CASE › Ms. B, a 26-year-old woman, presents to your office with her 3-year-old son for a well-child examination. During the course of the conversation, she asks you if she should be giving her child probiotics to improve his general health. Many of her friends, who also have their children in day care, have told her that probiotics, “are nature’s way of fighting infection.” Her son currently takes no medications, and has no history of asthma or recent gastrointestinal disturbances. He was treated for 2 ear infections last winter, approximately 3 months apart. His physical exam is normal and, after today, his immunizations will be up to date. How should you respond?

The use of probiotics as over-the-counter treatments for a variety of conditions continues to grow, with retail sales of functional probiotic foods and supplements topping $35 billion worldwide in 2014.¹ In children, claims of benefit for gastrointestinal (GI) disorders, colic, and allergy prevention, as well as prevention and treatment of upper respiratory infections (URIs) have existed for over 10 years.^2-4 The human gut flora develops rapidly after birth and is known to be influenced by route of delivery (vaginal vs cesarean), type of feeding (breast vs formula), and other environmental factors.⁵ The use of probiotics to influence the types of bacteria in a child’s intestinal tract continues to be an area of active research. (For more on probiotic formulations, see TABLE 1.)

This article summarizes recent research on probiotic use in infants and children. New data support the use of probiotics for the treatment of colic and atopic eczema; however, the data on using probiotics in the management of URIs is less robust and mixed. And while probiotics improve irritable bowel syndrome (IBS) stomach pain, they do not help with related diarrhea or constipation. All of these data are summarized in TABLE 2.^6-29

L reuteri improves symptoms in breastfed infants with colic

Infant colic is a relatively common condition known to negatively impact maternal mental health and the mother/child relationship.⁶ Numerous randomized controlled trials (RCTs) over the years have demonstrated mixed results with using probiotics to decrease crying times, with differences noted between infants who are solely breastfed and those who are not.⁷

In the most recent meta-analysis of 6 studies (n=427) that focused only on the probiotic Lactobacillus reuteri, breastfed infants with colic receiving a daily dose of 10⁸ colony forming units (CFU) cried an average of 56 fewer minutes/day than those in the control group (95% confidence interval [CI], -64.4 to -47.3; P=.001) at day 21 of treatment.⁸ Although 2 studies in this meta-analysis included a small number of mixed-fed and formula-fed infants, the majority of trials do not show benefit for these infants. Trials assessing the use of L reuteri for prevention of colic have not shown positive results.⁷

Probiotics may help prevent and shorten the course of URIs

The mechanisms by which probiotics may prevent or shorten the course of URIs are not obvious. Current theories include boosting the immune function of the respiratory mucosa, acting as a competitive inhibitor for viruses, and secreting antiviral compounds.⁹ Multiple reviews published in the last 3 years, however, add to the evidence that the apparent benefit is real.

A 2013 meta-analysis assessed data from 4 RCTs (N=1805), which used Lactobacillus rhamnosus as the sole probiotic for prevention of URIs. In treated children, otitis media incidence was reduced by 24% (relative risk [RR] 0.76; 95% CI, 0.64-0.91) and risk of URI was reduced by 38% (RR 0.62; 95% CI, 0.50-0.78).¹⁰ The number needed to treat (NNT) was 4 for URI prevention, and the authors noted that adverse events were similar in the treatment and control groups.

A 2014 systematic review and meta-analysis of 20 RCTs examining duration of illness included 10 studies dedicated to pediatric subjects (age 12 months to 12 years).¹¹ There were significantly fewer days of illness per person (standardized mean difference -0.31; 95% CI, -0.41 to -0.11) and each illness episode was shorter by three-quarters of a day (weighted mean difference -0.77; 95% CI, -1.5 to -0.04) in participants who received a probiotic vs those who received a placebo. Probiotics used in these studies belonged to the Lactobacillus and Bifidobacterium genera.

A 2015 systematic review of 14 RCTs assessing the benefits of probiotics, particularly Lactobacillus and Bifidobacterium strains, on URI occurrence and symptoms, showed mixed results.¹² Seven of 12 studies found lowered rates of URI and otitis media incidence, 7 of 11 RCTs reported a significant reduction in severity scores for URI, and 4 of 8 RCTs reported significant reductions in school absenteeism between the probiotic and control groups. In a summary statement, the authors noted that “at least one beneficial effect of prophylactic probiotics was observed in the majority of RCTs,” and that “none of the studies reported any serious adverse events.”

Perinatal probiotics: No benefit for allergic conditions—except eczema

Allergic disease is on the rise and continues to plague children with reduced quality of life, potentially life-threatening reactions, and missed activities, including school. The gut microbiome likely influences a child’s allergic propensity through its effects on T-helper cells, transforming growth factor (TGF), and immunoglobulin A (IgA)—all known components of the allergic response. As the hygiene hypothesis suggests, the quantity and types of bacteria that inhabit the GI tract early in life play a significant role in determining a person’s later allergic responses.¹³

In a 2013 meta-analysis of 20 trials (N=4866), researchers looked specifically at probiotic use and the diagnosis of asthma and incident wheezing. Single and combination products of Lactobacillus and Bifidobacterium given prenatally and/or postnatally were included in the studies. The authors found no evidence to support a protective association between perinatal use of probiotics and diagnosed asthma (RR=0.99; 95% CI, 0.81-0.21) or childhood incident wheezing (RR=0.97; 95% CI, 0.87-1.09; 9 trials, 1949 infants).¹⁴

In a more recent meta-analysis (2015) conducted to inform the World Allergy Organization, 29 studies were evaluated to assess the impact of probiotics on allergic symptoms of the skin, respiratory system, and GI tract.¹⁵ No significant benefit was noted for any allergic condition except for eczema. Probiotics reduced the risk of eczema when given during the last trimester of pregnancy (RR=0.71; 95% CI, 0.60-0.84), when used by breastfeeding mothers (RR=0.57; 95% CI, 0.47-0.69), and when given to infants (RR=0.80; 95% CI, 0.68-0.94).

Lactobacillus reuteri decreased crying in breastfed infants with colic by nearly an hour a day.A 2014 systematic review and meta-analysis (N=2797) explored probiotic use specifically for the prevention of eczema.¹⁶ The pooled relative risk for all the studies was 0.74 (95% CI, 0.67-0.82). Evidence was strongest for probiotics containing the Lactobacillus species rhamnosus and paracasei, as well as for Bifidobacterium lactis. No benefit was noted with Lactobacillus acidophilus or other Bifidobacterium species. These newer reviews on eczema prevention contrast with an older Cochrane review published in 2008 (12 RCTs, N=781), which did not show significant benefit for the treatment of eczema.¹⁷

Probiotics improve IBS stomach pain, but not diarrhea or constipation

IBS is a functional disorder of the GI tract that affects up to 20% of children and teenagers and leads to a significant decrease in quality of life.¹⁸ Current theories of causation include bacterial overgrowth and neuronal hyperactivity, which may be amenable to change with supplemental probiotics.

A 2015 systematic review of non-pharmacological treatments for functional abdominal pain disorders identified 4 studies dedicated to IBS in children.¹⁹ A subgroup analysis of 3 RCTs (n=309) that looked at giving L rhamnosus to 5- to 17-year-olds with IBS showed improved abdominal pain (according to various pain scales) compared to the placebo group. Study participants received at least 3 x 10⁹ CFU twice a day for 4 to 8 weeks. Relative risk for improvement was 1.7 (95% CI, 1.27-2.27) with an NNT of 4. None of these studies showed significant improvement in either frequency or severity of diarrhea or constipation.

A separate crossover RCT (N=59) compared placebo to VSL#3, a product containing 8 probiotics (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, L acidophilus, Lactobacillus plantarum, L paracasei, Lactobacillus bulgaricus, and Streptococcus hermophiles), given in age-dependent doses for 6 weeks to children aged 4 to 18 years.²⁰ The frequency and intensity of abdominal pain were measured on a 5-point Likert scale. The group treated with VSL#3 dropped 1.0 ± 0.2 points vs 0.5 ± 0.2 points in the control group (P<.05) and reported an improved quality of life.

These agents reduce antibiotic-associated diarrhea

Antibiotic-associated diarrhea (AAD) occurs in 5% to 30% of children who receive antibiotic therapy.²¹ It occurs most frequently with the use of cephalosporins, penicillin, fluoroquinolones, and clindamycin, and is likely caused by an alteration of the normal gut flora. Colitis caused by Clostridium difficile remains the most serious antibiotic-associated GI complication.

A systematic review of the specific probiotic Saccharomyces boulardii conducted in 2015 analyzed data from 6 RCTs (n=1653) to determine the effect of co-administration of this probiotic with antibiotics.²² The pooled relative risk for AAD in children receiving the probiotic was 0.43 (95% CI, 0.3-0.6) compared to antibiotics alone. The absolute risk of AAD dropped from 20.9% to 8.8%, translating to a NNT of 8. Two of the RCTs specifically looked at rates of C difficile infection (n=579). C difficile infection rates dropped by 75% (RR=.25; 95% CI, 0.08-0.73) in the treatment group. This dramatic treatment effect was not seen in studies involving adults.

A similar systematic review focusing on L rhamnosus conducted in 2015 pooled data from 5 RCTs (n=445) to see if the probiotic would decrease AAD in children if it was co-administered with antibiotics.²³ The relative risk for AAD in this treatment group was 0.48 (95% CI, 0.26-0.89) with an absolute risk reduction of 13.4% (23% compared to 9.6%), translating to an NNT of 7.

A Cochrane review published in 2015 included 23 studies (N=3938) and found similar results with an RR for AAD of 0.46 for treated children (95% CI, 0.35-0.61).²⁴ Doses of probiotics ranged from 5 to 40 billion CFU/day. Although many probiotic species were used in these studies, S boulardii and L rhamnosus were cited as having the strongest data to support use in this context.

Probiotics reduce the duration, frequency of acute infectious diarrhea

Diarrhea remains the second leading cause of death among children one to 59 months of age worldwide.²⁵ Current World Health Organization recommendations include oral rehydration salts, continued feeding to avoid dehydration, and zinc to decrease the duration and severity of illness.²⁶ Multiple studies in adults confirm that a variety of probiotics decrease both the duration and severity of diarrhea in acute gastroenteritis.²⁷

Lactobacillus rhamnosus reduced the incidence of otitis media and upper respiratory infections by 24% and 38%, respectively.The authors of a 2013 systematic review of probiotics for the treatment of community-acquired acute diarrhea in children less than 5 years of age analyzed data from 8 RCTs (N=1755).²⁸ Various probiotics were used including Lactobacillus species, Streptococcus thermophilus, Bifidobacterium species, and Saccharomyces boulardii for between 4 and 10 days. Six of these studies (n=1164) measured diarrhea duration and found a 14% reduction (95% CI, 3.8%-24.2%) in days of illness for those children treated vs those receiving placebo. Five studies (n=925) measured the difference in stool frequency on Day 2 of illness and reported a reduction of 13.1% (95% CI, 0.8%-5.3%) in the number of stools in the treated group vs the placebo group.

This review augments a Cochrane meta-analysis of 63 studies (N=8014) published in 2010.²⁷ Fifty-six of these studies included infants and children. Pooled analysis of the varied probiotic treatments showed a mean reduction in duration of diarrhea of just over a day (24.76 hours; 95% CI, 15.9-33.6 hours; n=4555, trials=35) and decreased stool frequency on Day 2 of treatment (mean difference 0.80; 95% CI, 0.45-1.14; n=2751, trials=20). The authors concluded that probiotics “have clear beneficial effects in shortening the duration and reducing stool frequency in acute infectious diarrhea.”

Pediatric society weighs in. In 2014, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition issued guidelines regarding probiotic use for the treatment of acute gastroenteritis.²⁹ In addition to rehydration therapy, these guidelines recommend the use of L rhamnosus and/or S boulardii as first-line treatments. Lower quality evidence is available for the use of L reuteri.

CASE › In response to Ms. B’s query about starting her young son on probiotics, you tell her that studies have shown that probiotics are safe for children when given in appropriate doses. They have been shown to help children recover from diarrheal illnesses and can help reduce the number of colds and ear infections when taken regularly. The reason you are giving them determines which strains you should use. You recommend giving her child a formulation of probiotic that contains Lactobacillus or Bifidobacterium with a dose range of 2 to 10 billion CFUs taken daily to reduce the risk of her child getting another ear infection.

CORRESPONDENCE
Paul Dassow, MD, MSPH, 1100 E. 3rd St, Chattanooga, TN 37403; [email protected].

CASE › Ms. B, a 26-year-old woman, presents to your office with her 3-year-old son for a well-child examination. During the course of the conversation, she asks you if she should be giving her child probiotics to improve his general health. Many of her friends, who also have their children in day care, have told her that probiotics, “are nature’s way of fighting infection.” Her son currently takes no medications, and has no history of asthma or recent gastrointestinal disturbances. He was treated for 2 ear infections last winter, approximately 3 months apart. His physical exam is normal and, after today, his immunizations will be up to date. How should you respond?

The use of probiotics as over-the-counter treatments for a variety of conditions continues to grow, with retail sales of functional probiotic foods and supplements topping $35 billion worldwide in 2014.¹ In children, claims of benefit for gastrointestinal (GI) disorders, colic, and allergy prevention, as well as prevention and treatment of upper respiratory infections (URIs) have existed for over 10 years.^2-4 The human gut flora develops rapidly after birth and is known to be influenced by route of delivery (vaginal vs cesarean), type of feeding (breast vs formula), and other environmental factors.⁵ The use of probiotics to influence the types of bacteria in a child’s intestinal tract continues to be an area of active research. (For more on probiotic formulations, see TABLE 1.)

This article summarizes recent research on probiotic use in infants and children. New data support the use of probiotics for the treatment of colic and atopic eczema; however, the data on using probiotics in the management of URIs is less robust and mixed. And while probiotics improve irritable bowel syndrome (IBS) stomach pain, they do not help with related diarrhea or constipation. All of these data are summarized in TABLE 2.^6-29

L reuteri improves symptoms in breastfed infants with colic

Infant colic is a relatively common condition known to negatively impact maternal mental health and the mother/child relationship.⁶ Numerous randomized controlled trials (RCTs) over the years have demonstrated mixed results with using probiotics to decrease crying times, with differences noted between infants who are solely breastfed and those who are not.⁷

In the most recent meta-analysis of 6 studies (n=427) that focused only on the probiotic Lactobacillus reuteri, breastfed infants with colic receiving a daily dose of 10⁸ colony forming units (CFU) cried an average of 56 fewer minutes/day than those in the control group (95% confidence interval [CI], -64.4 to -47.3; P=.001) at day 21 of treatment.⁸ Although 2 studies in this meta-analysis included a small number of mixed-fed and formula-fed infants, the majority of trials do not show benefit for these infants. Trials assessing the use of L reuteri for prevention of colic have not shown positive results.⁷

Probiotics may help prevent and shorten the course of URIs

The mechanisms by which probiotics may prevent or shorten the course of URIs are not obvious. Current theories include boosting the immune function of the respiratory mucosa, acting as a competitive inhibitor for viruses, and secreting antiviral compounds.⁹ Multiple reviews published in the last 3 years, however, add to the evidence that the apparent benefit is real.

A 2013 meta-analysis assessed data from 4 RCTs (N=1805), which used Lactobacillus rhamnosus as the sole probiotic for prevention of URIs. In treated children, otitis media incidence was reduced by 24% (relative risk [RR] 0.76; 95% CI, 0.64-0.91) and risk of URI was reduced by 38% (RR 0.62; 95% CI, 0.50-0.78).¹⁰ The number needed to treat (NNT) was 4 for URI prevention, and the authors noted that adverse events were similar in the treatment and control groups.

A 2014 systematic review and meta-analysis of 20 RCTs examining duration of illness included 10 studies dedicated to pediatric subjects (age 12 months to 12 years).¹¹ There were significantly fewer days of illness per person (standardized mean difference -0.31; 95% CI, -0.41 to -0.11) and each illness episode was shorter by three-quarters of a day (weighted mean difference -0.77; 95% CI, -1.5 to -0.04) in participants who received a probiotic vs those who received a placebo. Probiotics used in these studies belonged to the Lactobacillus and Bifidobacterium genera.

A 2015 systematic review of 14 RCTs assessing the benefits of probiotics, particularly Lactobacillus and Bifidobacterium strains, on URI occurrence and symptoms, showed mixed results.¹² Seven of 12 studies found lowered rates of URI and otitis media incidence, 7 of 11 RCTs reported a significant reduction in severity scores for URI, and 4 of 8 RCTs reported significant reductions in school absenteeism between the probiotic and control groups. In a summary statement, the authors noted that “at least one beneficial effect of prophylactic probiotics was observed in the majority of RCTs,” and that “none of the studies reported any serious adverse events.”

Perinatal probiotics: No benefit for allergic conditions—except eczema

Allergic disease is on the rise and continues to plague children with reduced quality of life, potentially life-threatening reactions, and missed activities, including school. The gut microbiome likely influences a child’s allergic propensity through its effects on T-helper cells, transforming growth factor (TGF), and immunoglobulin A (IgA)—all known components of the allergic response. As the hygiene hypothesis suggests, the quantity and types of bacteria that inhabit the GI tract early in life play a significant role in determining a person’s later allergic responses.¹³

In a 2013 meta-analysis of 20 trials (N=4866), researchers looked specifically at probiotic use and the diagnosis of asthma and incident wheezing. Single and combination products of Lactobacillus and Bifidobacterium given prenatally and/or postnatally were included in the studies. The authors found no evidence to support a protective association between perinatal use of probiotics and diagnosed asthma (RR=0.99; 95% CI, 0.81-0.21) or childhood incident wheezing (RR=0.97; 95% CI, 0.87-1.09; 9 trials, 1949 infants).¹⁴

In a more recent meta-analysis (2015) conducted to inform the World Allergy Organization, 29 studies were evaluated to assess the impact of probiotics on allergic symptoms of the skin, respiratory system, and GI tract.¹⁵ No significant benefit was noted for any allergic condition except for eczema. Probiotics reduced the risk of eczema when given during the last trimester of pregnancy (RR=0.71; 95% CI, 0.60-0.84), when used by breastfeeding mothers (RR=0.57; 95% CI, 0.47-0.69), and when given to infants (RR=0.80; 95% CI, 0.68-0.94).

Lactobacillus reuteri decreased crying in breastfed infants with colic by nearly an hour a day.A 2014 systematic review and meta-analysis (N=2797) explored probiotic use specifically for the prevention of eczema.¹⁶ The pooled relative risk for all the studies was 0.74 (95% CI, 0.67-0.82). Evidence was strongest for probiotics containing the Lactobacillus species rhamnosus and paracasei, as well as for Bifidobacterium lactis. No benefit was noted with Lactobacillus acidophilus or other Bifidobacterium species. These newer reviews on eczema prevention contrast with an older Cochrane review published in 2008 (12 RCTs, N=781), which did not show significant benefit for the treatment of eczema.¹⁷

Probiotics improve IBS stomach pain, but not diarrhea or constipation

IBS is a functional disorder of the GI tract that affects up to 20% of children and teenagers and leads to a significant decrease in quality of life.¹⁸ Current theories of causation include bacterial overgrowth and neuronal hyperactivity, which may be amenable to change with supplemental probiotics.

A 2015 systematic review of non-pharmacological treatments for functional abdominal pain disorders identified 4 studies dedicated to IBS in children.¹⁹ A subgroup analysis of 3 RCTs (n=309) that looked at giving L rhamnosus to 5- to 17-year-olds with IBS showed improved abdominal pain (according to various pain scales) compared to the placebo group. Study participants received at least 3 x 10⁹ CFU twice a day for 4 to 8 weeks. Relative risk for improvement was 1.7 (95% CI, 1.27-2.27) with an NNT of 4. None of these studies showed significant improvement in either frequency or severity of diarrhea or constipation.

A separate crossover RCT (N=59) compared placebo to VSL#3, a product containing 8 probiotics (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, L acidophilus, Lactobacillus plantarum, L paracasei, Lactobacillus bulgaricus, and Streptococcus hermophiles), given in age-dependent doses for 6 weeks to children aged 4 to 18 years.²⁰ The frequency and intensity of abdominal pain were measured on a 5-point Likert scale. The group treated with VSL#3 dropped 1.0 ± 0.2 points vs 0.5 ± 0.2 points in the control group (P<.05) and reported an improved quality of life.

These agents reduce antibiotic-associated diarrhea

Antibiotic-associated diarrhea (AAD) occurs in 5% to 30% of children who receive antibiotic therapy.²¹ It occurs most frequently with the use of cephalosporins, penicillin, fluoroquinolones, and clindamycin, and is likely caused by an alteration of the normal gut flora. Colitis caused by Clostridium difficile remains the most serious antibiotic-associated GI complication.

A systematic review of the specific probiotic Saccharomyces boulardii conducted in 2015 analyzed data from 6 RCTs (n=1653) to determine the effect of co-administration of this probiotic with antibiotics.²² The pooled relative risk for AAD in children receiving the probiotic was 0.43 (95% CI, 0.3-0.6) compared to antibiotics alone. The absolute risk of AAD dropped from 20.9% to 8.8%, translating to a NNT of 8. Two of the RCTs specifically looked at rates of C difficile infection (n=579). C difficile infection rates dropped by 75% (RR=.25; 95% CI, 0.08-0.73) in the treatment group. This dramatic treatment effect was not seen in studies involving adults.

