may reduce their effectiveness, rendering them no better than placebo. In addition, there is no significant difference in the rate of exacerbations in patients taking ICS/LABA combinations and those receiving IACs alone.

Determining the optimal treatment for a particular patient requires an assessment of comorbidities, including potential adverse drug effects.

Pulmonary rehabilitation should be recommended for all newly diagnosed patients, while appropriate drug therapies should be individualized based on the GOLD symptoms/risk evaluation categories (TABLE 3).³ While daily OCS and daily antibiotics have the potential to reduce exacerbation rates, for example, the risks of adverse effects and toxicities outweigh the benefits for patients whose condition is stable.

Determining the optimal treatment for a particular patient also requires an assessment of comorbidities, including potential adverse drug effects (TABLE 4).^{3,27-29,33,46-52} Selection of medication should be driven by patient and physician preference to optimize adherence and clinical outcomes, although cost and accessibility often play a significant role, as well.

CORRESPONDENCE
Nabila Ahmed-Sarwar, PharmD, BCPS, CDE, St. John Fisher College, Wegmans School of Pharmacy, 3690 East Avenue, Rochester, NY 14618; [email protected]

ACKNOWLEDGEMENTS
The authors thank the following people for their assistance in the preparation of this manuscript: Matthew Stryker, PharmD, Timothy Adler, PharmD, and Angela K. Nagel, PharmD, BCPS.