A similar systematic review focusing on L rhamnosus conducted in 2015 pooled data from 5 RCTs (n=445) to see if the probiotic would decrease AAD in children if it was co-administered with antibiotics.²³ The relative risk for AAD in this treatment group was 0.48 (95% CI, 0.26-0.89) with an absolute risk reduction of 13.4% (23% compared to 9.6%), translating to an NNT of 7.

A Cochrane review published in 2015 included 23 studies (N=3938) and found similar results with an RR for AAD of 0.46 for treated children (95% CI, 0.35-0.61).²⁴ Doses of probiotics ranged from 5 to 40 billion CFU/day. Although many probiotic species were used in these studies, S boulardii and L rhamnosus were cited as having the strongest data to support use in this context.

Probiotics reduce the duration, frequency of acute infectious diarrhea

Diarrhea remains the second leading cause of death among children one to 59 months of age worldwide.²⁵ Current World Health Organization recommendations include oral rehydration salts, continued feeding to avoid dehydration, and zinc to decrease the duration and severity of illness.²⁶ Multiple studies in adults confirm that a variety of probiotics decrease both the duration and severity of diarrhea in acute gastroenteritis.²⁷

Lactobacillus rhamnosus reduced the incidence of otitis media and upper respiratory infections by 24% and 38%, respectively.The authors of a 2013 systematic review of probiotics for the treatment of community-acquired acute diarrhea in children less than 5 years of age analyzed data from 8 RCTs (N=1755).²⁸ Various probiotics were used including Lactobacillus species, Streptococcus thermophilus, Bifidobacterium species, and Saccharomyces boulardii for between 4 and 10 days. Six of these studies (n=1164) measured diarrhea duration and found a 14% reduction (95% CI, 3.8%-24.2%) in days of illness for those children treated vs those receiving placebo. Five studies (n=925) measured the difference in stool frequency on Day 2 of illness and reported a reduction of 13.1% (95% CI, 0.8%-5.3%) in the number of stools in the treated group vs the placebo group.

This review augments a Cochrane meta-analysis of 63 studies (N=8014) published in 2010.²⁷ Fifty-six of these studies included infants and children. Pooled analysis of the varied probiotic treatments showed a mean reduction in duration of diarrhea of just over a day (24.76 hours; 95% CI, 15.9-33.6 hours; n=4555, trials=35) and decreased stool frequency on Day 2 of treatment (mean difference 0.80; 95% CI, 0.45-1.14; n=2751, trials=20). The authors concluded that probiotics “have clear beneficial effects in shortening the duration and reducing stool frequency in acute infectious diarrhea.”

Pediatric society weighs in. In 2014, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition issued guidelines regarding probiotic use for the treatment of acute gastroenteritis.²⁹ In addition to rehydration therapy, these guidelines recommend the use of L rhamnosus and/or S boulardii as first-line treatments. Lower quality evidence is available for the use of L reuteri.

CASE › In response to Ms. B’s query about starting her young son on probiotics, you tell her that studies have shown that probiotics are safe for children when given in appropriate doses. They have been shown to help children recover from diarrheal illnesses and can help reduce the number of colds and ear infections when taken regularly. The reason you are giving them determines which strains you should use. You recommend giving her child a formulation of probiotic that contains Lactobacillus or Bifidobacterium with a dose range of 2 to 10 billion CFUs taken daily to reduce the risk of her child getting another ear infection.

CORRESPONDENCE
Paul Dassow, MD, MSPH, 1100 E. 3rd St, Chattanooga, TN 37403; [email protected].

CASE › Ms. B, a 26-year-old woman, presents to your office with her 3-year-old son for a well-child examination. During the course of the conversation, she asks you if she should be giving her child probiotics to improve his general health. Many of her friends, who also have their children in day care, have told her that probiotics, “are nature’s way of fighting infection.” Her son currently takes no medications, and has no history of asthma or recent gastrointestinal disturbances. He was treated for 2 ear infections last winter, approximately 3 months apart. His physical exam is normal and, after today, his immunizations will be up to date. How should you respond?

The use of probiotics as over-the-counter treatments for a variety of conditions continues to grow, with retail sales of functional probiotic foods and supplements topping $35 billion worldwide in 2014.¹ In children, claims of benefit for gastrointestinal (GI) disorders, colic, and allergy prevention, as well as prevention and treatment of upper respiratory infections (URIs) have existed for over 10 years.^2-4 The human gut flora develops rapidly after birth and is known to be influenced by route of delivery (vaginal vs cesarean), type of feeding (breast vs formula), and other environmental factors.⁵ The use of probiotics to influence the types of bacteria in a child’s intestinal tract continues to be an area of active research. (For more on probiotic formulations, see TABLE 1.)

This article summarizes recent research on probiotic use in infants and children. New data support the use of probiotics for the treatment of colic and atopic eczema; however, the data on using probiotics in the management of URIs is less robust and mixed. And while probiotics improve irritable bowel syndrome (IBS) stomach pain, they do not help with related diarrhea or constipation. All of these data are summarized in TABLE 2.^6-29

L reuteri improves symptoms in breastfed infants with colic

Infant colic is a relatively common condition known to negatively impact maternal mental health and the mother/child relationship.⁶ Numerous randomized controlled trials (RCTs) over the years have demonstrated mixed results with using probiotics to decrease crying times, with differences noted between infants who are solely breastfed and those who are not.⁷

In the most recent meta-analysis of 6 studies (n=427) that focused only on the probiotic Lactobacillus reuteri, breastfed infants with colic receiving a daily dose of 10⁸ colony forming units (CFU) cried an average of 56 fewer minutes/day than those in the control group (95% confidence interval [CI], -64.4 to -47.3; P=.001) at day 21 of treatment.⁸ Although 2 studies in this meta-analysis included a small number of mixed-fed and formula-fed infants, the majority of trials do not show benefit for these infants. Trials assessing the use of L reuteri for prevention of colic have not shown positive results.⁷

Probiotics may help prevent and shorten the course of URIs

The mechanisms by which probiotics may prevent or shorten the course of URIs are not obvious. Current theories include boosting the immune function of the respiratory mucosa, acting as a competitive inhibitor for viruses, and secreting antiviral compounds.⁹ Multiple reviews published in the last 3 years, however, add to the evidence that the apparent benefit is real.

A 2013 meta-analysis assessed data from 4 RCTs (N=1805), which used Lactobacillus rhamnosus as the sole probiotic for prevention of URIs. In treated children, otitis media incidence was reduced by 24% (relative risk [RR] 0.76; 95% CI, 0.64-0.91) and risk of URI was reduced by 38% (RR 0.62; 95% CI, 0.50-0.78).¹⁰ The number needed to treat (NNT) was 4 for URI prevention, and the authors noted that adverse events were similar in the treatment and control groups.

A 2014 systematic review and meta-analysis of 20 RCTs examining duration of illness included 10 studies dedicated to pediatric subjects (age 12 months to 12 years).¹¹ There were significantly fewer days of illness per person (standardized mean difference -0.31; 95% CI, -0.41 to -0.11) and each illness episode was shorter by three-quarters of a day (weighted mean difference -0.77; 95% CI, -1.5 to -0.04) in participants who received a probiotic vs those who received a placebo. Probiotics used in these studies belonged to the Lactobacillus and Bifidobacterium genera.

A 2015 systematic review of 14 RCTs assessing the benefits of probiotics, particularly Lactobacillus and Bifidobacterium strains, on URI occurrence and symptoms, showed mixed results.¹² Seven of 12 studies found lowered rates of URI and otitis media incidence, 7 of 11 RCTs reported a significant reduction in severity scores for URI, and 4 of 8 RCTs reported significant reductions in school absenteeism between the probiotic and control groups. In a summary statement, the authors noted that “at least one beneficial effect of prophylactic probiotics was observed in the majority of RCTs,” and that “none of the studies reported any serious adverse events.”

Perinatal probiotics: No benefit for allergic conditions—except eczema

Allergic disease is on the rise and continues to plague children with reduced quality of life, potentially life-threatening reactions, and missed activities, including school. The gut microbiome likely influences a child’s allergic propensity through its effects on T-helper cells, transforming growth factor (TGF), and immunoglobulin A (IgA)—all known components of the allergic response. As the hygiene hypothesis suggests, the quantity and types of bacteria that inhabit the GI tract early in life play a significant role in determining a person’s later allergic responses.¹³

In a 2013 meta-analysis of 20 trials (N=4866), researchers looked specifically at probiotic use and the diagnosis of asthma and incident wheezing. Single and combination products of Lactobacillus and Bifidobacterium given prenatally and/or postnatally were included in the studies. The authors found no evidence to support a protective association between perinatal use of probiotics and diagnosed asthma (RR=0.99; 95% CI, 0.81-0.21) or childhood incident wheezing (RR=0.97; 95% CI, 0.87-1.09; 9 trials, 1949 infants).¹⁴

In a more recent meta-analysis (2015) conducted to inform the World Allergy Organization, 29 studies were evaluated to assess the impact of probiotics on allergic symptoms of the skin, respiratory system, and GI tract.¹⁵ No significant benefit was noted for any allergic condition except for eczema. Probiotics reduced the risk of eczema when given during the last trimester of pregnancy (RR=0.71; 95% CI, 0.60-0.84), when used by breastfeeding mothers (RR=0.57; 95% CI, 0.47-0.69), and when given to infants (RR=0.80; 95% CI, 0.68-0.94).

Lactobacillus reuteri decreased crying in breastfed infants with colic by nearly an hour a day.A 2014 systematic review and meta-analysis (N=2797) explored probiotic use specifically for the prevention of eczema.¹⁶ The pooled relative risk for all the studies was 0.74 (95% CI, 0.67-0.82). Evidence was strongest for probiotics containing the Lactobacillus species rhamnosus and paracasei, as well as for Bifidobacterium lactis. No benefit was noted with Lactobacillus acidophilus or other Bifidobacterium species. These newer reviews on eczema prevention contrast with an older Cochrane review published in 2008 (12 RCTs, N=781), which did not show significant benefit for the treatment of eczema.¹⁷

Probiotics improve IBS stomach pain, but not diarrhea or constipation

IBS is a functional disorder of the GI tract that affects up to 20% of children and teenagers and leads to a significant decrease in quality of life.¹⁸ Current theories of causation include bacterial overgrowth and neuronal hyperactivity, which may be amenable to change with supplemental probiotics.

A 2015 systematic review of non-pharmacological treatments for functional abdominal pain disorders identified 4 studies dedicated to IBS in children.¹⁹ A subgroup analysis of 3 RCTs (n=309) that looked at giving L rhamnosus to 5- to 17-year-olds with IBS showed improved abdominal pain (according to various pain scales) compared to the placebo group. Study participants received at least 3 x 10⁹ CFU twice a day for 4 to 8 weeks. Relative risk for improvement was 1.7 (95% CI, 1.27-2.27) with an NNT of 4. None of these studies showed significant improvement in either frequency or severity of diarrhea or constipation.

A separate crossover RCT (N=59) compared placebo to VSL#3, a product containing 8 probiotics (Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, L acidophilus, Lactobacillus plantarum, L paracasei, Lactobacillus bulgaricus, and Streptococcus hermophiles), given in age-dependent doses for 6 weeks to children aged 4 to 18 years.²⁰ The frequency and intensity of abdominal pain were measured on a 5-point Likert scale. The group treated with VSL#3 dropped 1.0 ± 0.2 points vs 0.5 ± 0.2 points in the control group (P<.05) and reported an improved quality of life.

These agents reduce antibiotic-associated diarrhea

Antibiotic-associated diarrhea (AAD) occurs in 5% to 30% of children who receive antibiotic therapy.²¹ It occurs most frequently with the use of cephalosporins, penicillin, fluoroquinolones, and clindamycin, and is likely caused by an alteration of the normal gut flora. Colitis caused by Clostridium difficile remains the most serious antibiotic-associated GI complication.

A systematic review of the specific probiotic Saccharomyces boulardii conducted in 2015 analyzed data from 6 RCTs (n=1653) to determine the effect of co-administration of this probiotic with antibiotics.²² The pooled relative risk for AAD in children receiving the probiotic was 0.43 (95% CI, 0.3-0.6) compared to antibiotics alone. The absolute risk of AAD dropped from 20.9% to 8.8%, translating to a NNT of 8. Two of the RCTs specifically looked at rates of C difficile infection (n=579). C difficile infection rates dropped by 75% (RR=.25; 95% CI, 0.08-0.73) in the treatment group. This dramatic treatment effect was not seen in studies involving adults.

A similar systematic review focusing on L rhamnosus conducted in 2015 pooled data from 5 RCTs (n=445) to see if the probiotic would decrease AAD in children if it was co-administered with antibiotics.²³ The relative risk for AAD in this treatment group was 0.48 (95% CI, 0.26-0.89) with an absolute risk reduction of 13.4% (23% compared to 9.6%), translating to an NNT of 7.

A Cochrane review published in 2015 included 23 studies (N=3938) and found similar results with an RR for AAD of 0.46 for treated children (95% CI, 0.35-0.61).²⁴ Doses of probiotics ranged from 5 to 40 billion CFU/day. Although many probiotic species were used in these studies, S boulardii and L rhamnosus were cited as having the strongest data to support use in this context.

Probiotics reduce the duration, frequency of acute infectious diarrhea

Diarrhea remains the second leading cause of death among children one to 59 months of age worldwide.²⁵ Current World Health Organization recommendations include oral rehydration salts, continued feeding to avoid dehydration, and zinc to decrease the duration and severity of illness.²⁶ Multiple studies in adults confirm that a variety of probiotics decrease both the duration and severity of diarrhea in acute gastroenteritis.²⁷

Lactobacillus rhamnosus reduced the incidence of otitis media and upper respiratory infections by 24% and 38%, respectively.The authors of a 2013 systematic review of probiotics for the treatment of community-acquired acute diarrhea in children less than 5 years of age analyzed data from 8 RCTs (N=1755).²⁸ Various probiotics were used including Lactobacillus species, Streptococcus thermophilus, Bifidobacterium species, and Saccharomyces boulardii for between 4 and 10 days. Six of these studies (n=1164) measured diarrhea duration and found a 14% reduction (95% CI, 3.8%-24.2%) in days of illness for those children treated vs those receiving placebo. Five studies (n=925) measured the difference in stool frequency on Day 2 of illness and reported a reduction of 13.1% (95% CI, 0.8%-5.3%) in the number of stools in the treated group vs the placebo group.

This review augments a Cochrane meta-analysis of 63 studies (N=8014) published in 2010.²⁷ Fifty-six of these studies included infants and children. Pooled analysis of the varied probiotic treatments showed a mean reduction in duration of diarrhea of just over a day (24.76 hours; 95% CI, 15.9-33.6 hours; n=4555, trials=35) and decreased stool frequency on Day 2 of treatment (mean difference 0.80; 95% CI, 0.45-1.14; n=2751, trials=20). The authors concluded that probiotics “have clear beneficial effects in shortening the duration and reducing stool frequency in acute infectious diarrhea.”

Pediatric society weighs in. In 2014, the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition issued guidelines regarding probiotic use for the treatment of acute gastroenteritis.²⁹ In addition to rehydration therapy, these guidelines recommend the use of L rhamnosus and/or S boulardii as first-line treatments. Lower quality evidence is available for the use of L reuteri.

CASE › In response to Ms. B’s query about starting her young son on probiotics, you tell her that studies have shown that probiotics are safe for children when given in appropriate doses. They have been shown to help children recover from diarrheal illnesses and can help reduce the number of colds and ear infections when taken regularly. The reason you are giving them determines which strains you should use. You recommend giving her child a formulation of probiotic that contains Lactobacillus or Bifidobacterium with a dose range of 2 to 10 billion CFUs taken daily to reduce the risk of her child getting another ear infection.

CORRESPONDENCE
Paul Dassow, MD, MSPH, 1100 E. 3rd St, Chattanooga, TN 37403; [email protected].

ILLUSTRATIVE CASE

A 26-year-old G2P1001 at 35 weeks, 2 days of gestation presents with leakage of clear fluid for the last 2 hours. There is obvious pooling in the vaginal vault, and rupture of membranes is confirmed with appropriate testing. Her cervix is closed, she is not in labor, and tests of fetal well-being are reassuring. She had an uncomplicated vaginal delivery with her first child. How should you manage this situation?

Preterm premature rupture of membranes (PPROM)—when rupture of membranes occurs before 37 weeks’ gestation—affects about 3% of all pregnancies in the United States, and is a major contributor to perinatal morbidity and mortality.^2,3 PPROM management remains controversial, especially during the late preterm stage (ie, 34 weeks to 36 weeks, 6 days). Non-reassuring fetal status, clinical chorioamnionitis, cord prolapse, and significant placental abruption are clear indications for delivery. In the absence of those factors, delivery vs expectant management is determined by gestational age. Between 23 and 34 weeks’ gestation, when the fetus is at or close to viability, expectant management is recommended, provided there are no signs of infection or maternal or fetal compromise.⁴ This is because of the significant morbidity and mortality associated with births before 34 weeks’ gestation.⁴

The American College of Obstetricians and Gynecologists (ACOG) currently recommends delivery for all women with rupture of membranes after 34 weeks’ gestation, while acknowledging that this recommendation is based on “limited and inconsistent scientific evidence.”⁵ The recommendation for delivery after 34 weeks is predicated on the belief that disability-free survival is high in late preterm infants. However, there is a growing body of evidence that shows negative short- and long-term effects for these children, including medical concerns, academic difficulties, and more frequent hospital admissions in early childhood.^6,7

Higher birth weights, fewer C-sections, and no increased sepsis with wait-and-see

The Preterm Pre-labour Rupture Of the Membranes close to Term (PPROMT) trial was a multicenter (65 institutions across 11 countries), randomized controlled trial (RCT) that included 1839 women with singleton pregnancies and confirmed rupture of membranes between 34 weeks and 36 weeks, 6 days’ gestation.¹ Conducted from May 2004 to June 2013, participants were randomized to expectant management (915 women) vs immediate delivery by induction (924 women). Patients and care providers were not masked to treatment allocation, but those determining the primary outcome were masked to group allocation.

One woman in each group was lost to follow-up, and 2 additional women withdrew from the immediate birth group. Women already in active labor or with clinical indications for delivery (chorioamnionitis, abruption, cord prolapse, fetal distress) were excluded. The baseline characteristics of the 2 groups were similar.

Women in the induction group had delivery scheduled as soon as possible after randomization. Women in the expectant management group were allowed to go into spontaneous labor and were only induced if they reached term or the clinician identified other indications for immediate delivery.

The primary outcome was probable or confirmed neonatal sepsis. Secondary infant outcomes included a composite neonatal morbidity and mortality indicator (sepsis, mechanical ventilation ≥24 hours, still birth, or neonatal death), respiratory distress syndrome, any mechanical ventilation, birth weight, and duration of stay in a neonatal intensive care unit (NICU) or special care nursery. Secondary maternal outcomes included antepartum or intrapartum hemorrhage, intrapartum fever, mode of delivery, duration of hospital stay, and development of chorioamnionitis in the expectant management group.

The primary outcome of neonatal sepsis occurred in 2% of the neonates assigned to immediate delivery and 3% of neonates assigned to expectant management (relative risk [RR]=0.8; 95% confidence interval [CI], 0.5-1.3; P=.37). There was also no statistically significant difference in composite neonatal morbidity and mortality (RR=1.2; 95% CI, 0.9-1.6; P=.32). However, infants born in the immediate delivery group had significantly lower birth weights (2574.7 g vs 2673.2 g; absolute difference= -125 g; P<.0001), a higher incidence of respiratory distress (RR=1.6; 95% CI, 1.1-2.3; P=.008; number needed to treat [NNT]=32), and spent more time in the NICU/special care nursery (4 days vs 2 days; P<.0001).

This study is the largest to show that immediate birth increases the risk of respiratory distress and duration of NICU stay.

Compared to immediate delivery, expectant management was associated with a higher likelihood of antepartum or intrapartum hemorrhage (RR=0.6; 95% CI, 0.4-0.9; P=.02; number needed to harm [NNH]=50) and intrapartum fever (RR=0.4; 95% CI, 0.2-0.9; P=.02; NNH=100). In the women assigned to immediate delivery, 26% had a cesarean section, compared to 19% in the expectant management group (RR=1.4; 95% CI, 1.2-1.7, P=.0001; NNT=14). A total of 56 women (6%) assigned to the expectant management group developed clinically significant chorioamnionitis requiring delivery. All other secondary maternal and neonatal outcomes were equivalent with no significant differences between the 2 groups.

WHAT'S NEW?

Largest study to show no increased sepsis with expectant management

Two prior RCTs (the PPROMEXIL trial⁸ and PPROMEXIL-2⁹), involving a total of 736 women, evaluated expectant management vs induction in the late preterm stage of pregnancy. There was no increased risk of neonatal sepsis with expectant management in either study. However, those studies did not have sufficient power to show a statistically significant change in any of the outcomes.

The PPROMT study is the largest one to show that immediate birth increases the risk of respiratory distress and duration of NICU/special care stay for the baby and increases the risk of cesarean section for the mother. It also showed that the risk of neonatal sepsis was not higher in the expectant management group.

CAVEATS

Findings only apply to singleton pregnancies

Delivery of the infants in the expectant management group was not by specified protocol; each birth was managed according to the policies of the local center and clinician judgment. Because of this, there was variation in fetal and maternal monitoring. The vast majority of women in both groups (92% to 93%) received intrapartum antibiotics. Expectant management should include careful monitoring for infection and hemorrhage and may need to be changed to immediate delivery if one of these occurs.

The study participants all had singleton pregnancies; this recommendation cannot be extended to non-singleton pregnancies. However, a prior cesarean section was not an exclusion criterion for the study, and these recommendations would be valid for that group of women, too.

CHALLENGES TO IMPLEMENTATION

Going against the tide of ACOG

The most recent ACOG guidelines, updated October 2016, recommend induction of labor for women with ruptured membranes in the late preterm stages.⁵ This may present a challenge to widespread acceptance of expectant management for PPROM.

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.

ILLUSTRATIVE CASE

A 26-year-old G2P1001 at 35 weeks, 2 days of gestation presents with leakage of clear fluid for the last 2 hours. There is obvious pooling in the vaginal vault, and rupture of membranes is confirmed with appropriate testing. Her cervix is closed, she is not in labor, and tests of fetal well-being are reassuring. She had an uncomplicated vaginal delivery with her first child. How should you manage this situation?

Preterm premature rupture of membranes (PPROM)—when rupture of membranes occurs before 37 weeks’ gestation—affects about 3% of all pregnancies in the United States, and is a major contributor to perinatal morbidity and mortality.^2,3 PPROM management remains controversial, especially during the late preterm stage (ie, 34 weeks to 36 weeks, 6 days). Non-reassuring fetal status, clinical chorioamnionitis, cord prolapse, and significant placental abruption are clear indications for delivery. In the absence of those factors, delivery vs expectant management is determined by gestational age. Between 23 and 34 weeks’ gestation, when the fetus is at or close to viability, expectant management is recommended, provided there are no signs of infection or maternal or fetal compromise.⁴ This is because of the significant morbidity and mortality associated with births before 34 weeks’ gestation.⁴

The American College of Obstetricians and Gynecologists (ACOG) currently recommends delivery for all women with rupture of membranes after 34 weeks’ gestation, while acknowledging that this recommendation is based on “limited and inconsistent scientific evidence.”⁵ The recommendation for delivery after 34 weeks is predicated on the belief that disability-free survival is high in late preterm infants. However, there is a growing body of evidence that shows negative short- and long-term effects for these children, including medical concerns, academic difficulties, and more frequent hospital admissions in early childhood.^6,7

Higher birth weights, fewer C-sections, and no increased sepsis with wait-and-see

The Preterm Pre-labour Rupture Of the Membranes close to Term (PPROMT) trial was a multicenter (65 institutions across 11 countries), randomized controlled trial (RCT) that included 1839 women with singleton pregnancies and confirmed rupture of membranes between 34 weeks and 36 weeks, 6 days’ gestation.¹ Conducted from May 2004 to June 2013, participants were randomized to expectant management (915 women) vs immediate delivery by induction (924 women). Patients and care providers were not masked to treatment allocation, but those determining the primary outcome were masked to group allocation.

One woman in each group was lost to follow-up, and 2 additional women withdrew from the immediate birth group. Women already in active labor or with clinical indications for delivery (chorioamnionitis, abruption, cord prolapse, fetal distress) were excluded. The baseline characteristics of the 2 groups were similar.

Women in the induction group had delivery scheduled as soon as possible after randomization. Women in the expectant management group were allowed to go into spontaneous labor and were only induced if they reached term or the clinician identified other indications for immediate delivery.

The primary outcome was probable or confirmed neonatal sepsis. Secondary infant outcomes included a composite neonatal morbidity and mortality indicator (sepsis, mechanical ventilation ≥24 hours, still birth, or neonatal death), respiratory distress syndrome, any mechanical ventilation, birth weight, and duration of stay in a neonatal intensive care unit (NICU) or special care nursery. Secondary maternal outcomes included antepartum or intrapartum hemorrhage, intrapartum fever, mode of delivery, duration of hospital stay, and development of chorioamnionitis in the expectant management group.

The primary outcome of neonatal sepsis occurred in 2% of the neonates assigned to immediate delivery and 3% of neonates assigned to expectant management (relative risk [RR]=0.8; 95% confidence interval [CI], 0.5-1.3; P=.37). There was also no statistically significant difference in composite neonatal morbidity and mortality (RR=1.2; 95% CI, 0.9-1.6; P=.32). However, infants born in the immediate delivery group had significantly lower birth weights (2574.7 g vs 2673.2 g; absolute difference= -125 g; P<.0001), a higher incidence of respiratory distress (RR=1.6; 95% CI, 1.1-2.3; P=.008; number needed to treat [NNT]=32), and spent more time in the NICU/special care nursery (4 days vs 2 days; P<.0001).

This study is the largest to show that immediate birth increases the risk of respiratory distress and duration of NICU stay.

Compared to immediate delivery, expectant management was associated with a higher likelihood of antepartum or intrapartum hemorrhage (RR=0.6; 95% CI, 0.4-0.9; P=.02; number needed to harm [NNH]=50) and intrapartum fever (RR=0.4; 95% CI, 0.2-0.9; P=.02; NNH=100). In the women assigned to immediate delivery, 26% had a cesarean section, compared to 19% in the expectant management group (RR=1.4; 95% CI, 1.2-1.7, P=.0001; NNT=14). A total of 56 women (6%) assigned to the expectant management group developed clinically significant chorioamnionitis requiring delivery. All other secondary maternal and neonatal outcomes were equivalent with no significant differences between the 2 groups.

WHAT'S NEW?

Largest study to show no increased sepsis with expectant management

Two prior RCTs (the PPROMEXIL trial⁸ and PPROMEXIL-2⁹), involving a total of 736 women, evaluated expectant management vs induction in the late preterm stage of pregnancy. There was no increased risk of neonatal sepsis with expectant management in either study. However, those studies did not have sufficient power to show a statistically significant change in any of the outcomes.

The PPROMT study is the largest one to show that immediate birth increases the risk of respiratory distress and duration of NICU/special care stay for the baby and increases the risk of cesarean section for the mother. It also showed that the risk of neonatal sepsis was not higher in the expectant management group.

CAVEATS

Findings only apply to singleton pregnancies

Delivery of the infants in the expectant management group was not by specified protocol; each birth was managed according to the policies of the local center and clinician judgment. Because of this, there was variation in fetal and maternal monitoring. The vast majority of women in both groups (92% to 93%) received intrapartum antibiotics. Expectant management should include careful monitoring for infection and hemorrhage and may need to be changed to immediate delivery if one of these occurs.

The study participants all had singleton pregnancies; this recommendation cannot be extended to non-singleton pregnancies. However, a prior cesarean section was not an exclusion criterion for the study, and these recommendations would be valid for that group of women, too.

CHALLENGES TO IMPLEMENTATION

Going against the tide of ACOG

The most recent ACOG guidelines, updated October 2016, recommend induction of labor for women with ruptured membranes in the late preterm stages.⁵ This may present a challenge to widespread acceptance of expectant management for PPROM.

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.

ILLUSTRATIVE CASE

A 26-year-old G2P1001 at 35 weeks, 2 days of gestation presents with leakage of clear fluid for the last 2 hours. There is obvious pooling in the vaginal vault, and rupture of membranes is confirmed with appropriate testing. Her cervix is closed, she is not in labor, and tests of fetal well-being are reassuring. She had an uncomplicated vaginal delivery with her first child. How should you manage this situation?

Preterm premature rupture of membranes (PPROM)—when rupture of membranes occurs before 37 weeks’ gestation—affects about 3% of all pregnancies in the United States, and is a major contributor to perinatal morbidity and mortality.^2,3 PPROM management remains controversial, especially during the late preterm stage (ie, 34 weeks to 36 weeks, 6 days). Non-reassuring fetal status, clinical chorioamnionitis, cord prolapse, and significant placental abruption are clear indications for delivery. In the absence of those factors, delivery vs expectant management is determined by gestational age. Between 23 and 34 weeks’ gestation, when the fetus is at or close to viability, expectant management is recommended, provided there are no signs of infection or maternal or fetal compromise.⁴ This is because of the significant morbidity and mortality associated with births before 34 weeks’ gestation.⁴

The American College of Obstetricians and Gynecologists (ACOG) currently recommends delivery for all women with rupture of membranes after 34 weeks’ gestation, while acknowledging that this recommendation is based on “limited and inconsistent scientific evidence.”⁵ The recommendation for delivery after 34 weeks is predicated on the belief that disability-free survival is high in late preterm infants. However, there is a growing body of evidence that shows negative short- and long-term effects for these children, including medical concerns, academic difficulties, and more frequent hospital admissions in early childhood.^6,7

Higher birth weights, fewer C-sections, and no increased sepsis with wait-and-see

The Preterm Pre-labour Rupture Of the Membranes close to Term (PPROMT) trial was a multicenter (65 institutions across 11 countries), randomized controlled trial (RCT) that included 1839 women with singleton pregnancies and confirmed rupture of membranes between 34 weeks and 36 weeks, 6 days’ gestation.¹ Conducted from May 2004 to June 2013, participants were randomized to expectant management (915 women) vs immediate delivery by induction (924 women). Patients and care providers were not masked to treatment allocation, but those determining the primary outcome were masked to group allocation.

One woman in each group was lost to follow-up, and 2 additional women withdrew from the immediate birth group. Women already in active labor or with clinical indications for delivery (chorioamnionitis, abruption, cord prolapse, fetal distress) were excluded. The baseline characteristics of the 2 groups were similar.

Women in the induction group had delivery scheduled as soon as possible after randomization. Women in the expectant management group were allowed to go into spontaneous labor and were only induced if they reached term or the clinician identified other indications for immediate delivery.

The primary outcome was probable or confirmed neonatal sepsis. Secondary infant outcomes included a composite neonatal morbidity and mortality indicator (sepsis, mechanical ventilation ≥24 hours, still birth, or neonatal death), respiratory distress syndrome, any mechanical ventilation, birth weight, and duration of stay in a neonatal intensive care unit (NICU) or special care nursery. Secondary maternal outcomes included antepartum or intrapartum hemorrhage, intrapartum fever, mode of delivery, duration of hospital stay, and development of chorioamnionitis in the expectant management group.

The primary outcome of neonatal sepsis occurred in 2% of the neonates assigned to immediate delivery and 3% of neonates assigned to expectant management (relative risk [RR]=0.8; 95% confidence interval [CI], 0.5-1.3; P=.37). There was also no statistically significant difference in composite neonatal morbidity and mortality (RR=1.2; 95% CI, 0.9-1.6; P=.32). However, infants born in the immediate delivery group had significantly lower birth weights (2574.7 g vs 2673.2 g; absolute difference= -125 g; P<.0001), a higher incidence of respiratory distress (RR=1.6; 95% CI, 1.1-2.3; P=.008; number needed to treat [NNT]=32), and spent more time in the NICU/special care nursery (4 days vs 2 days; P<.0001).

This study is the largest to show that immediate birth increases the risk of respiratory distress and duration of NICU stay.

Compared to immediate delivery, expectant management was associated with a higher likelihood of antepartum or intrapartum hemorrhage (RR=0.6; 95% CI, 0.4-0.9; P=.02; number needed to harm [NNH]=50) and intrapartum fever (RR=0.4; 95% CI, 0.2-0.9; P=.02; NNH=100). In the women assigned to immediate delivery, 26% had a cesarean section, compared to 19% in the expectant management group (RR=1.4; 95% CI, 1.2-1.7, P=.0001; NNT=14). A total of 56 women (6%) assigned to the expectant management group developed clinically significant chorioamnionitis requiring delivery. All other secondary maternal and neonatal outcomes were equivalent with no significant differences between the 2 groups.

WHAT'S NEW?

Largest study to show no increased sepsis with expectant management

Two prior RCTs (the PPROMEXIL trial⁸ and PPROMEXIL-2⁹), involving a total of 736 women, evaluated expectant management vs induction in the late preterm stage of pregnancy. There was no increased risk of neonatal sepsis with expectant management in either study. However, those studies did not have sufficient power to show a statistically significant change in any of the outcomes.

The PPROMT study is the largest one to show that immediate birth increases the risk of respiratory distress and duration of NICU/special care stay for the baby and increases the risk of cesarean section for the mother. It also showed that the risk of neonatal sepsis was not higher in the expectant management group.

CAVEATS

Findings only apply to singleton pregnancies

Delivery of the infants in the expectant management group was not by specified protocol; each birth was managed according to the policies of the local center and clinician judgment. Because of this, there was variation in fetal and maternal monitoring. The vast majority of women in both groups (92% to 93%) received intrapartum antibiotics. Expectant management should include careful monitoring for infection and hemorrhage and may need to be changed to immediate delivery if one of these occurs.

The study participants all had singleton pregnancies; this recommendation cannot be extended to non-singleton pregnancies. However, a prior cesarean section was not an exclusion criterion for the study, and these recommendations would be valid for that group of women, too.

CHALLENGES TO IMPLEMENTATION

Going against the tide of ACOG

The most recent ACOG guidelines, updated October 2016, recommend induction of labor for women with ruptured membranes in the late preterm stages.⁵ This may present a challenge to widespread acceptance of expectant management for PPROM.

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.

Approximately 156 million Americans (49% of the population) have tried cannabis.¹ About 5.7 million people ages 12 years and older use it daily or almost daily, a number that has nearly doubled since 2006.² There are 6600 new users in the United States every day,² and almost half of all high school students will have tried it by graduation.³

There is limited evidence that cannabis may have medical benefit in some circumstances.⁴ (See “Medical marijuana: A treatment worth trying?” J Fam Pract. 2016;65:178-185 or http://www.mdedge.com/jfponline/article/106836/medical-marijuana-treatment-worth-trying.) As a result, it is now legal for medical purposes in 25 states. Recreational use by adults is also legal in 4 states and the District of Columbia.⁵ The US Food and Drug Administration, however, has reaffirmed its stance that marijuana is a Schedule I drug on the basis of its “high potential for abuse” and the absence of “currently accepted medical uses.”⁶

The effects of legalizing the medical and recreational use of cannabis for individuals—and society as a whole—are uncertain. Debate is ongoing about the risks, benefits, and rights of individuals. Some argue it is safer than alcohol or that criminalization has been ineffective and even harmful. Others make the case for personal liberty and autonomy. Still, others are convinced legalization is a misdirected experiment that will result in diverse adverse outcomes. Regardless, it is important that primary care providers understand the ramifications of marijuana use. This evidence-based narrative highlights major negative consequences of non-medical cannabinoid use.

Although the potential adverse consequences are vast, the literature on this subject is limited for various reasons:

• Many studies are observational with a small sample size.
• Most studies examine smoked cannabis—not other routes of delivery.
• When smoked, the dose, frequency, duration, and smoking technique are variable.
• The quantity of Δ-9-tetrahydrocannabinol (THC), the primary psychoactive component in cannabis, is variable. (For more on the chemical properties of the marijuana plant, see “Cannabinoids: A diverse group of chemicals.”⁷)
• Most studies do not examine medical users, who are expected to use less cannabis or lower doses of THC.
• There are confounding effects of other drugs, notably tobacco, which is used by up to 90% of cannabis users.⁸

Lower quality of life. In general, regular non-medical cannabis use is associated with a lower quality of life and poorer socioeconomic outcomes (TABLE 1).^9-12 Physical and mental health is ranked lower by heavy users as compared to extremely low users.⁹ Some who attempt butane extraction of THC from the plant have experienced explosions and severe burns.¹³

Studies regarding cannabis use and weight are conflicting. Appetite and weight may increase initially, and young adults who increase their use of the drug are more likely to find themselves on an increasing obesity trajectory.¹⁴ However, in an observational study of nearly 11,000 participants ages 20 to 59 years, cannabis users had a lower body mass index, better lipid parameters, and were less likely to have diabetes than non-using counterparts.¹⁵

Elevated rates of MI. Chronic effects may include oral health problems,¹⁶ gynecomastia, and changes in sexual function.¹⁷ Elevated rates of myocardial infarction, cardiomyopathy, limb arteritis, and stroke have been observed.¹⁸ Synthetic cannabinoids have been associated with heart attacks and acute renal injury in youth;^19,20 however, plant-based marijuana does not affect the kidneys. In addition, high doses of plant-based marijuana can result in cannabinoid hyperemesis syndrome, characterized by cyclic vomiting and compulsive bathing that resolves with cessation of the drug.²¹

Cannabis users have a lower body mass index, better lipid parameters, and are less likely to have diabetes than their non-using counterparts.No major pulmonary effects. Interestingly, cannabis does not appear to have major negative pulmonary effects. Acutely, smoking marijuana causes bronchodilation.²² Chronic, low-level use over 20 years is associated with an increase in forced expiratory volume in one second (FEV₁), but this upward trend diminishes and may reverse in high-level users.²³ Although higher lung volumes are observed, cannabis does not appear to contribute to the development of chronic obstructive pulmonary disease, but can cause chronic bronchitis that resolves with smoking cessation.²² Chronic use has also been tied to airway infection. Lastly, fungal growth has been found on marijuana plants, which is concerning because of the potential to expose people to Aspergillus.^22,24

Cannabis and cancer? The jury is out. Cannabis contains at least 33 carcinogens²⁵ and may be contaminated with pesticides,²⁶ but research about its relationship with cancer is incomplete. Although smoking results in histopathologic changes of the bronchial mucosa, evidence of lung cancer is mixed.^22,25,27 Some studies have suggested associations with cancers of the brain, testis, prostate, and cervix,^25,27 as well as certain rare cancers in children due to parental exposure.^25,27

There are conflicting data about assoc­iations with head and neck squamous cell carcinoma,^25,27,28 bladder cancer,^25,29 and non-Hodgkin’s lymphoma.^25,30 Some studies suggest marijuana offers protection against certain types of cancer. In fact, it appears that some cannabinoids found in marijuana, such as cannabidiol (CBD), may be antineoplastic.³¹ The potential oncogenic effects of edible and topical cannabinoid products have not been investigated.

Use linked to car accidents. More recent work indicates cannabis use is associated with injuries in motor vehicle,³² non-traffic,³³ and workplace³⁴ settings. In fact, a meta-analysis found a near-doubling of motor vehicle accidents with recent use.³² Risk is dose-dependent and heightened with alcohol.^35-37 Psychomotor impairment persists for at least 6 hours after smoking cannabis,³⁸ at least 10 hours after ingesting it,³⁷ and may last up to 24 hours, as indicated by a study involving pilots using a flight simulator.³⁹

Cannabis contains at least 33 carcinogens and may be contaminated with pesticides.In contrast to alcohol, there is a greater decrement in routine vs complex driving tasks in experimental studies.^35,36 Behavioral strategies, like driving slowly, are employed to compensate for impairment, but the ability to do so is lost with alcohol co-ingestion.³⁵ Importantly, individuals using marijuana may not recognize the presence or extent of the impairment they are experiencing,^37,39 placing themselves and others in danger.

Data are insufficient to ascribe to marijuana an increase in overall mortality,⁴⁰ and there have been no reported overdose deaths from respiratory depression. However, a few deaths and a greater number of hospitalizations, due mainly to central nervous system effects including agitation, depression, coma, delirium, and toxic psychosis, have been attributed to the use of synthetic cannabinoids.²⁰

Cannabis use can pose a risk to the fetus. About 5% of pregnant women report recent marijuana use² for recreational or medical reasons (eg, morning sickness), and there is concern about its effects on the developing fetus. Certain rare pediatric cancers^22,25 and birth defects⁴¹ have been reported with cannabis use (TABLE 2^22,25,41,42). Neonatal withdrawal is minor, if present at all.⁴² Moderate evidence indicates prenatal and breastfeeding exposure can result in multiple developmental problems, as well as an increased likelihood of initiating tobacco and marijuana use as teens.^41,42

Cognitive effects of cannabis are a concern. The central nervous system is not fully myelinated until the age of 18, and complete maturation continues beyond that. Due to neuroplasticity, life experiences and exogenous agents may result in further changes. Cannabis produces changes in brain structure and function that are evident on neuroimaging.⁴³ Although accidental pediatric intoxication is alarming, negative consequences are likely to be of short duration.

Regular use by youth, on the other hand, negatively affects cognition and delays brain maturation, especially for younger initiates.^9,38,44 With abstinence, deficits tend to normalize, but they may last indefinitely among young people who continue to use marijuana.⁴⁴

Dyscognition is less severe and is more likely to resolve with abstinence in adults,⁴⁴ which may tip the scale for adults weighing whether to use cannabis for a medical purpose.⁴⁵ Keep in mind that individuals may not be aware of their cognitive deficits,⁴⁶ even though nearly all domains (from basic motor coordination to more complex executive function tasks, such as the ability to control emotions and behavior) are affected.⁴⁴ A possible exception may be improvement in attention with acute use in daily, but not occasional, users.⁴⁴ Highly focused attention, however, is not always beneficial if it delays redirection toward a new urgent stimulus.

Mood benefit? Research suggests otherwise. The psychiatric effects of cannabis are not fully understood. Users may claim mood benefit, but research suggests marijuana prompts the development or worsening of anxiety, depression, and suicidality.^12,47 Violence, paranoia, and borderline personality features have also been associated with use.^38,47 Amotivational syndrome, a disorder that includes apathy, callousness, and antisocial behavior, has been described, but the interplay between cannabis and motivation beyond recent use is unclear.⁴⁸

Psychomotor impairment persists for at least 6 hours after smoking cannabis, at least 10 hours after ingesting it, and may last up to 24 hours.Lifetime cannabis use is related to panic,⁴⁹ yet correlational studies suggest both benefit and problems for individuals who use cannabis for posttraumatic stress disorder.⁵⁰ It is now well established that marijuana use is an independent causal risk factor for the development of psychosis, particularly in vulnerable youth, and that it worsens schizophrenia in those who suffer from it.⁵¹ Human experimental studies suggest this may be because the effect of THC is counteracted by CBD.⁵² Synthetic cannabinoids are even more potent anxiogenic and psychogenic agents than plant-based marijuana.^19,20

Cannabis Use Disorder

About 9% of those who try cannabis develop Cannabis Use Disorder, which is characterized by continued use of the substance despite significant distress or impairment.⁵³ Cannabis Use Disorder is essentially an addiction. Primary risk factors include male gender, younger age at marijuana initiation, and personal or family history of other substance or psychiatric problems.⁵³

Although cannabis use often precedes use of other addiction-prone substances, it remains unclear if it is a “gateway” to the use of other illicit drugs.⁵⁴ Marijuana withdrawal is relatively minor and is comparable to that for tobacco.⁵⁵ While there are no known effective pharmacotherapies for discontinuing cannabis use, addiction therapy—including cognitive behavioral therapy and trigger management—is effective.⁵⁶

So how should the evidence inform your care?

Screen all patients for use of cannabinoids and other addiction-prone substances.⁵⁷ Follow any affirmative answers to your questions about cannabis use by asking about potential negative consequences of use. For example, ask patients:

• How often during the past 6 months did you find that you were unable to stop using cannabis once you started?
• How often during the past 6 months did you fail to do what was expected of you because of using cannabis? (For more questions, see the Cannabis Use Disorder Identification Test available at: http://www.otago.ac.nz/nationaladdictioncentre/pdfs/cudit-r.pdf.)

Other validated screening tools include the Severity of Dependence Scale, the Cannabis Abuse Screening Test, and the Problematic Use of Marijuana.⁵⁸

Counsel patients about possible adverse effects and inform them there is no evidence that recreational marijuana or synthetic cannabinoids can be used safely over time. Consider medical use requests only if there is a favorable risk/benefit balance, other recognized treatment options have been exhausted, and you have a strong understanding of the use of cannabis in the medical condition being considered.⁴

Marijuana use is an independent causal risk factor for the development of psychosis—particularly in vulnerable youth.Since brief interventions using motivational interviewing to reduce or eliminate recreational use have not been found to be effective,⁵⁹ referral to an addiction specialist may be indicated. If a diagnosis of cannabis use disorder is established, then abstinence from addiction-prone substances including marijuana, programs like Marijuana Anonymous (Available at: https://www.marijuana-anonymous.org/), and individualized addiction therapy scaled to the severity of the condition can be effective.⁵⁶ Because psychiatric conditions frequently co-occur and complicate addiction,⁵³ they should be screened for and managed, as well.

Drug testing. Cannabis Use Disorder has significant relapse potential.⁶⁰ Abstinence and treatment adherence should be ascertained through regular follow-up that includes a clinical interview, exam, and body fluid drug testing. Point-of-care urine analysis for substances of potential addiction has limited utility. Definitive testing of urine with gas chromotography/mass spectrometry (GC/MS) or liquid chromatography (LC/MS-MS) can eliminate THC false-positives and false-negatives that can occur with point-of-care urine immunoassays. In addition, GCMS and LC/MS-MS can identify synthetic cannabinoids; in-office immunoassays cannot.

If the patient relapses, subsequent medical care should be coordinated with an addiction specialist with the goal of helping the patient to abstain from cannabis.

CORRESPONDENCE
Steven Wright, MD, FAAFP, 5325 Ridge Trail, Littleton, CO 80123; [email protected].

Approximately 156 million Americans (49% of the population) have tried cannabis.¹ About 5.7 million people ages 12 years and older use it daily or almost daily, a number that has nearly doubled since 2006.² There are 6600 new users in the United States every day,² and almost half of all high school students will have tried it by graduation.³

There is limited evidence that cannabis may have medical benefit in some circumstances.⁴ (See “Medical marijuana: A treatment worth trying?” J Fam Pract. 2016;65:178-185 or http://www.mdedge.com/jfponline/article/106836/medical-marijuana-treatment-worth-trying.) As a result, it is now legal for medical purposes in 25 states. Recreational use by adults is also legal in 4 states and the District of Columbia.⁵ The US Food and Drug Administration, however, has reaffirmed its stance that marijuana is a Schedule I drug on the basis of its “high potential for abuse” and the absence of “currently accepted medical uses.”⁶

The effects of legalizing the medical and recreational use of cannabis for individuals—and society as a whole—are uncertain. Debate is ongoing about the risks, benefits, and rights of individuals. Some argue it is safer than alcohol or that criminalization has been ineffective and even harmful. Others make the case for personal liberty and autonomy. Still, others are convinced legalization is a misdirected experiment that will result in diverse adverse outcomes. Regardless, it is important that primary care providers understand the ramifications of marijuana use. This evidence-based narrative highlights major negative consequences of non-medical cannabinoid use.

Although the potential adverse consequences are vast, the literature on this subject is limited for various reasons:

• Many studies are observational with a small sample size.
• Most studies examine smoked cannabis—not other routes of delivery.
• When smoked, the dose, frequency, duration, and smoking technique are variable.
• The quantity of Δ-9-tetrahydrocannabinol (THC), the primary psychoactive component in cannabis, is variable. (For more on the chemical properties of the marijuana plant, see “Cannabinoids: A diverse group of chemicals.”⁷)
• Most studies do not examine medical users, who are expected to use less cannabis or lower doses of THC.
• There are confounding effects of other drugs, notably tobacco, which is used by up to 90% of cannabis users.⁸

Lower quality of life. In general, regular non-medical cannabis use is associated with a lower quality of life and poorer socioeconomic outcomes (TABLE 1).^9-12 Physical and mental health is ranked lower by heavy users as compared to extremely low users.⁹ Some who attempt butane extraction of THC from the plant have experienced explosions and severe burns.¹³

Studies regarding cannabis use and weight are conflicting. Appetite and weight may increase initially, and young adults who increase their use of the drug are more likely to find themselves on an increasing obesity trajectory.¹⁴ However, in an observational study of nearly 11,000 participants ages 20 to 59 years, cannabis users had a lower body mass index, better lipid parameters, and were less likely to have diabetes than non-using counterparts.¹⁵

Elevated rates of MI. Chronic effects may include oral health problems,¹⁶ gynecomastia, and changes in sexual function.¹⁷ Elevated rates of myocardial infarction, cardiomyopathy, limb arteritis, and stroke have been observed.¹⁸ Synthetic cannabinoids have been associated with heart attacks and acute renal injury in youth;^19,20 however, plant-based marijuana does not affect the kidneys. In addition, high doses of plant-based marijuana can result in cannabinoid hyperemesis syndrome, characterized by cyclic vomiting and compulsive bathing that resolves with cessation of the drug.²¹

Cannabis users have a lower body mass index, better lipid parameters, and are less likely to have diabetes than their non-using counterparts.No major pulmonary effects. Interestingly, cannabis does not appear to have major negative pulmonary effects. Acutely, smoking marijuana causes bronchodilation.²² Chronic, low-level use over 20 years is associated with an increase in forced expiratory volume in one second (FEV₁), but this upward trend diminishes and may reverse in high-level users.²³ Although higher lung volumes are observed, cannabis does not appear to contribute to the development of chronic obstructive pulmonary disease, but can cause chronic bronchitis that resolves with smoking cessation.²² Chronic use has also been tied to airway infection. Lastly, fungal growth has been found on marijuana plants, which is concerning because of the potential to expose people to Aspergillus.^22,24

Cannabis and cancer? The jury is out. Cannabis contains at least 33 carcinogens²⁵ and may be contaminated with pesticides,²⁶ but research about its relationship with cancer is incomplete. Although smoking results in histopathologic changes of the bronchial mucosa, evidence of lung cancer is mixed.^22,25,27 Some studies have suggested associations with cancers of the brain, testis, prostate, and cervix,^25,27 as well as certain rare cancers in children due to parental exposure.^25,27

There are conflicting data about assoc­iations with head and neck squamous cell carcinoma,^25,27,28 bladder cancer,^25,29 and non-Hodgkin’s lymphoma.^25,30 Some studies suggest marijuana offers protection against certain types of cancer. In fact, it appears that some cannabinoids found in marijuana, such as cannabidiol (CBD), may be antineoplastic.³¹ The potential oncogenic effects of edible and topical cannabinoid products have not been investigated.

Use linked to car accidents. More recent work indicates cannabis use is associated with injuries in motor vehicle,³² non-traffic,³³ and workplace³⁴ settings. In fact, a meta-analysis found a near-doubling of motor vehicle accidents with recent use.³² Risk is dose-dependent and heightened with alcohol.^35-37 Psychomotor impairment persists for at least 6 hours after smoking cannabis,³⁸ at least 10 hours after ingesting it,³⁷ and may last up to 24 hours, as indicated by a study involving pilots using a flight simulator.³⁹

Cannabis contains at least 33 carcinogens and may be contaminated with pesticides.In contrast to alcohol, there is a greater decrement in routine vs complex driving tasks in experimental studies.^35,36 Behavioral strategies, like driving slowly, are employed to compensate for impairment, but the ability to do so is lost with alcohol co-ingestion.³⁵ Importantly, individuals using marijuana may not recognize the presence or extent of the impairment they are experiencing,^37,39 placing themselves and others in danger.

Data are insufficient to ascribe to marijuana an increase in overall mortality,⁴⁰ and there have been no reported overdose deaths from respiratory depression. However, a few deaths and a greater number of hospitalizations, due mainly to central nervous system effects including agitation, depression, coma, delirium, and toxic psychosis, have been attributed to the use of synthetic cannabinoids.²⁰

Cannabis use can pose a risk to the fetus. About 5% of pregnant women report recent marijuana use² for recreational or medical reasons (eg, morning sickness), and there is concern about its effects on the developing fetus. Certain rare pediatric cancers^22,25 and birth defects⁴¹ have been reported with cannabis use (TABLE 2^22,25,41,42). Neonatal withdrawal is minor, if present at all.⁴² Moderate evidence indicates prenatal and breastfeeding exposure can result in multiple developmental problems, as well as an increased likelihood of initiating tobacco and marijuana use as teens.^41,42

Cognitive effects of cannabis are a concern. The central nervous system is not fully myelinated until the age of 18, and complete maturation continues beyond that. Due to neuroplasticity, life experiences and exogenous agents may result in further changes. Cannabis produces changes in brain structure and function that are evident on neuroimaging.⁴³ Although accidental pediatric intoxication is alarming, negative consequences are likely to be of short duration.

Regular use by youth, on the other hand, negatively affects cognition and delays brain maturation, especially for younger initiates.^9,38,44 With abstinence, deficits tend to normalize, but they may last indefinitely among young people who continue to use marijuana.⁴⁴

Dyscognition is less severe and is more likely to resolve with abstinence in adults,⁴⁴ which may tip the scale for adults weighing whether to use cannabis for a medical purpose.⁴⁵ Keep in mind that individuals may not be aware of their cognitive deficits,⁴⁶ even though nearly all domains (from basic motor coordination to more complex executive function tasks, such as the ability to control emotions and behavior) are affected.⁴⁴ A possible exception may be improvement in attention with acute use in daily, but not occasional, users.⁴⁴ Highly focused attention, however, is not always beneficial if it delays redirection toward a new urgent stimulus.

Mood benefit? Research suggests otherwise. The psychiatric effects of cannabis are not fully understood. Users may claim mood benefit, but research suggests marijuana prompts the development or worsening of anxiety, depression, and suicidality.^12,47 Violence, paranoia, and borderline personality features have also been associated with use.^38,47 Amotivational syndrome, a disorder that includes apathy, callousness, and antisocial behavior, has been described, but the interplay between cannabis and motivation beyond recent use is unclear.⁴⁸

Psychomotor impairment persists for at least 6 hours after smoking cannabis, at least 10 hours after ingesting it, and may last up to 24 hours.Lifetime cannabis use is related to panic,⁴⁹ yet correlational studies suggest both benefit and problems for individuals who use cannabis for posttraumatic stress disorder.⁵⁰ It is now well established that marijuana use is an independent causal risk factor for the development of psychosis, particularly in vulnerable youth, and that it worsens schizophrenia in those who suffer from it.⁵¹ Human experimental studies suggest this may be because the effect of THC is counteracted by CBD.⁵² Synthetic cannabinoids are even more potent anxiogenic and psychogenic agents than plant-based marijuana.^19,20

Cannabis Use Disorder

About 9% of those who try cannabis develop Cannabis Use Disorder, which is characterized by continued use of the substance despite significant distress or impairment.⁵³ Cannabis Use Disorder is essentially an addiction. Primary risk factors include male gender, younger age at marijuana initiation, and personal or family history of other substance or psychiatric problems.⁵³

Although cannabis use often precedes use of other addiction-prone substances, it remains unclear if it is a “gateway” to the use of other illicit drugs.⁵⁴ Marijuana withdrawal is relatively minor and is comparable to that for tobacco.⁵⁵ While there are no known effective pharmacotherapies for discontinuing cannabis use, addiction therapy—including cognitive behavioral therapy and trigger management—is effective.⁵⁶

So how should the evidence inform your care?

Screen all patients for use of cannabinoids and other addiction-prone substances.⁵⁷ Follow any affirmative answers to your questions about cannabis use by asking about potential negative consequences of use. For example, ask patients:

• How often during the past 6 months did you find that you were unable to stop using cannabis once you started?
• How often during the past 6 months did you fail to do what was expected of you because of using cannabis? (For more questions, see the Cannabis Use Disorder Identification Test available at: http://www.otago.ac.nz/nationaladdictioncentre/pdfs/cudit-r.pdf.)

Other validated screening tools include the Severity of Dependence Scale, the Cannabis Abuse Screening Test, and the Problematic Use of Marijuana.⁵⁸

Counsel patients about possible adverse effects and inform them there is no evidence that recreational marijuana or synthetic cannabinoids can be used safely over time. Consider medical use requests only if there is a favorable risk/benefit balance, other recognized treatment options have been exhausted, and you have a strong understanding of the use of cannabis in the medical condition being considered.⁴

Marijuana use is an independent causal risk factor for the development of psychosis—particularly in vulnerable youth.Since brief interventions using motivational interviewing to reduce or eliminate recreational use have not been found to be effective,⁵⁹ referral to an addiction specialist may be indicated. If a diagnosis of cannabis use disorder is established, then abstinence from addiction-prone substances including marijuana, programs like Marijuana Anonymous (Available at: https://www.marijuana-anonymous.org/), and individualized addiction therapy scaled to the severity of the condition can be effective.⁵⁶ Because psychiatric conditions frequently co-occur and complicate addiction,⁵³ they should be screened for and managed, as well.

Drug testing. Cannabis Use Disorder has significant relapse potential.⁶⁰ Abstinence and treatment adherence should be ascertained through regular follow-up that includes a clinical interview, exam, and body fluid drug testing. Point-of-care urine analysis for substances of potential addiction has limited utility. Definitive testing of urine with gas chromotography/mass spectrometry (GC/MS) or liquid chromatography (LC/MS-MS) can eliminate THC false-positives and false-negatives that can occur with point-of-care urine immunoassays. In addition, GCMS and LC/MS-MS can identify synthetic cannabinoids; in-office immunoassays cannot.

If the patient relapses, subsequent medical care should be coordinated with an addiction specialist with the goal of helping the patient to abstain from cannabis.

CORRESPONDENCE
Steven Wright, MD, FAAFP, 5325 Ridge Trail, Littleton, CO 80123; [email protected].

Approximately 156 million Americans (49% of the population) have tried cannabis.¹ About 5.7 million people ages 12 years and older use it daily or almost daily, a number that has nearly doubled since 2006.² There are 6600 new users in the United States every day,² and almost half of all high school students will have tried it by graduation.³

There is limited evidence that cannabis may have medical benefit in some circumstances.⁴ (See “Medical marijuana: A treatment worth trying?” J Fam Pract. 2016;65:178-185 or http://www.mdedge.com/jfponline/article/106836/medical-marijuana-treatment-worth-trying.) As a result, it is now legal for medical purposes in 25 states. Recreational use by adults is also legal in 4 states and the District of Columbia.⁵ The US Food and Drug Administration, however, has reaffirmed its stance that marijuana is a Schedule I drug on the basis of its “high potential for abuse” and the absence of “currently accepted medical uses.”⁶

The effects of legalizing the medical and recreational use of cannabis for individuals—and society as a whole—are uncertain. Debate is ongoing about the risks, benefits, and rights of individuals. Some argue it is safer than alcohol or that criminalization has been ineffective and even harmful. Others make the case for personal liberty and autonomy. Still, others are convinced legalization is a misdirected experiment that will result in diverse adverse outcomes. Regardless, it is important that primary care providers understand the ramifications of marijuana use. This evidence-based narrative highlights major negative consequences of non-medical cannabinoid use.

Although the potential adverse consequences are vast, the literature on this subject is limited for various reasons:

• Many studies are observational with a small sample size.
• Most studies examine smoked cannabis—not other routes of delivery.
• When smoked, the dose, frequency, duration, and smoking technique are variable.
• The quantity of Δ-9-tetrahydrocannabinol (THC), the primary psychoactive component in cannabis, is variable. (For more on the chemical properties of the marijuana plant, see “Cannabinoids: A diverse group of chemicals.”⁷)
• Most studies do not examine medical users, who are expected to use less cannabis or lower doses of THC.
• There are confounding effects of other drugs, notably tobacco, which is used by up to 90% of cannabis users.⁸

Lower quality of life. In general, regular non-medical cannabis use is associated with a lower quality of life and poorer socioeconomic outcomes (TABLE 1).^9-12 Physical and mental health is ranked lower by heavy users as compared to extremely low users.⁹ Some who attempt butane extraction of THC from the plant have experienced explosions and severe burns.¹³

Studies regarding cannabis use and weight are conflicting. Appetite and weight may increase initially, and young adults who increase their use of the drug are more likely to find themselves on an increasing obesity trajectory.¹⁴ However, in an observational study of nearly 11,000 participants ages 20 to 59 years, cannabis users had a lower body mass index, better lipid parameters, and were less likely to have diabetes than non-using counterparts.¹⁵

Elevated rates of MI. Chronic effects may include oral health problems,¹⁶ gynecomastia, and changes in sexual function.¹⁷ Elevated rates of myocardial infarction, cardiomyopathy, limb arteritis, and stroke have been observed.¹⁸ Synthetic cannabinoids have been associated with heart attacks and acute renal injury in youth;^19,20 however, plant-based marijuana does not affect the kidneys. In addition, high doses of plant-based marijuana can result in cannabinoid hyperemesis syndrome, characterized by cyclic vomiting and compulsive bathing that resolves with cessation of the drug.²¹

Cannabis users have a lower body mass index, better lipid parameters, and are less likely to have diabetes than their non-using counterparts.No major pulmonary effects. Interestingly, cannabis does not appear to have major negative pulmonary effects. Acutely, smoking marijuana causes bronchodilation.²² Chronic, low-level use over 20 years is associated with an increase in forced expiratory volume in one second (FEV₁), but this upward trend diminishes and may reverse in high-level users.²³ Although higher lung volumes are observed, cannabis does not appear to contribute to the development of chronic obstructive pulmonary disease, but can cause chronic bronchitis that resolves with smoking cessation.²² Chronic use has also been tied to airway infection. Lastly, fungal growth has been found on marijuana plants, which is concerning because of the potential to expose people to Aspergillus.^22,24

Cannabis and cancer? The jury is out. Cannabis contains at least 33 carcinogens²⁵ and may be contaminated with pesticides,²⁶ but research about its relationship with cancer is incomplete. Although smoking results in histopathologic changes of the bronchial mucosa, evidence of lung cancer is mixed.^22,25,27 Some studies have suggested associations with cancers of the brain, testis, prostate, and cervix,^25,27 as well as certain rare cancers in children due to parental exposure.^25,27

There are conflicting data about assoc­iations with head and neck squamous cell carcinoma,^25,27,28 bladder cancer,^25,29 and non-Hodgkin’s lymphoma.^25,30 Some studies suggest marijuana offers protection against certain types of cancer. In fact, it appears that some cannabinoids found in marijuana, such as cannabidiol (CBD), may be antineoplastic.³¹ The potential oncogenic effects of edible and topical cannabinoid products have not been investigated.

Use linked to car accidents. More recent work indicates cannabis use is associated with injuries in motor vehicle,³² non-traffic,³³ and workplace³⁴ settings. In fact, a meta-analysis found a near-doubling of motor vehicle accidents with recent use.³² Risk is dose-dependent and heightened with alcohol.^35-37 Psychomotor impairment persists for at least 6 hours after smoking cannabis,³⁸ at least 10 hours after ingesting it,³⁷ and may last up to 24 hours, as indicated by a study involving pilots using a flight simulator.³⁹

Cannabis contains at least 33 carcinogens and may be contaminated with pesticides.In contrast to alcohol, there is a greater decrement in routine vs complex driving tasks in experimental studies.^35,36 Behavioral strategies, like driving slowly, are employed to compensate for impairment, but the ability to do so is lost with alcohol co-ingestion.³⁵ Importantly, individuals using marijuana may not recognize the presence or extent of the impairment they are experiencing,^37,39 placing themselves and others in danger.

Data are insufficient to ascribe to marijuana an increase in overall mortality,⁴⁰ and there have been no reported overdose deaths from respiratory depression. However, a few deaths and a greater number of hospitalizations, due mainly to central nervous system effects including agitation, depression, coma, delirium, and toxic psychosis, have been attributed to the use of synthetic cannabinoids.²⁰

Cannabis use can pose a risk to the fetus. About 5% of pregnant women report recent marijuana use² for recreational or medical reasons (eg, morning sickness), and there is concern about its effects on the developing fetus. Certain rare pediatric cancers^22,25 and birth defects⁴¹ have been reported with cannabis use (TABLE 2^22,25,41,42). Neonatal withdrawal is minor, if present at all.⁴² Moderate evidence indicates prenatal and breastfeeding exposure can result in multiple developmental problems, as well as an increased likelihood of initiating tobacco and marijuana use as teens.^41,42

Cognitive effects of cannabis are a concern. The central nervous system is not fully myelinated until the age of 18, and complete maturation continues beyond that. Due to neuroplasticity, life experiences and exogenous agents may result in further changes. Cannabis produces changes in brain structure and function that are evident on neuroimaging.⁴³ Although accidental pediatric intoxication is alarming, negative consequences are likely to be of short duration.

Regular use by youth, on the other hand, negatively affects cognition and delays brain maturation, especially for younger initiates.^9,38,44 With abstinence, deficits tend to normalize, but they may last indefinitely among young people who continue to use marijuana.⁴⁴

Dyscognition is less severe and is more likely to resolve with abstinence in adults,⁴⁴ which may tip the scale for adults weighing whether to use cannabis for a medical purpose.⁴⁵ Keep in mind that individuals may not be aware of their cognitive deficits,⁴⁶ even though nearly all domains (from basic motor coordination to more complex executive function tasks, such as the ability to control emotions and behavior) are affected.⁴⁴ A possible exception may be improvement in attention with acute use in daily, but not occasional, users.⁴⁴ Highly focused attention, however, is not always beneficial if it delays redirection toward a new urgent stimulus.

Mood benefit? Research suggests otherwise. The psychiatric effects of cannabis are not fully understood. Users may claim mood benefit, but research suggests marijuana prompts the development or worsening of anxiety, depression, and suicidality.^12,47 Violence, paranoia, and borderline personality features have also been associated with use.^38,47 Amotivational syndrome, a disorder that includes apathy, callousness, and antisocial behavior, has been described, but the interplay between cannabis and motivation beyond recent use is unclear.⁴⁸

Psychomotor impairment persists for at least 6 hours after smoking cannabis, at least 10 hours after ingesting it, and may last up to 24 hours.Lifetime cannabis use is related to panic,⁴⁹ yet correlational studies suggest both benefit and problems for individuals who use cannabis for posttraumatic stress disorder.⁵⁰ It is now well established that marijuana use is an independent causal risk factor for the development of psychosis, particularly in vulnerable youth, and that it worsens schizophrenia in those who suffer from it.⁵¹ Human experimental studies suggest this may be because the effect of THC is counteracted by CBD.⁵² Synthetic cannabinoids are even more potent anxiogenic and psychogenic agents than plant-based marijuana.^19,20

Cannabis Use Disorder

About 9% of those who try cannabis develop Cannabis Use Disorder, which is characterized by continued use of the substance despite significant distress or impairment.⁵³ Cannabis Use Disorder is essentially an addiction. Primary risk factors include male gender, younger age at marijuana initiation, and personal or family history of other substance or psychiatric problems.⁵³

Although cannabis use often precedes use of other addiction-prone substances, it remains unclear if it is a “gateway” to the use of other illicit drugs.⁵⁴ Marijuana withdrawal is relatively minor and is comparable to that for tobacco.⁵⁵ While there are no known effective pharmacotherapies for discontinuing cannabis use, addiction therapy—including cognitive behavioral therapy and trigger management—is effective.⁵⁶

So how should the evidence inform your care?

Screen all patients for use of cannabinoids and other addiction-prone substances.⁵⁷ Follow any affirmative answers to your questions about cannabis use by asking about potential negative consequences of use. For example, ask patients:

• How often during the past 6 months did you find that you were unable to stop using cannabis once you started?
• How often during the past 6 months did you fail to do what was expected of you because of using cannabis? (For more questions, see the Cannabis Use Disorder Identification Test available at: http://www.otago.ac.nz/nationaladdictioncentre/pdfs/cudit-r.pdf.)

Other validated screening tools include the Severity of Dependence Scale, the Cannabis Abuse Screening Test, and the Problematic Use of Marijuana.⁵⁸

Counsel patients about possible adverse effects and inform them there is no evidence that recreational marijuana or synthetic cannabinoids can be used safely over time. Consider medical use requests only if there is a favorable risk/benefit balance, other recognized treatment options have been exhausted, and you have a strong understanding of the use of cannabis in the medical condition being considered.⁴

Marijuana use is an independent causal risk factor for the development of psychosis—particularly in vulnerable youth.Since brief interventions using motivational interviewing to reduce or eliminate recreational use have not been found to be effective,⁵⁹ referral to an addiction specialist may be indicated. If a diagnosis of cannabis use disorder is established, then abstinence from addiction-prone substances including marijuana, programs like Marijuana Anonymous (Available at: https://www.marijuana-anonymous.org/), and individualized addiction therapy scaled to the severity of the condition can be effective.⁵⁶ Because psychiatric conditions frequently co-occur and complicate addiction,⁵³ they should be screened for and managed, as well.

Drug testing. Cannabis Use Disorder has significant relapse potential.⁶⁰ Abstinence and treatment adherence should be ascertained through regular follow-up that includes a clinical interview, exam, and body fluid drug testing. Point-of-care urine analysis for substances of potential addiction has limited utility. Definitive testing of urine with gas chromotography/mass spectrometry (GC/MS) or liquid chromatography (LC/MS-MS) can eliminate THC false-positives and false-negatives that can occur with point-of-care urine immunoassays. In addition, GCMS and LC/MS-MS can identify synthetic cannabinoids; in-office immunoassays cannot.

If the patient relapses, subsequent medical care should be coordinated with an addiction specialist with the goal of helping the patient to abstain from cannabis.

CORRESPONDENCE
Steven Wright, MD, FAAFP, 5325 Ridge Trail, Littleton, CO 80123; [email protected].

Medications can have an unpredictable and variable effect on weight. Some drugs trigger weight gain in one patient while inducing weight loss in another. Others may lead to weight loss initially but cause weight gain when taken long term.¹ Often, a drug’s effect on a patient’s weight depends on his or her medical history and lifestyle, including factors like insulin resistance, diet, and exercise level.

To make matters worse, clinical studies of drug-related effects on weight can be misleading. Because researchers often report a mean weight change—an average of those who had little or no change in weight when taking the drug and individuals who may have gained a significant amount of weight—a drug’s potential to cause weight gain may be underestimated. Few studies include an analysis of the range—eg, how many participants gained or lost various percentages of body weight. What’s more, pharmacology studies typically follow participants for a few months to a few years, whereas weight changes can be cumulative when a medication is taken for many years.

The nation’s continually growing obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain. Until recently, the medical literature offered little guidance.

In 2015, the Endocrine Society published clinical practice guidelines for pharmacologic management of obesity, including data on medications that cause weight gain and suggesting alternatives that are weight-neutral or promote weight loss.²

In the pages that follow, we present case studies, tables, and a review of the latest evidence to highlight optimal drug treatment for patients who are overweight or obese, and are also being treated for diabetes, hypertension, and depression. You’ll find a brief discussion of weight management strategies related to other drugs and conditions in the sidebar.^2-5

CASE 1 › 40-year-old man with diabetes and hyperlipidemia

Brian P, who has come in for an annual checkup, has a body mass index (BMI) of 30 kg/m². He also has hyperlipidemia and type 2 diabetes, for which he has been taking metformin for several years. A year ago, his hemoglobin A1c (HbA1c) was 7.3%, so his physician added glyburide to his regimen.

In the year since, Mr. P has gained 12 lbs (5.4 kg) but achieved only a minimal reduction in HbA1c (to 6.8%). He expresses concern about the cardiovascular effects of the extra weight and says that diet and exercise have not helped him control his weight.

CASE 2 › Older woman with hypertension and hypothyroidism

Addie K, age 64, is obese (BMI, 37 kg/m²) and has hypertension and hypothyroidism, for which she takes metoprolol and levothyroxine. Ms. K says that she is careful about what she eats and exercises several times a week, but still has seen her weight increase steadily for the past several years.

The nation's obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain.

CASE 3 › Young man with depression

Charlie D, a 21-year-old college student, is a new patient. He has depression and is obese (BMI, 34 kg/m²). The patient says he was diagnosed with depression by his former primary care physician, who prescribed paroxetine a year ago. He requests a refill of the paroxetine, which he reports has successfully boosted his mood. When asked about his weight, he admits that he has gained 8 lbs (3.6 kg) since he began taking the drug.

If these were your patients, what weight management steps would you take? Before we provide some recommendations, let’s review the evidence.

While some antidiabetic agents are weight-neutral and others promote weight loss, several therapies are associated with weight gain⁶ (TABLE 1³). Patients like Mr. P can gain as much as 10 kg in 3 to 6 months after beginning treatment with insulin, thiazolidinediones (TZDs), sulfonylureas, and other insulin secretagogues.^2,7

A recent systematic review and meta-analysis of 257 randomized controlled trials (RCTs) found weight gain to be associated with the use of pioglitazone (2.6 kg), glimepiride (2.1 kg), glyburide (2.6 kg), glipizide (2.2 kg), and sitagliptin (0.55 kg). A modest weight loss was associated with acarbose, exenatide, liraglutide, metformin, miglitol, and pramlintide.⁸

Sulfonylureas are generally associated with a 1.5 to 2.5 kg weight gain.^9-11 In an analysis of 27 RCTs of noninsulin antidiabetic drugs in patients whose disease was not controlled by metformin alone, TZDs, sulfonylureas, and meglitinides were associated with a 1.77 to 2.08 kg weight gain.⁹ Furthermore, those taking sulfonylureas and meglitinides had higher rates of hypoglycemia compared with patients taking placebo (relative risk, 4.50-7.50). In fact, sulfonylureas have the highest risk of serious hypoglycemia of any noninsulin therapy.⁶

In contrast, metformin—the most commonly prescribed oral agent for type 2 diabetes—promotes mild weight loss by multiple mechanisms and has a good safety profile.^12,13 Thus, some physicians use metformin off label for weight loss and diabetes prevention and have suggested that it be approved for these indications.¹³

Glycemic control and weight loss

Glucagon-like peptide-1 (GLP-1) agonists lead to weight loss by decreasing appetite and enhancing satiety, as well as improving glycemic control. Liraglutide received Food and Drug Administration (FDA) approval in 2014 as a treatment for chronic weight management at a higher dose (3 mg/d) than that used to treat diabetes (1.8 mg/d).¹⁴

For patients who are obese and who require insulin to manage type 2 diabetes, the Endocrine Society recommends concomitantly prescribing at least one weight loss-promoting medication.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic medication that reduce glucose reabsorption by the kidneys, leading to increased urinary glucose excretion.¹⁵ The associated weight loss, in addition to a reduction in hyperglycemia, may be due to the subsequent calorie loss through glycosuria.

Both dipeptidyl peptidase-4 (DPP-4) inhibitors and alpha-glucosidase inhibitors (AGIs) appear to be weight-neutral or to induce minimal changes in weight.¹⁶ Although the systematic review mentioned earlier found a 0.55 kg weight gain associated with sitagliptin,⁸ most studies of DPP-4 inhibitors report weight neutrality.^17-19 Pramlintide, the amylin analogue that has FDA approval for use in combination with existing insulin treatment, can prevent weight gain or lead to weight loss.^20,21

The Endocrine Society Clinical Practice Guideline recommends concomitantly prescribing at least one weight loss-promoting medication (such as metformin, a GLP-1 agonist, or pramlintide) to patients with obesity and type 2 diabetes who require insulin to mitigate weight gain due to insulin.²

The 2016 Comprehensive Type 2 Diabetes Management Algorithm published by the American Association of Clinical Endocrinologists and American College of Endocrinology recommends that the initiation of diabetes therapies be based on the risks of weight gain and hypoglycemia, among other factors. The algorithm calls for metformin as first-line therapy, followed by a GLP-1 agonist as a second-line therapy, and an SGLT2 inhibitor as a third-line therapy.⁶

Finally, FDA-approved anti-obesity medications may be appropriate for patients with diabetes who are unable to lose weight with lifestyle interventions alone.²² Each medication is associated with improvements in glucose in addition to other metabolic parameters.

CASE 1 › A better choice for Mr. P

Because Mr. P has gained weight—and, indeed, developed obesity—since he started taking glyburide, it is clear that a sulfonylurea is not the best choice for this patient. An antidiabetic agent that is weight-neutral or that promotes weight loss, such as an SGLT2 inhibitor or a GLP-1 agonist, would be more suitable. The drug should be prescribed in conjunction with his metformin, which has a favorable weight profile and helps reduce HbA1c, as both SGLT2 inhibitors and GLP-1 agonists also do.

If Mr. P were to switch to an SGLT2 inhibitor, a combination pill containing metformin would be an effective way to limit the patient’s pill burden.

Treating hypertension without weight gain

Thiazide diuretics are often recommended as first-line agents for the treatment of hypertension, but their dose-related adverse effects, including dyslipidemia and insulin resistance, are undesirable for patients who are overweight or obese and at risk for metabolic syndrome and type 2 diabetes.²³ Beta-adrenergic blockers have been shown to promote weight gain and prevent weight loss, especially in patients who have both hypertension and diabetes.²⁴ In addition to having potential adverse metabolic effects on lipids and/or insulin sensitivity, beta-blockers can decrease metabolic rate by 10% and they may have other negative effects on energy metabolism, as well.²⁵

When a patient who is obese has a condition for which a beta-blocker is a necessity, a selective agent with a vasodilating component is recommended.

In a meta-analysis of 8 RCTs that lasted ≥6 months, changes in body weight were higher in participants on beta-blockers, with a median difference of 1.2 kg (−0.4 to 3.5 kg) between those on beta-blockers and the control group.²⁶ The evidence suggests that beta-blockers should not necessarily be first-line treatment for hypertension in patients who are overweight or obese and that obesity management in patients with hypertension may be harder if they are being treated with a beta-blocker.

There are exceptions, however. When beta-blockers are required—for patients with coronary artery disease, heart failure, or an arrhythmia, for example—a selective agent with a vasodilating component, such as carvedilol or nebivolol, is recommended.² These drugs appear to have less potential for weight gain and to have minimal effect on lipid and glucose metabolism.^26,27

In a study of 1106 patients with hypertension, those taking metoprolol had a statistically significant mean weight gain of 1.19 kg (P<.001) compared with patients taking carvedilol (mean weight gain, 0.17 kg; P=.36).²⁴ While 4.5% of those in the metoprolol group gained ≥7% of their body weight, that was true of only 1.1% of those taking carvedilol. Thus, weight gain can sometimes be minimized by choosing a different medication within the same drug class.

ACE inhibitors, ARBs, and calcium channel blockers

Antihypertensive medications that are not associated with weight gain or insulin resistance include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) (TABLE 2).³ Angiotensin contributes to obesity-related hypertension, as it is overexpressed in obesity, making ACE inhibitors and ARBs desirable options for the treatment of patients who are obese. And, because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.

CASE 2 › Switching antihypertensives

Switching Ms. K from metoprolol, a beta-blocker, to an ACE inhibitor, ARB, or CCB may help prevent further weight gain, and possibly even lead to weight loss. Any drug in any of these 3 classes of medications would be a reasonable choice. However, if the patient had a condition that warranted use of a beta-blocker, a selective agent with a vasodilating component such as carvedilol or nebivolol might be helpful.

Choosing an antidepressant when weight is an issue

For patients with psychiatric conditions, weight gain is often multifactorial. One key issue: Weight gain is a common adverse effect of many antidepressants (TABLE 3).³ Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.²

In a meta-analysis of 116 studies, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline were associated with weight loss in short-term use (4-12 weeks) and weight neutrality when used for >4 months.¹ Patients who had type 2 diabetes as well as depression had an average weight loss from fluoxetine of 5.1 kg (3.3–6.9 kg) at 24- to 26-week follow up.²⁸

Because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.Among SSRI and tricyclic (TCA) antidepressants, paroxetine and amitriptyline, respectively, had the greatest risk for weight gain.^1,29 No significant weight effect was observed for either citalopram or escitalopram. Keep in mind, however, that the effect of each antidepressant on weight may vary greatly from one patient to another.¹ For example, while Mr. D gained 3.6 kg on paroxetine, some patients gain no weight at all.

In the systematic review and meta-analysis of 257 RCTs, weight gain was associated with the use of amitriptyline (1.8 kg) and mirtazapine (1.5 kg), while weight loss was associated with bupropion and fluoxetine (-1.3 kg for each).⁸

Bupropion, a norepinephrine and dopamine reuptake inhibitor, is the only antidepressant that has been consistently shown to cause weight loss.^30,31 Clinical trials have found that it decreases body weight by suppressing appetite and reducing food cravings.³⁰ Bupropion is approved for the treatment of depression and as a smoking cessation aide. And, in 2014, a bupropion-naltrexone combination received FDA approval for chronic weight management, sold under the brand name Contrave.³²

Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.

As different classes of antidepressants are often prescribed for different types of depression, it is important to be aware that the few that are weight-neutral and weight-loss-promoting are not appropriate for all patients with depression. For example, bupropion is an activating agent and can exacerbate anxiety. Thus, a patient with concomitant depression and anxiety might be a better candidate for another antidepressant, which could lead to some weight gain but would better manage the individual’s symptoms. In such cases, the rule of thumb should be to prescribe the lowest dose required for clinical efficacy for the shortest duration necessary.

CASE 3 › Change antidepressants— and keep a close watch

Depending on the nature of Mr. D’s depression, bupropion, fluoxetine, or sertraline might be a reasonable alternative to paroxetine to prevent or reduce further drug-induced weight gain.

Frequent follow-up visits should be scheduled until the transition has been completed and his condition stabilized. If Mr. D’s new antidepressant is bupropion, monitoring him for signs of anxiety would be required.

CORRESPONDENCE
Katherine H. Saunders, MD, Comprehensive Weight Control Center, Weill Cornell Medicine, 1165 York Avenue, New York, NY 10065; [email protected].

Medications can have an unpredictable and variable effect on weight. Some drugs trigger weight gain in one patient while inducing weight loss in another. Others may lead to weight loss initially but cause weight gain when taken long term.¹ Often, a drug’s effect on a patient’s weight depends on his or her medical history and lifestyle, including factors like insulin resistance, diet, and exercise level.

To make matters worse, clinical studies of drug-related effects on weight can be misleading. Because researchers often report a mean weight change—an average of those who had little or no change in weight when taking the drug and individuals who may have gained a significant amount of weight—a drug’s potential to cause weight gain may be underestimated. Few studies include an analysis of the range—eg, how many participants gained or lost various percentages of body weight. What’s more, pharmacology studies typically follow participants for a few months to a few years, whereas weight changes can be cumulative when a medication is taken for many years.

The nation’s continually growing obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain. Until recently, the medical literature offered little guidance.

In 2015, the Endocrine Society published clinical practice guidelines for pharmacologic management of obesity, including data on medications that cause weight gain and suggesting alternatives that are weight-neutral or promote weight loss.²

In the pages that follow, we present case studies, tables, and a review of the latest evidence to highlight optimal drug treatment for patients who are overweight or obese, and are also being treated for diabetes, hypertension, and depression. You’ll find a brief discussion of weight management strategies related to other drugs and conditions in the sidebar.^2-5

CASE 1 › 40-year-old man with diabetes and hyperlipidemia

Brian P, who has come in for an annual checkup, has a body mass index (BMI) of 30 kg/m². He also has hyperlipidemia and type 2 diabetes, for which he has been taking metformin for several years. A year ago, his hemoglobin A1c (HbA1c) was 7.3%, so his physician added glyburide to his regimen.

In the year since, Mr. P has gained 12 lbs (5.4 kg) but achieved only a minimal reduction in HbA1c (to 6.8%). He expresses concern about the cardiovascular effects of the extra weight and says that diet and exercise have not helped him control his weight.

CASE 2 › Older woman with hypertension and hypothyroidism

Addie K, age 64, is obese (BMI, 37 kg/m²) and has hypertension and hypothyroidism, for which she takes metoprolol and levothyroxine. Ms. K says that she is careful about what she eats and exercises several times a week, but still has seen her weight increase steadily for the past several years.

The nation's obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain.

CASE 3 › Young man with depression

Charlie D, a 21-year-old college student, is a new patient. He has depression and is obese (BMI, 34 kg/m²). The patient says he was diagnosed with depression by his former primary care physician, who prescribed paroxetine a year ago. He requests a refill of the paroxetine, which he reports has successfully boosted his mood. When asked about his weight, he admits that he has gained 8 lbs (3.6 kg) since he began taking the drug.

If these were your patients, what weight management steps would you take? Before we provide some recommendations, let’s review the evidence.

While some antidiabetic agents are weight-neutral and others promote weight loss, several therapies are associated with weight gain⁶ (TABLE 1³). Patients like Mr. P can gain as much as 10 kg in 3 to 6 months after beginning treatment with insulin, thiazolidinediones (TZDs), sulfonylureas, and other insulin secretagogues.^2,7

A recent systematic review and meta-analysis of 257 randomized controlled trials (RCTs) found weight gain to be associated with the use of pioglitazone (2.6 kg), glimepiride (2.1 kg), glyburide (2.6 kg), glipizide (2.2 kg), and sitagliptin (0.55 kg). A modest weight loss was associated with acarbose, exenatide, liraglutide, metformin, miglitol, and pramlintide.⁸

Sulfonylureas are generally associated with a 1.5 to 2.5 kg weight gain.^9-11 In an analysis of 27 RCTs of noninsulin antidiabetic drugs in patients whose disease was not controlled by metformin alone, TZDs, sulfonylureas, and meglitinides were associated with a 1.77 to 2.08 kg weight gain.⁹ Furthermore, those taking sulfonylureas and meglitinides had higher rates of hypoglycemia compared with patients taking placebo (relative risk, 4.50-7.50). In fact, sulfonylureas have the highest risk of serious hypoglycemia of any noninsulin therapy.⁶

In contrast, metformin—the most commonly prescribed oral agent for type 2 diabetes—promotes mild weight loss by multiple mechanisms and has a good safety profile.^12,13 Thus, some physicians use metformin off label for weight loss and diabetes prevention and have suggested that it be approved for these indications.¹³

Glycemic control and weight loss

Glucagon-like peptide-1 (GLP-1) agonists lead to weight loss by decreasing appetite and enhancing satiety, as well as improving glycemic control. Liraglutide received Food and Drug Administration (FDA) approval in 2014 as a treatment for chronic weight management at a higher dose (3 mg/d) than that used to treat diabetes (1.8 mg/d).¹⁴

For patients who are obese and who require insulin to manage type 2 diabetes, the Endocrine Society recommends concomitantly prescribing at least one weight loss-promoting medication.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic medication that reduce glucose reabsorption by the kidneys, leading to increased urinary glucose excretion.¹⁵ The associated weight loss, in addition to a reduction in hyperglycemia, may be due to the subsequent calorie loss through glycosuria.

Both dipeptidyl peptidase-4 (DPP-4) inhibitors and alpha-glucosidase inhibitors (AGIs) appear to be weight-neutral or to induce minimal changes in weight.¹⁶ Although the systematic review mentioned earlier found a 0.55 kg weight gain associated with sitagliptin,⁸ most studies of DPP-4 inhibitors report weight neutrality.^17-19 Pramlintide, the amylin analogue that has FDA approval for use in combination with existing insulin treatment, can prevent weight gain or lead to weight loss.^20,21

The Endocrine Society Clinical Practice Guideline recommends concomitantly prescribing at least one weight loss-promoting medication (such as metformin, a GLP-1 agonist, or pramlintide) to patients with obesity and type 2 diabetes who require insulin to mitigate weight gain due to insulin.²

The 2016 Comprehensive Type 2 Diabetes Management Algorithm published by the American Association of Clinical Endocrinologists and American College of Endocrinology recommends that the initiation of diabetes therapies be based on the risks of weight gain and hypoglycemia, among other factors. The algorithm calls for metformin as first-line therapy, followed by a GLP-1 agonist as a second-line therapy, and an SGLT2 inhibitor as a third-line therapy.⁶

Finally, FDA-approved anti-obesity medications may be appropriate for patients with diabetes who are unable to lose weight with lifestyle interventions alone.²² Each medication is associated with improvements in glucose in addition to other metabolic parameters.

CASE 1 › A better choice for Mr. P

Because Mr. P has gained weight—and, indeed, developed obesity—since he started taking glyburide, it is clear that a sulfonylurea is not the best choice for this patient. An antidiabetic agent that is weight-neutral or that promotes weight loss, such as an SGLT2 inhibitor or a GLP-1 agonist, would be more suitable. The drug should be prescribed in conjunction with his metformin, which has a favorable weight profile and helps reduce HbA1c, as both SGLT2 inhibitors and GLP-1 agonists also do.

If Mr. P were to switch to an SGLT2 inhibitor, a combination pill containing metformin would be an effective way to limit the patient’s pill burden.

Treating hypertension without weight gain

Thiazide diuretics are often recommended as first-line agents for the treatment of hypertension, but their dose-related adverse effects, including dyslipidemia and insulin resistance, are undesirable for patients who are overweight or obese and at risk for metabolic syndrome and type 2 diabetes.²³ Beta-adrenergic blockers have been shown to promote weight gain and prevent weight loss, especially in patients who have both hypertension and diabetes.²⁴ In addition to having potential adverse metabolic effects on lipids and/or insulin sensitivity, beta-blockers can decrease metabolic rate by 10% and they may have other negative effects on energy metabolism, as well.²⁵

When a patient who is obese has a condition for which a beta-blocker is a necessity, a selective agent with a vasodilating component is recommended.

In a meta-analysis of 8 RCTs that lasted ≥6 months, changes in body weight were higher in participants on beta-blockers, with a median difference of 1.2 kg (−0.4 to 3.5 kg) between those on beta-blockers and the control group.²⁶ The evidence suggests that beta-blockers should not necessarily be first-line treatment for hypertension in patients who are overweight or obese and that obesity management in patients with hypertension may be harder if they are being treated with a beta-blocker.

There are exceptions, however. When beta-blockers are required—for patients with coronary artery disease, heart failure, or an arrhythmia, for example—a selective agent with a vasodilating component, such as carvedilol or nebivolol, is recommended.² These drugs appear to have less potential for weight gain and to have minimal effect on lipid and glucose metabolism.^26,27

In a study of 1106 patients with hypertension, those taking metoprolol had a statistically significant mean weight gain of 1.19 kg (P<.001) compared with patients taking carvedilol (mean weight gain, 0.17 kg; P=.36).²⁴ While 4.5% of those in the metoprolol group gained ≥7% of their body weight, that was true of only 1.1% of those taking carvedilol. Thus, weight gain can sometimes be minimized by choosing a different medication within the same drug class.

ACE inhibitors, ARBs, and calcium channel blockers

Antihypertensive medications that are not associated with weight gain or insulin resistance include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) (TABLE 2).³ Angiotensin contributes to obesity-related hypertension, as it is overexpressed in obesity, making ACE inhibitors and ARBs desirable options for the treatment of patients who are obese. And, because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.

CASE 2 › Switching antihypertensives

Switching Ms. K from metoprolol, a beta-blocker, to an ACE inhibitor, ARB, or CCB may help prevent further weight gain, and possibly even lead to weight loss. Any drug in any of these 3 classes of medications would be a reasonable choice. However, if the patient had a condition that warranted use of a beta-blocker, a selective agent with a vasodilating component such as carvedilol or nebivolol might be helpful.

Choosing an antidepressant when weight is an issue

For patients with psychiatric conditions, weight gain is often multifactorial. One key issue: Weight gain is a common adverse effect of many antidepressants (TABLE 3).³ Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.²

In a meta-analysis of 116 studies, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline were associated with weight loss in short-term use (4-12 weeks) and weight neutrality when used for >4 months.¹ Patients who had type 2 diabetes as well as depression had an average weight loss from fluoxetine of 5.1 kg (3.3–6.9 kg) at 24- to 26-week follow up.²⁸

Because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.Among SSRI and tricyclic (TCA) antidepressants, paroxetine and amitriptyline, respectively, had the greatest risk for weight gain.^1,29 No significant weight effect was observed for either citalopram or escitalopram. Keep in mind, however, that the effect of each antidepressant on weight may vary greatly from one patient to another.¹ For example, while Mr. D gained 3.6 kg on paroxetine, some patients gain no weight at all.

In the systematic review and meta-analysis of 257 RCTs, weight gain was associated with the use of amitriptyline (1.8 kg) and mirtazapine (1.5 kg), while weight loss was associated with bupropion and fluoxetine (-1.3 kg for each).⁸

Bupropion, a norepinephrine and dopamine reuptake inhibitor, is the only antidepressant that has been consistently shown to cause weight loss.^30,31 Clinical trials have found that it decreases body weight by suppressing appetite and reducing food cravings.³⁰ Bupropion is approved for the treatment of depression and as a smoking cessation aide. And, in 2014, a bupropion-naltrexone combination received FDA approval for chronic weight management, sold under the brand name Contrave.³²

Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.

As different classes of antidepressants are often prescribed for different types of depression, it is important to be aware that the few that are weight-neutral and weight-loss-promoting are not appropriate for all patients with depression. For example, bupropion is an activating agent and can exacerbate anxiety. Thus, a patient with concomitant depression and anxiety might be a better candidate for another antidepressant, which could lead to some weight gain but would better manage the individual’s symptoms. In such cases, the rule of thumb should be to prescribe the lowest dose required for clinical efficacy for the shortest duration necessary.

CASE 3 › Change antidepressants— and keep a close watch

Depending on the nature of Mr. D’s depression, bupropion, fluoxetine, or sertraline might be a reasonable alternative to paroxetine to prevent or reduce further drug-induced weight gain.

Frequent follow-up visits should be scheduled until the transition has been completed and his condition stabilized. If Mr. D’s new antidepressant is bupropion, monitoring him for signs of anxiety would be required.

CORRESPONDENCE
Katherine H. Saunders, MD, Comprehensive Weight Control Center, Weill Cornell Medicine, 1165 York Avenue, New York, NY 10065; [email protected].

Medications can have an unpredictable and variable effect on weight. Some drugs trigger weight gain in one patient while inducing weight loss in another. Others may lead to weight loss initially but cause weight gain when taken long term.¹ Often, a drug’s effect on a patient’s weight depends on his or her medical history and lifestyle, including factors like insulin resistance, diet, and exercise level.

To make matters worse, clinical studies of drug-related effects on weight can be misleading. Because researchers often report a mean weight change—an average of those who had little or no change in weight when taking the drug and individuals who may have gained a significant amount of weight—a drug’s potential to cause weight gain may be underestimated. Few studies include an analysis of the range—eg, how many participants gained or lost various percentages of body weight. What’s more, pharmacology studies typically follow participants for a few months to a few years, whereas weight changes can be cumulative when a medication is taken for many years.

The nation’s continually growing obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain. Until recently, the medical literature offered little guidance.

In 2015, the Endocrine Society published clinical practice guidelines for pharmacologic management of obesity, including data on medications that cause weight gain and suggesting alternatives that are weight-neutral or promote weight loss.²

In the pages that follow, we present case studies, tables, and a review of the latest evidence to highlight optimal drug treatment for patients who are overweight or obese, and are also being treated for diabetes, hypertension, and depression. You’ll find a brief discussion of weight management strategies related to other drugs and conditions in the sidebar.^2-5

CASE 1 › 40-year-old man with diabetes and hyperlipidemia

Brian P, who has come in for an annual checkup, has a body mass index (BMI) of 30 kg/m². He also has hyperlipidemia and type 2 diabetes, for which he has been taking metformin for several years. A year ago, his hemoglobin A1c (HbA1c) was 7.3%, so his physician added glyburide to his regimen.

In the year since, Mr. P has gained 12 lbs (5.4 kg) but achieved only a minimal reduction in HbA1c (to 6.8%). He expresses concern about the cardiovascular effects of the extra weight and says that diet and exercise have not helped him control his weight.

CASE 2 › Older woman with hypertension and hypothyroidism

Addie K, age 64, is obese (BMI, 37 kg/m²) and has hypertension and hypothyroidism, for which she takes metoprolol and levothyroxine. Ms. K says that she is careful about what she eats and exercises several times a week, but still has seen her weight increase steadily for the past several years.

The nation's obesity epidemic makes it crucial for physicians to consider the weight effects of medications being prescribed and to balance the benefits of treatment with the potential for weight gain.

CASE 3 › Young man with depression

Charlie D, a 21-year-old college student, is a new patient. He has depression and is obese (BMI, 34 kg/m²). The patient says he was diagnosed with depression by his former primary care physician, who prescribed paroxetine a year ago. He requests a refill of the paroxetine, which he reports has successfully boosted his mood. When asked about his weight, he admits that he has gained 8 lbs (3.6 kg) since he began taking the drug.

If these were your patients, what weight management steps would you take? Before we provide some recommendations, let’s review the evidence.

While some antidiabetic agents are weight-neutral and others promote weight loss, several therapies are associated with weight gain⁶ (TABLE 1³). Patients like Mr. P can gain as much as 10 kg in 3 to 6 months after beginning treatment with insulin, thiazolidinediones (TZDs), sulfonylureas, and other insulin secretagogues.^2,7

A recent systematic review and meta-analysis of 257 randomized controlled trials (RCTs) found weight gain to be associated with the use of pioglitazone (2.6 kg), glimepiride (2.1 kg), glyburide (2.6 kg), glipizide (2.2 kg), and sitagliptin (0.55 kg). A modest weight loss was associated with acarbose, exenatide, liraglutide, metformin, miglitol, and pramlintide.⁸

Sulfonylureas are generally associated with a 1.5 to 2.5 kg weight gain.^9-11 In an analysis of 27 RCTs of noninsulin antidiabetic drugs in patients whose disease was not controlled by metformin alone, TZDs, sulfonylureas, and meglitinides were associated with a 1.77 to 2.08 kg weight gain.⁹ Furthermore, those taking sulfonylureas and meglitinides had higher rates of hypoglycemia compared with patients taking placebo (relative risk, 4.50-7.50). In fact, sulfonylureas have the highest risk of serious hypoglycemia of any noninsulin therapy.⁶

In contrast, metformin—the most commonly prescribed oral agent for type 2 diabetes—promotes mild weight loss by multiple mechanisms and has a good safety profile.^12,13 Thus, some physicians use metformin off label for weight loss and diabetes prevention and have suggested that it be approved for these indications.¹³

Glycemic control and weight loss

Glucagon-like peptide-1 (GLP-1) agonists lead to weight loss by decreasing appetite and enhancing satiety, as well as improving glycemic control. Liraglutide received Food and Drug Administration (FDA) approval in 2014 as a treatment for chronic weight management at a higher dose (3 mg/d) than that used to treat diabetes (1.8 mg/d).¹⁴

For patients who are obese and who require insulin to manage type 2 diabetes, the Endocrine Society recommends concomitantly prescribing at least one weight loss-promoting medication.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of antidiabetic medication that reduce glucose reabsorption by the kidneys, leading to increased urinary glucose excretion.¹⁵ The associated weight loss, in addition to a reduction in hyperglycemia, may be due to the subsequent calorie loss through glycosuria.

Both dipeptidyl peptidase-4 (DPP-4) inhibitors and alpha-glucosidase inhibitors (AGIs) appear to be weight-neutral or to induce minimal changes in weight.¹⁶ Although the systematic review mentioned earlier found a 0.55 kg weight gain associated with sitagliptin,⁸ most studies of DPP-4 inhibitors report weight neutrality.^17-19 Pramlintide, the amylin analogue that has FDA approval for use in combination with existing insulin treatment, can prevent weight gain or lead to weight loss.^20,21

The Endocrine Society Clinical Practice Guideline recommends concomitantly prescribing at least one weight loss-promoting medication (such as metformin, a GLP-1 agonist, or pramlintide) to patients with obesity and type 2 diabetes who require insulin to mitigate weight gain due to insulin.²

The 2016 Comprehensive Type 2 Diabetes Management Algorithm published by the American Association of Clinical Endocrinologists and American College of Endocrinology recommends that the initiation of diabetes therapies be based on the risks of weight gain and hypoglycemia, among other factors. The algorithm calls for metformin as first-line therapy, followed by a GLP-1 agonist as a second-line therapy, and an SGLT2 inhibitor as a third-line therapy.⁶

Finally, FDA-approved anti-obesity medications may be appropriate for patients with diabetes who are unable to lose weight with lifestyle interventions alone.²² Each medication is associated with improvements in glucose in addition to other metabolic parameters.

CASE 1 › A better choice for Mr. P

Because Mr. P has gained weight—and, indeed, developed obesity—since he started taking glyburide, it is clear that a sulfonylurea is not the best choice for this patient. An antidiabetic agent that is weight-neutral or that promotes weight loss, such as an SGLT2 inhibitor or a GLP-1 agonist, would be more suitable. The drug should be prescribed in conjunction with his metformin, which has a favorable weight profile and helps reduce HbA1c, as both SGLT2 inhibitors and GLP-1 agonists also do.

If Mr. P were to switch to an SGLT2 inhibitor, a combination pill containing metformin would be an effective way to limit the patient’s pill burden.

Treating hypertension without weight gain

Thiazide diuretics are often recommended as first-line agents for the treatment of hypertension, but their dose-related adverse effects, including dyslipidemia and insulin resistance, are undesirable for patients who are overweight or obese and at risk for metabolic syndrome and type 2 diabetes.²³ Beta-adrenergic blockers have been shown to promote weight gain and prevent weight loss, especially in patients who have both hypertension and diabetes.²⁴ In addition to having potential adverse metabolic effects on lipids and/or insulin sensitivity, beta-blockers can decrease metabolic rate by 10% and they may have other negative effects on energy metabolism, as well.²⁵

When a patient who is obese has a condition for which a beta-blocker is a necessity, a selective agent with a vasodilating component is recommended.

In a meta-analysis of 8 RCTs that lasted ≥6 months, changes in body weight were higher in participants on beta-blockers, with a median difference of 1.2 kg (−0.4 to 3.5 kg) between those on beta-blockers and the control group.²⁶ The evidence suggests that beta-blockers should not necessarily be first-line treatment for hypertension in patients who are overweight or obese and that obesity management in patients with hypertension may be harder if they are being treated with a beta-blocker.

There are exceptions, however. When beta-blockers are required—for patients with coronary artery disease, heart failure, or an arrhythmia, for example—a selective agent with a vasodilating component, such as carvedilol or nebivolol, is recommended.² These drugs appear to have less potential for weight gain and to have minimal effect on lipid and glucose metabolism.^26,27

In a study of 1106 patients with hypertension, those taking metoprolol had a statistically significant mean weight gain of 1.19 kg (P<.001) compared with patients taking carvedilol (mean weight gain, 0.17 kg; P=.36).²⁴ While 4.5% of those in the metoprolol group gained ≥7% of their body weight, that was true of only 1.1% of those taking carvedilol. Thus, weight gain can sometimes be minimized by choosing a different medication within the same drug class.

ACE inhibitors, ARBs, and calcium channel blockers

Antihypertensive medications that are not associated with weight gain or insulin resistance include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) (TABLE 2).³ Angiotensin contributes to obesity-related hypertension, as it is overexpressed in obesity, making ACE inhibitors and ARBs desirable options for the treatment of patients who are obese. And, because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.

CASE 2 › Switching antihypertensives

Switching Ms. K from metoprolol, a beta-blocker, to an ACE inhibitor, ARB, or CCB may help prevent further weight gain, and possibly even lead to weight loss. Any drug in any of these 3 classes of medications would be a reasonable choice. However, if the patient had a condition that warranted use of a beta-blocker, a selective agent with a vasodilating component such as carvedilol or nebivolol might be helpful.

Choosing an antidepressant when weight is an issue

For patients with psychiatric conditions, weight gain is often multifactorial. One key issue: Weight gain is a common adverse effect of many antidepressants (TABLE 3).³ Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.²

In a meta-analysis of 116 studies, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline were associated with weight loss in short-term use (4-12 weeks) and weight neutrality when used for >4 months.¹ Patients who had type 2 diabetes as well as depression had an average weight loss from fluoxetine of 5.1 kg (3.3–6.9 kg) at 24- to 26-week follow up.²⁸

Because many patients who are obese also suffer from type 2 diabetes or prediabetes, they’re likely to benefit from the renal protection provided by ACE inhibitors and ARBs, as well.Among SSRI and tricyclic (TCA) antidepressants, paroxetine and amitriptyline, respectively, had the greatest risk for weight gain.^1,29 No significant weight effect was observed for either citalopram or escitalopram. Keep in mind, however, that the effect of each antidepressant on weight may vary greatly from one patient to another.¹ For example, while Mr. D gained 3.6 kg on paroxetine, some patients gain no weight at all.

In the systematic review and meta-analysis of 257 RCTs, weight gain was associated with the use of amitriptyline (1.8 kg) and mirtazapine (1.5 kg), while weight loss was associated with bupropion and fluoxetine (-1.3 kg for each).⁸

Bupropion, a norepinephrine and dopamine reuptake inhibitor, is the only antidepressant that has been consistently shown to cause weight loss.^30,31 Clinical trials have found that it decreases body weight by suppressing appetite and reducing food cravings.³⁰ Bupropion is approved for the treatment of depression and as a smoking cessation aide. And, in 2014, a bupropion-naltrexone combination received FDA approval for chronic weight management, sold under the brand name Contrave.³²

Within classes of antidepressants, there is a range of weight gain potential, which can vary depending on the duration of therapy.

As different classes of antidepressants are often prescribed for different types of depression, it is important to be aware that the few that are weight-neutral and weight-loss-promoting are not appropriate for all patients with depression. For example, bupropion is an activating agent and can exacerbate anxiety. Thus, a patient with concomitant depression and anxiety might be a better candidate for another antidepressant, which could lead to some weight gain but would better manage the individual’s symptoms. In such cases, the rule of thumb should be to prescribe the lowest dose required for clinical efficacy for the shortest duration necessary.

CASE 3 › Change antidepressants— and keep a close watch

Depending on the nature of Mr. D’s depression, bupropion, fluoxetine, or sertraline might be a reasonable alternative to paroxetine to prevent or reduce further drug-induced weight gain.

Frequent follow-up visits should be scheduled until the transition has been completed and his condition stabilized. If Mr. D’s new antidepressant is bupropion, monitoring him for signs of anxiety would be required.

CORRESPONDENCE
Katherine H. Saunders, MD, Comprehensive Weight Control Center, Weill Cornell Medicine, 1165 York Avenue, New York, NY 10065; [email protected].

ABSTRACT

Purpose To determine the characteristics and clinical course of Rhus dermatitis in patients who seek assistance from primary care clinicians, as well as treatment approaches used by patients and recommended by clinicians, and treatment approaches associated with better outcomes.

Methods This was a prospective cohort study with standardized baseline data collection on patients and their rashes, followed by examination of patient-completed diaries of signs, symptoms, and treatments.

Results Thirty-six clinicians identified 186 interested patients, of which 89 completed and returned diaries and consent forms. Of those 89 patients, 92% reported pruritus; 91%, erythema; 87%, papules; and 49%, vesicles or bullae at baseline. Their rashes involved the head/face/neck, 61%; trunk, 56%; legs, 54%; and arms, 22%.

Patients seeking help for poison ivy can expect the rash to last an additional 2 weeks on average, regardless of the treatment prescribed.From the date of clinical consultation, the mean (standard deviation [SD]; range) duration of any symptom or sign was 14.4 days (8.0; 1-43). Patients most often had tried a topical antipruritic, astringent, or low-potency corticosteroid before seeking care. Clinicians prescribed oral or parenteral corticosteroids 81% of the time, sometimes in combination with a high-potency topical corticosteroid (25%) or oral antihistamine (31%). Only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles.

Conclusions Patients who visit a primary care clinician for Rhus dermatitis can expect the rash to last another 2 weeks on average (total duration: one day to 6 weeks) regardless of what treatment is prescribed. Parenteral corticosteroids plus high-potency topical corticosteroids may reduce the duration of the itching.

Rhus dermatitis (poison ivy, oak, and sumac) is a common cause of contact dermatitis throughout the United States. The condition is usually mild and often not brought to the attention of primary care clinicians. Some patients, however, do see a health care provider for treatment, most often because of pruritus. This form of contact dermatitis results from a type IV hypersensitivity reaction to urushiol, a colorless oil in the leaves, stem, root, and fruit of poison ivy, poison oak, and poison sumac. The reaction, which occurs 24 to 72 hours following contact with the skin, can be prevented by washing the skin promptly with a detergent soap after exposure. By the age of 8, most people are sensitized to urushiol.¹

According to most standard texts and clinical reviews, untreated Rhus dermatitis usually resolves in one to 3 weeks. What is not known is whether particular patient or rash characteristics might affect prognosis and thereby influence treatment recommendations—eg, age, gender, race, location of the rash, prior episodes, chronic illnesses such as diabetes, or chronic use of medications such as nonsteroidal anti-inflammatory drugs and corticosteroids.

Impetus for our study. An informal survey of 10 clinician members of the Oklahoma Physicians Resource/Research Network (OKPRN), a statewide practice-based research network, suggested that primary care clinicians treat between one and 10 patients with poison ivy each week during the spring, summer, and fall (median 2.5). Their reported armamentarium included more than 15 different over-the-counter topical agents, several oral antihistamines, and a variety of topical, oral, and parenteral corticosteroids.

Systemic corticosteroids plus high-potency topical corticosteroids reduced the duration of itching.Surprisingly, there is very little published evidence on which to base treatment decisions. Using PubMed and the search terms, Rhus dermatitis, poison ivy, and poison oak, we found only 3 placebo-controlled clinical trials of Rhus dermatitis treatments in the English language literature after 1966. Based on these studies, Zanfel, a mixture of alcohol-soluble and anionic surfactant, may be somewhat effective, but pimecrolimus and jewelweed extract were no more effective than placebo.^2-4 There is some evidence that topical corticosteroids are effective only before vesicles appear.⁵ In one uncontrolled study, intramuscular injection of betamethasone and dexamethasone yielded about a 30% reduction in symptoms within 48 hours.⁶ Assuming that systemic corticosteroids do produce benefit, however, the most effective dose and duration of treatment have not been determined.^7,8

To address some of these gaps in our knowledge base, OKPRN members asked that we undertake a longitudinal cohort study of patients reporting to primary care practices.

We conducted this study between May 2010 and October 2014. The project was approved by the University of Oklahoma Health Sciences Center Institutional Review Board. Clinician members of OKPRN were invited to participate in the study via listserv, fax, or letter. We instructed clinicians and office staff to ask patients with Rhus dermatitis if they might be interested in participating in a study, which would require that they keep a symptom diary and would earn them a $20 gift card. Interested patients were given a packet of information, and a member of the research team later called the patients with additional information, including an explanation of informed consent and instructions on completing and returning the diary and written consent form.

Clinicians recorded information about the patient and the rash on a customized template, releasing it to the team after written consent was obtained from the patient. Categories for characterizing the rash were head/face, arms/hands, trunk, and legs/feet. A subset of 5 participating clinicians, selected to include a variety of practice types and patient populations, were also asked to produce, from their billing software, the number of patients and encounters in which poison ivy was addressed in each month of 2013.

On the diary, patients were instructed to record the presence or absence of pruritus, erythema, raised lesions, and vesicles/bullae at the end of each day until the rash resolved, or for 6 weeks following onset of the rash, whichever came first. Patients were asked to mail their diaries to the principal investigator once they were free of symptoms for one week or after 6 weeks from the onset of symptoms, whichever came first.

We asked both patients and clinicians to report medications used before and after the primary care encounter. A member of the research team assigned these medications to one of 12 categories: topical antihistamines, topical soaps (eg, Zanfel or Tecnu), topical astringents, other topical antipruritics, topical aloe vera, topical bleach, low-potency topical corticosteroids, moderate-potency topical corticosteroids, high-potency topical corticosteroids, oral antihistamines, oral corticosteroids, and parenteral corticosteroids.

We used independent T-tests to evaluate associations between baseline variables, patient-initiated treatments, and clinician-initiated treatments and the time to complete resolution of individual signs and symptoms and complete resolution of all signs and symptoms following the clinical encounter. We created additional outcome variables for initial resolution followed by recurrence of itching, erythema, papules, and vesicles. The purpose of these variables was to determine if some treatments were initially effective but without lasting effect.

We used the chi square test to assess associations between clinician-initiated treatments and recurrence of signs or symptoms following initial resolution. To account for chance associations resulting from multiple analyses, we chose to set the level of statistical significance at P=.01. However, because of the lower-than-projected sample size, we chose to also report variables with P<.05 so that the reader could judge the likelihood that a larger sample might have disclosed other important associations.

We assumed that an average of 4 categories of treatment would be tried (eg, topical corticosteroids, systemic corticosteroids, topical antihistamines, and other topical agents), and that the mean number of days until resolution would be 21, with a standard deviation (SD) of 4 days. Setting power at 80% and alpha at .05, we calculated it would take 105 patients per group (N=420) to detect a difference of 2 days in time until resolution.

RESULTS

Over the 5-year study period, 36 clinicians identified 186 patients who expressed an interest in the study, and they transmitted the patient contact information to the research team. Patients were seen in a traditional primary care setting. All 186 patients were enrolled by phone. However, only 89 completed and returned their diaries and signed consent forms; of these, 60% were female, 92% were white, 4% were black, 4% were American Indians, 2% were Hispanic, and 7% had diabetes mellitus.

Five practices contributed data on numbers of poison ivy encounters per month and total encounters per month for the year 2013. They included an inner city academic practice in central Oklahoma and a rural community health center, a suburban private practice, and 2 private practices in a town of 30,000 in eastern Oklahoma. The largest average number of encounters occurred between April and August.

The distribution of enrolled-patient visits by month and season corresponded roughly to the proportions of all patient visits for poison ivy, with 1% occurring in the winter, 35% in the spring, 55% during the summer, and 9% in the fall. Virtually all study participants (92%) complained of pruritus and had erythema (91%) and papules (87%). Forty-nine percent had vesicles or bullae. The area of the body most often affected was the head/face/­­neck, 61%, followed by the trunk, 56%; legs, 54%; and arms, 22%.

From the date of initial clinical consultation, the mean/median (SD; range) duration of symptoms and signs were: pruritus, 10.9/9 days (7.1; 0-43); erythema, 13.7/13 days (7.7; 0-42); papules, 10.1/9.5 days (6.5; 0-37); and vesicles, 5.3/5 days (4.1; 0-15). The mean/median (SD; range) duration of any symptom or sign was 14.4/13.5 days (8; 1-43). Rashes with vesicles tended to last longer (16.1 vs 12.9 days), but this difference did not reach statistical significance.

Treatments used by patients before and after their primary care visit are shown in TABLE 1. Seventy-three percent of patients had tried something from one treatment category before consulting a clinician, and 31% had tried something from more than one category. They were most likely to have used a topical antipruritic, astringent, or low-potency corticosteroid, or a combination of these. Clinicians always recommended some treatment and, in 76% of cases, treatments from more than one category. They most often prescribed oral or parenteral corticosteroids (81% of the time), sometimes in combination with a high-potency topical corticosteroid (25% of the time) or oral antihistamine (31%). Oral corticosteroids were used for an average of 11 days; parenteral corticosteroids were given once. Oral antihistamines were recommended for 30% of patients, with an average course duration of 13 days. Clinicians did not prescribe systemic corticosteroids or any other treatment type more often based on location of the rash or presence of vesicles.

No statistically significant associations were found between the baseline non-treatment variables and duration of symptoms and signs. Patient-initiated treatments were also not associated with duration of symptoms and signs following the initial clinician visit.

Of the treatments prescribed by clinicians or independently chosen by patients following their initial office visit, only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles. Use of topical soaps was associated with a longer duration of papules (P<.0001) and of total duration of signs or symptoms (P=.0004) compared with other treatments.

Location and characteristics of the rash were not associated with likelihood of recurrence following treatment. Post-visit use of a topical soap was associated with recurrence of itching (P=.001) and erythema (P=.01). Recurrence of erythema was also more frequent in patients prescribed topical astringents (beta coefficient=0.28; P=.008), and recurrence of papules was more common in patients treated with low-potency topical corticosteroids (P<.0001). These results and several others that almost reached statistical significance are shown in TABLE 2.

In the multivariable models, the only variable associated with duration of pruritus was the combination of systemic and high-potency topical corticosteroids (8 vs 12 days.) Use of only parenteral or only high-potency topical corticosteroids did not predict shorter duration of pruritus. Use of topical soaps was associated with longer duration of papules (33 vs 9.6 days) and longer duration of any symptoms (33 vs 13.9 days). It was also associated with a higher likelihood of recurrence of pruritus (chi square test [χ²], 10.67) and recurrence of erythema (χ², 5.92) after initial resolution. Topical astringent use was predictive of recurrence of erythema (χ², 7.01) and use of low-potency corticosteroids was associated with recurrence of papules (χ², 20.96).

DISCUSSION

While network clinicians felt that studying poison ivy was of interest and importance, and we had preliminary survey information to suggest it was a common problem treated in primary care, our data suggest that clinical encounters for poison ivy are actually quite uncommon (less than 0.4% of all encounters) even during peak months. Our problems with recruitment were therefore unexpected, and we ended up with far fewer enrolled patients than we had projected, and needed, based on our power analysis. Also based on our preliminary survey, we anticipated considerably more variation in treatment approach than we found. Most clinicians recommended either an oral, parenteral, or high-potency topical corticosteroid, and some also recommended an oral antihistamine, usually diphenhydramine.

The literature and common sense suggest that most patients who seek medical treatment for poison ivy are primarily concerned about itching. Even with the smaller-than-anticipated number of participants in this study, we were able to show that the combination of a systemic (oral or parenteral) corticosteroid and a high-potency topical corticosteroid was associated with a statistically significant shorter duration of pruritus with no recurrence following treatment. We found no evidence that systemic corticosteroids alone, parenteral corticosteroids alone, or high-potency topical corticosteroids alone had any effect on duration of signs or symptoms, even at an alpha of .05. We also found no evidence that oral antihistamines were associated with a shorter duration of pruritus (P=.06); with a larger sample size, we might have found a difference.

Since only 2 patients used topical soaps following their initial clinician visit, the associations between use of these products and longer duration of signs and symptoms and with recurrence of signs and symptoms, although statistically significant, should be viewed with skepticism and with an eye toward possible confounders (eg, people who used these agents may have been more likely to notice and record minor symptoms). Furthermore, these agents have been effective only when used before or at the onset of the rash.

Study limitations. The study has a number of limitations. It had a high drop-out rate. Some patients might not have had poison ivy, but it is generally considered easy to diagnose with accuracy. We cannot be sure that all of the enrolled patients had Rhus dermatitis. Enrollment was based on the clinical impression of the patients’ primary care clinicians. The sample size reduced the power of the study to detect small differences in treatment effects and prevented more complex analyses (eg, combinations of medications, interactions).

The possibility of self-selection bias, weaknesses of the cohort design, and patient-reported outcome measures were additional limitations. The study was also carried out in a single southwestern state, which may not be representative of some other locations. However, it is one of only a few studies published on Rhus dermatitis and possibly the only one conducted in primary care settings.

CORRESPONDENCE
Cara Vaught, MPH, University of Oklahoma Health Sciences Center, Department of Family and Preventive Medicine, 900 NE 10th Street, Oklahoma City, OK 73104; [email protected].

ACKNOWLEDGEMENT
The authors thank the Oklahoma Physicians Resource/Research Network (OKPRN) and the OKPRN clinician members (as well as their staff and patients) for their contributions to this study. The authors also thank Bradley Long, Matthew Marr, and Kellie Hetherington for their involvement in the data collection for this study.

ABSTRACT

Purpose To determine the characteristics and clinical course of Rhus dermatitis in patients who seek assistance from primary care clinicians, as well as treatment approaches used by patients and recommended by clinicians, and treatment approaches associated with better outcomes.

Methods This was a prospective cohort study with standardized baseline data collection on patients and their rashes, followed by examination of patient-completed diaries of signs, symptoms, and treatments.

Results Thirty-six clinicians identified 186 interested patients, of which 89 completed and returned diaries and consent forms. Of those 89 patients, 92% reported pruritus; 91%, erythema; 87%, papules; and 49%, vesicles or bullae at baseline. Their rashes involved the head/face/neck, 61%; trunk, 56%; legs, 54%; and arms, 22%.

Patients seeking help for poison ivy can expect the rash to last an additional 2 weeks on average, regardless of the treatment prescribed.From the date of clinical consultation, the mean (standard deviation [SD]; range) duration of any symptom or sign was 14.4 days (8.0; 1-43). Patients most often had tried a topical antipruritic, astringent, or low-potency corticosteroid before seeking care. Clinicians prescribed oral or parenteral corticosteroids 81% of the time, sometimes in combination with a high-potency topical corticosteroid (25%) or oral antihistamine (31%). Only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles.

Conclusions Patients who visit a primary care clinician for Rhus dermatitis can expect the rash to last another 2 weeks on average (total duration: one day to 6 weeks) regardless of what treatment is prescribed. Parenteral corticosteroids plus high-potency topical corticosteroids may reduce the duration of the itching.

Rhus dermatitis (poison ivy, oak, and sumac) is a common cause of contact dermatitis throughout the United States. The condition is usually mild and often not brought to the attention of primary care clinicians. Some patients, however, do see a health care provider for treatment, most often because of pruritus. This form of contact dermatitis results from a type IV hypersensitivity reaction to urushiol, a colorless oil in the leaves, stem, root, and fruit of poison ivy, poison oak, and poison sumac. The reaction, which occurs 24 to 72 hours following contact with the skin, can be prevented by washing the skin promptly with a detergent soap after exposure. By the age of 8, most people are sensitized to urushiol.¹

According to most standard texts and clinical reviews, untreated Rhus dermatitis usually resolves in one to 3 weeks. What is not known is whether particular patient or rash characteristics might affect prognosis and thereby influence treatment recommendations—eg, age, gender, race, location of the rash, prior episodes, chronic illnesses such as diabetes, or chronic use of medications such as nonsteroidal anti-inflammatory drugs and corticosteroids.

Impetus for our study. An informal survey of 10 clinician members of the Oklahoma Physicians Resource/Research Network (OKPRN), a statewide practice-based research network, suggested that primary care clinicians treat between one and 10 patients with poison ivy each week during the spring, summer, and fall (median 2.5). Their reported armamentarium included more than 15 different over-the-counter topical agents, several oral antihistamines, and a variety of topical, oral, and parenteral corticosteroids.

Systemic corticosteroids plus high-potency topical corticosteroids reduced the duration of itching.Surprisingly, there is very little published evidence on which to base treatment decisions. Using PubMed and the search terms, Rhus dermatitis, poison ivy, and poison oak, we found only 3 placebo-controlled clinical trials of Rhus dermatitis treatments in the English language literature after 1966. Based on these studies, Zanfel, a mixture of alcohol-soluble and anionic surfactant, may be somewhat effective, but pimecrolimus and jewelweed extract were no more effective than placebo.^2-4 There is some evidence that topical corticosteroids are effective only before vesicles appear.⁵ In one uncontrolled study, intramuscular injection of betamethasone and dexamethasone yielded about a 30% reduction in symptoms within 48 hours.⁶ Assuming that systemic corticosteroids do produce benefit, however, the most effective dose and duration of treatment have not been determined.^7,8

To address some of these gaps in our knowledge base, OKPRN members asked that we undertake a longitudinal cohort study of patients reporting to primary care practices.

We conducted this study between May 2010 and October 2014. The project was approved by the University of Oklahoma Health Sciences Center Institutional Review Board. Clinician members of OKPRN were invited to participate in the study via listserv, fax, or letter. We instructed clinicians and office staff to ask patients with Rhus dermatitis if they might be interested in participating in a study, which would require that they keep a symptom diary and would earn them a $20 gift card. Interested patients were given a packet of information, and a member of the research team later called the patients with additional information, including an explanation of informed consent and instructions on completing and returning the diary and written consent form.

Clinicians recorded information about the patient and the rash on a customized template, releasing it to the team after written consent was obtained from the patient. Categories for characterizing the rash were head/face, arms/hands, trunk, and legs/feet. A subset of 5 participating clinicians, selected to include a variety of practice types and patient populations, were also asked to produce, from their billing software, the number of patients and encounters in which poison ivy was addressed in each month of 2013.

On the diary, patients were instructed to record the presence or absence of pruritus, erythema, raised lesions, and vesicles/bullae at the end of each day until the rash resolved, or for 6 weeks following onset of the rash, whichever came first. Patients were asked to mail their diaries to the principal investigator once they were free of symptoms for one week or after 6 weeks from the onset of symptoms, whichever came first.

We asked both patients and clinicians to report medications used before and after the primary care encounter. A member of the research team assigned these medications to one of 12 categories: topical antihistamines, topical soaps (eg, Zanfel or Tecnu), topical astringents, other topical antipruritics, topical aloe vera, topical bleach, low-potency topical corticosteroids, moderate-potency topical corticosteroids, high-potency topical corticosteroids, oral antihistamines, oral corticosteroids, and parenteral corticosteroids.

We used independent T-tests to evaluate associations between baseline variables, patient-initiated treatments, and clinician-initiated treatments and the time to complete resolution of individual signs and symptoms and complete resolution of all signs and symptoms following the clinical encounter. We created additional outcome variables for initial resolution followed by recurrence of itching, erythema, papules, and vesicles. The purpose of these variables was to determine if some treatments were initially effective but without lasting effect.

We used the chi square test to assess associations between clinician-initiated treatments and recurrence of signs or symptoms following initial resolution. To account for chance associations resulting from multiple analyses, we chose to set the level of statistical significance at P=.01. However, because of the lower-than-projected sample size, we chose to also report variables with P<.05 so that the reader could judge the likelihood that a larger sample might have disclosed other important associations.

We assumed that an average of 4 categories of treatment would be tried (eg, topical corticosteroids, systemic corticosteroids, topical antihistamines, and other topical agents), and that the mean number of days until resolution would be 21, with a standard deviation (SD) of 4 days. Setting power at 80% and alpha at .05, we calculated it would take 105 patients per group (N=420) to detect a difference of 2 days in time until resolution.

RESULTS

Over the 5-year study period, 36 clinicians identified 186 patients who expressed an interest in the study, and they transmitted the patient contact information to the research team. Patients were seen in a traditional primary care setting. All 186 patients were enrolled by phone. However, only 89 completed and returned their diaries and signed consent forms; of these, 60% were female, 92% were white, 4% were black, 4% were American Indians, 2% were Hispanic, and 7% had diabetes mellitus.

Five practices contributed data on numbers of poison ivy encounters per month and total encounters per month for the year 2013. They included an inner city academic practice in central Oklahoma and a rural community health center, a suburban private practice, and 2 private practices in a town of 30,000 in eastern Oklahoma. The largest average number of encounters occurred between April and August.

The distribution of enrolled-patient visits by month and season corresponded roughly to the proportions of all patient visits for poison ivy, with 1% occurring in the winter, 35% in the spring, 55% during the summer, and 9% in the fall. Virtually all study participants (92%) complained of pruritus and had erythema (91%) and papules (87%). Forty-nine percent had vesicles or bullae. The area of the body most often affected was the head/face/­­neck, 61%, followed by the trunk, 56%; legs, 54%; and arms, 22%.

From the date of initial clinical consultation, the mean/median (SD; range) duration of symptoms and signs were: pruritus, 10.9/9 days (7.1; 0-43); erythema, 13.7/13 days (7.7; 0-42); papules, 10.1/9.5 days (6.5; 0-37); and vesicles, 5.3/5 days (4.1; 0-15). The mean/median (SD; range) duration of any symptom or sign was 14.4/13.5 days (8; 1-43). Rashes with vesicles tended to last longer (16.1 vs 12.9 days), but this difference did not reach statistical significance.

Treatments used by patients before and after their primary care visit are shown in TABLE 1. Seventy-three percent of patients had tried something from one treatment category before consulting a clinician, and 31% had tried something from more than one category. They were most likely to have used a topical antipruritic, astringent, or low-potency corticosteroid, or a combination of these. Clinicians always recommended some treatment and, in 76% of cases, treatments from more than one category. They most often prescribed oral or parenteral corticosteroids (81% of the time), sometimes in combination with a high-potency topical corticosteroid (25% of the time) or oral antihistamine (31%). Oral corticosteroids were used for an average of 11 days; parenteral corticosteroids were given once. Oral antihistamines were recommended for 30% of patients, with an average course duration of 13 days. Clinicians did not prescribe systemic corticosteroids or any other treatment type more often based on location of the rash or presence of vesicles.

No statistically significant associations were found between the baseline non-treatment variables and duration of symptoms and signs. Patient-initiated treatments were also not associated with duration of symptoms and signs following the initial clinician visit.

Of the treatments prescribed by clinicians or independently chosen by patients following their initial office visit, only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles. Use of topical soaps was associated with a longer duration of papules (P<.0001) and of total duration of signs or symptoms (P=.0004) compared with other treatments.

Location and characteristics of the rash were not associated with likelihood of recurrence following treatment. Post-visit use of a topical soap was associated with recurrence of itching (P=.001) and erythema (P=.01). Recurrence of erythema was also more frequent in patients prescribed topical astringents (beta coefficient=0.28; P=.008), and recurrence of papules was more common in patients treated with low-potency topical corticosteroids (P<.0001). These results and several others that almost reached statistical significance are shown in TABLE 2.

In the multivariable models, the only variable associated with duration of pruritus was the combination of systemic and high-potency topical corticosteroids (8 vs 12 days.) Use of only parenteral or only high-potency topical corticosteroids did not predict shorter duration of pruritus. Use of topical soaps was associated with longer duration of papules (33 vs 9.6 days) and longer duration of any symptoms (33 vs 13.9 days). It was also associated with a higher likelihood of recurrence of pruritus (chi square test [χ²], 10.67) and recurrence of erythema (χ², 5.92) after initial resolution. Topical astringent use was predictive of recurrence of erythema (χ², 7.01) and use of low-potency corticosteroids was associated with recurrence of papules (χ², 20.96).

DISCUSSION

While network clinicians felt that studying poison ivy was of interest and importance, and we had preliminary survey information to suggest it was a common problem treated in primary care, our data suggest that clinical encounters for poison ivy are actually quite uncommon (less than 0.4% of all encounters) even during peak months. Our problems with recruitment were therefore unexpected, and we ended up with far fewer enrolled patients than we had projected, and needed, based on our power analysis. Also based on our preliminary survey, we anticipated considerably more variation in treatment approach than we found. Most clinicians recommended either an oral, parenteral, or high-potency topical corticosteroid, and some also recommended an oral antihistamine, usually diphenhydramine.

The literature and common sense suggest that most patients who seek medical treatment for poison ivy are primarily concerned about itching. Even with the smaller-than-anticipated number of participants in this study, we were able to show that the combination of a systemic (oral or parenteral) corticosteroid and a high-potency topical corticosteroid was associated with a statistically significant shorter duration of pruritus with no recurrence following treatment. We found no evidence that systemic corticosteroids alone, parenteral corticosteroids alone, or high-potency topical corticosteroids alone had any effect on duration of signs or symptoms, even at an alpha of .05. We also found no evidence that oral antihistamines were associated with a shorter duration of pruritus (P=.06); with a larger sample size, we might have found a difference.

Since only 2 patients used topical soaps following their initial clinician visit, the associations between use of these products and longer duration of signs and symptoms and with recurrence of signs and symptoms, although statistically significant, should be viewed with skepticism and with an eye toward possible confounders (eg, people who used these agents may have been more likely to notice and record minor symptoms). Furthermore, these agents have been effective only when used before or at the onset of the rash.

Study limitations. The study has a number of limitations. It had a high drop-out rate. Some patients might not have had poison ivy, but it is generally considered easy to diagnose with accuracy. We cannot be sure that all of the enrolled patients had Rhus dermatitis. Enrollment was based on the clinical impression of the patients’ primary care clinicians. The sample size reduced the power of the study to detect small differences in treatment effects and prevented more complex analyses (eg, combinations of medications, interactions).

The possibility of self-selection bias, weaknesses of the cohort design, and patient-reported outcome measures were additional limitations. The study was also carried out in a single southwestern state, which may not be representative of some other locations. However, it is one of only a few studies published on Rhus dermatitis and possibly the only one conducted in primary care settings.

CORRESPONDENCE
Cara Vaught, MPH, University of Oklahoma Health Sciences Center, Department of Family and Preventive Medicine, 900 NE 10th Street, Oklahoma City, OK 73104; [email protected].

ACKNOWLEDGEMENT
The authors thank the Oklahoma Physicians Resource/Research Network (OKPRN) and the OKPRN clinician members (as well as their staff and patients) for their contributions to this study. The authors also thank Bradley Long, Matthew Marr, and Kellie Hetherington for their involvement in the data collection for this study.

ABSTRACT

Purpose To determine the characteristics and clinical course of Rhus dermatitis in patients who seek assistance from primary care clinicians, as well as treatment approaches used by patients and recommended by clinicians, and treatment approaches associated with better outcomes.

Methods This was a prospective cohort study with standardized baseline data collection on patients and their rashes, followed by examination of patient-completed diaries of signs, symptoms, and treatments.

Results Thirty-six clinicians identified 186 interested patients, of which 89 completed and returned diaries and consent forms. Of those 89 patients, 92% reported pruritus; 91%, erythema; 87%, papules; and 49%, vesicles or bullae at baseline. Their rashes involved the head/face/neck, 61%; trunk, 56%; legs, 54%; and arms, 22%.

Patients seeking help for poison ivy can expect the rash to last an additional 2 weeks on average, regardless of the treatment prescribed.From the date of clinical consultation, the mean (standard deviation [SD]; range) duration of any symptom or sign was 14.4 days (8.0; 1-43). Patients most often had tried a topical antipruritic, astringent, or low-potency corticosteroid before seeking care. Clinicians prescribed oral or parenteral corticosteroids 81% of the time, sometimes in combination with a high-potency topical corticosteroid (25%) or oral antihistamine (31%). Only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles.

Conclusions Patients who visit a primary care clinician for Rhus dermatitis can expect the rash to last another 2 weeks on average (total duration: one day to 6 weeks) regardless of what treatment is prescribed. Parenteral corticosteroids plus high-potency topical corticosteroids may reduce the duration of the itching.

Rhus dermatitis (poison ivy, oak, and sumac) is a common cause of contact dermatitis throughout the United States. The condition is usually mild and often not brought to the attention of primary care clinicians. Some patients, however, do see a health care provider for treatment, most often because of pruritus. This form of contact dermatitis results from a type IV hypersensitivity reaction to urushiol, a colorless oil in the leaves, stem, root, and fruit of poison ivy, poison oak, and poison sumac. The reaction, which occurs 24 to 72 hours following contact with the skin, can be prevented by washing the skin promptly with a detergent soap after exposure. By the age of 8, most people are sensitized to urushiol.¹

According to most standard texts and clinical reviews, untreated Rhus dermatitis usually resolves in one to 3 weeks. What is not known is whether particular patient or rash characteristics might affect prognosis and thereby influence treatment recommendations—eg, age, gender, race, location of the rash, prior episodes, chronic illnesses such as diabetes, or chronic use of medications such as nonsteroidal anti-inflammatory drugs and corticosteroids.

Impetus for our study. An informal survey of 10 clinician members of the Oklahoma Physicians Resource/Research Network (OKPRN), a statewide practice-based research network, suggested that primary care clinicians treat between one and 10 patients with poison ivy each week during the spring, summer, and fall (median 2.5). Their reported armamentarium included more than 15 different over-the-counter topical agents, several oral antihistamines, and a variety of topical, oral, and parenteral corticosteroids.

Systemic corticosteroids plus high-potency topical corticosteroids reduced the duration of itching.Surprisingly, there is very little published evidence on which to base treatment decisions. Using PubMed and the search terms, Rhus dermatitis, poison ivy, and poison oak, we found only 3 placebo-controlled clinical trials of Rhus dermatitis treatments in the English language literature after 1966. Based on these studies, Zanfel, a mixture of alcohol-soluble and anionic surfactant, may be somewhat effective, but pimecrolimus and jewelweed extract were no more effective than placebo.^2-4 There is some evidence that topical corticosteroids are effective only before vesicles appear.⁵ In one uncontrolled study, intramuscular injection of betamethasone and dexamethasone yielded about a 30% reduction in symptoms within 48 hours.⁶ Assuming that systemic corticosteroids do produce benefit, however, the most effective dose and duration of treatment have not been determined.^7,8

To address some of these gaps in our knowledge base, OKPRN members asked that we undertake a longitudinal cohort study of patients reporting to primary care practices.

We conducted this study between May 2010 and October 2014. The project was approved by the University of Oklahoma Health Sciences Center Institutional Review Board. Clinician members of OKPRN were invited to participate in the study via listserv, fax, or letter. We instructed clinicians and office staff to ask patients with Rhus dermatitis if they might be interested in participating in a study, which would require that they keep a symptom diary and would earn them a $20 gift card. Interested patients were given a packet of information, and a member of the research team later called the patients with additional information, including an explanation of informed consent and instructions on completing and returning the diary and written consent form.

Clinicians recorded information about the patient and the rash on a customized template, releasing it to the team after written consent was obtained from the patient. Categories for characterizing the rash were head/face, arms/hands, trunk, and legs/feet. A subset of 5 participating clinicians, selected to include a variety of practice types and patient populations, were also asked to produce, from their billing software, the number of patients and encounters in which poison ivy was addressed in each month of 2013.

On the diary, patients were instructed to record the presence or absence of pruritus, erythema, raised lesions, and vesicles/bullae at the end of each day until the rash resolved, or for 6 weeks following onset of the rash, whichever came first. Patients were asked to mail their diaries to the principal investigator once they were free of symptoms for one week or after 6 weeks from the onset of symptoms, whichever came first.

We asked both patients and clinicians to report medications used before and after the primary care encounter. A member of the research team assigned these medications to one of 12 categories: topical antihistamines, topical soaps (eg, Zanfel or Tecnu), topical astringents, other topical antipruritics, topical aloe vera, topical bleach, low-potency topical corticosteroids, moderate-potency topical corticosteroids, high-potency topical corticosteroids, oral antihistamines, oral corticosteroids, and parenteral corticosteroids.

We used independent T-tests to evaluate associations between baseline variables, patient-initiated treatments, and clinician-initiated treatments and the time to complete resolution of individual signs and symptoms and complete resolution of all signs and symptoms following the clinical encounter. We created additional outcome variables for initial resolution followed by recurrence of itching, erythema, papules, and vesicles. The purpose of these variables was to determine if some treatments were initially effective but without lasting effect.

We used the chi square test to assess associations between clinician-initiated treatments and recurrence of signs or symptoms following initial resolution. To account for chance associations resulting from multiple analyses, we chose to set the level of statistical significance at P=.01. However, because of the lower-than-projected sample size, we chose to also report variables with P<.05 so that the reader could judge the likelihood that a larger sample might have disclosed other important associations.

We assumed that an average of 4 categories of treatment would be tried (eg, topical corticosteroids, systemic corticosteroids, topical antihistamines, and other topical agents), and that the mean number of days until resolution would be 21, with a standard deviation (SD) of 4 days. Setting power at 80% and alpha at .05, we calculated it would take 105 patients per group (N=420) to detect a difference of 2 days in time until resolution.

RESULTS

Over the 5-year study period, 36 clinicians identified 186 patients who expressed an interest in the study, and they transmitted the patient contact information to the research team. Patients were seen in a traditional primary care setting. All 186 patients were enrolled by phone. However, only 89 completed and returned their diaries and signed consent forms; of these, 60% were female, 92% were white, 4% were black, 4% were American Indians, 2% were Hispanic, and 7% had diabetes mellitus.

Five practices contributed data on numbers of poison ivy encounters per month and total encounters per month for the year 2013. They included an inner city academic practice in central Oklahoma and a rural community health center, a suburban private practice, and 2 private practices in a town of 30,000 in eastern Oklahoma. The largest average number of encounters occurred between April and August.

The distribution of enrolled-patient visits by month and season corresponded roughly to the proportions of all patient visits for poison ivy, with 1% occurring in the winter, 35% in the spring, 55% during the summer, and 9% in the fall. Virtually all study participants (92%) complained of pruritus and had erythema (91%) and papules (87%). Forty-nine percent had vesicles or bullae. The area of the body most often affected was the head/face/­­neck, 61%, followed by the trunk, 56%; legs, 54%; and arms, 22%.

From the date of initial clinical consultation, the mean/median (SD; range) duration of symptoms and signs were: pruritus, 10.9/9 days (7.1; 0-43); erythema, 13.7/13 days (7.7; 0-42); papules, 10.1/9.5 days (6.5; 0-37); and vesicles, 5.3/5 days (4.1; 0-15). The mean/median (SD; range) duration of any symptom or sign was 14.4/13.5 days (8; 1-43). Rashes with vesicles tended to last longer (16.1 vs 12.9 days), but this difference did not reach statistical significance.

Treatments used by patients before and after their primary care visit are shown in TABLE 1. Seventy-three percent of patients had tried something from one treatment category before consulting a clinician, and 31% had tried something from more than one category. They were most likely to have used a topical antipruritic, astringent, or low-potency corticosteroid, or a combination of these. Clinicians always recommended some treatment and, in 76% of cases, treatments from more than one category. They most often prescribed oral or parenteral corticosteroids (81% of the time), sometimes in combination with a high-potency topical corticosteroid (25% of the time) or oral antihistamine (31%). Oral corticosteroids were used for an average of 11 days; parenteral corticosteroids were given once. Oral antihistamines were recommended for 30% of patients, with an average course duration of 13 days. Clinicians did not prescribe systemic corticosteroids or any other treatment type more often based on location of the rash or presence of vesicles.

No statistically significant associations were found between the baseline non-treatment variables and duration of symptoms and signs. Patient-initiated treatments were also not associated with duration of symptoms and signs following the initial clinician visit.

Of the treatments prescribed by clinicians or independently chosen by patients following their initial office visit, only systemic corticosteroids plus high-potency topical corticosteroids were associated with a significantly shorter duration of itching (P=.005). No treatment was associated with reduced duration of erythema, papules, or vesicles. Use of topical soaps was associated with a longer duration of papules (P<.0001) and of total duration of signs or symptoms (P=.0004) compared with other treatments.

Location and characteristics of the rash were not associated with likelihood of recurrence following treatment. Post-visit use of a topical soap was associated with recurrence of itching (P=.001) and erythema (P=.01). Recurrence of erythema was also more frequent in patients prescribed topical astringents (beta coefficient=0.28; P=.008), and recurrence of papules was more common in patients treated with low-potency topical corticosteroids (P<.0001). These results and several others that almost reached statistical significance are shown in TABLE 2.

In the multivariable models, the only variable associated with duration of pruritus was the combination of systemic and high-potency topical corticosteroids (8 vs 12 days.) Use of only parenteral or only high-potency topical corticosteroids did not predict shorter duration of pruritus. Use of topical soaps was associated with longer duration of papules (33 vs 9.6 days) and longer duration of any symptoms (33 vs 13.9 days). It was also associated with a higher likelihood of recurrence of pruritus (chi square test [χ²], 10.67) and recurrence of erythema (χ², 5.92) after initial resolution. Topical astringent use was predictive of recurrence of erythema (χ², 7.01) and use of low-potency corticosteroids was associated with recurrence of papules (χ², 20.96).

DISCUSSION

While network clinicians felt that studying poison ivy was of interest and importance, and we had preliminary survey information to suggest it was a common problem treated in primary care, our data suggest that clinical encounters for poison ivy are actually quite uncommon (less than 0.4% of all encounters) even during peak months. Our problems with recruitment were therefore unexpected, and we ended up with far fewer enrolled patients than we had projected, and needed, based on our power analysis. Also based on our preliminary survey, we anticipated considerably more variation in treatment approach than we found. Most clinicians recommended either an oral, parenteral, or high-potency topical corticosteroid, and some also recommended an oral antihistamine, usually diphenhydramine.

The literature and common sense suggest that most patients who seek medical treatment for poison ivy are primarily concerned about itching. Even with the smaller-than-anticipated number of participants in this study, we were able to show that the combination of a systemic (oral or parenteral) corticosteroid and a high-potency topical corticosteroid was associated with a statistically significant shorter duration of pruritus with no recurrence following treatment. We found no evidence that systemic corticosteroids alone, parenteral corticosteroids alone, or high-potency topical corticosteroids alone had any effect on duration of signs or symptoms, even at an alpha of .05. We also found no evidence that oral antihistamines were associated with a shorter duration of pruritus (P=.06); with a larger sample size, we might have found a difference.

Since only 2 patients used topical soaps following their initial clinician visit, the associations between use of these products and longer duration of signs and symptoms and with recurrence of signs and symptoms, although statistically significant, should be viewed with skepticism and with an eye toward possible confounders (eg, people who used these agents may have been more likely to notice and record minor symptoms). Furthermore, these agents have been effective only when used before or at the onset of the rash.

Study limitations. The study has a number of limitations. It had a high drop-out rate. Some patients might not have had poison ivy, but it is generally considered easy to diagnose with accuracy. We cannot be sure that all of the enrolled patients had Rhus dermatitis. Enrollment was based on the clinical impression of the patients’ primary care clinicians. The sample size reduced the power of the study to detect small differences in treatment effects and prevented more complex analyses (eg, combinations of medications, interactions).

The possibility of self-selection bias, weaknesses of the cohort design, and patient-reported outcome measures were additional limitations. The study was also carried out in a single southwestern state, which may not be representative of some other locations. However, it is one of only a few studies published on Rhus dermatitis and possibly the only one conducted in primary care settings.

CORRESPONDENCE
Cara Vaught, MPH, University of Oklahoma Health Sciences Center, Department of Family and Preventive Medicine, 900 NE 10th Street, Oklahoma City, OK 73104; [email protected].

ACKNOWLEDGEMENT
The authors thank the Oklahoma Physicians Resource/Research Network (OKPRN) and the OKPRN clinician members (as well as their staff and patients) for their contributions to this study. The authors also thank Bradley Long, Matthew Marr, and Kellie Hetherington for their involvement in the data collection for this study.

CASE › James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 years have changed everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the US Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.¹

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer half-life than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of single-tablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

The US Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see TABLE 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories:²

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently recommended first-line therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (TABLE 2).²

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Most of the newer agents are more potent, less toxic, have a higher genetic barrier to resistance, and a longer half-life than their predecessors.Dolutegravir is generally well-tolerated with minimal adverse effects (≥2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (Tivicay plus Truvada). The combination of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvite­gravir/­­cobicistat/tenofovir alafenamide/emtricitabine­­ that was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.

Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵

Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸

Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. There is a once-daily formulation of raltegravir that's expected to be available late in 2017.²⁰

Before starting a regimen with abacavir, screen patients for the HLA-B*5701 allele, which predicts hypersensitivity to the drug.Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-based regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and self-limiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in late 2017, it will provide yet another daily STR option.²³

The addition of fixed-dose tenofovir alafenamide/emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

The DHHS guidelines also include “alternative” (TABLE 3²) and “other” regimens (available at: http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not. These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir- or cobicistat-boosted atazanavir or darunavir.

Consider the new 4-drug, single-tablet formulation for older patients with HIV or those with comorbidities such as hypertension or diabetes.The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The future of ART

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE › At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm³, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

CORRESPONDENCE
Jeffrey T. Kirchner, DO, FAAFP, AAHIVS, Medical Director, LGHP Comprehensive Care, 554 North Duke St., 3rd Floor, Lancaster, PA 1760; [email protected].

CASE › James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 years have changed everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the US Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.¹

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer half-life than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of single-tablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

The US Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see TABLE 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories:²

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently recommended first-line therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (TABLE 2).²

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Most of the newer agents are more potent, less toxic, have a higher genetic barrier to resistance, and a longer half-life than their predecessors.Dolutegravir is generally well-tolerated with minimal adverse effects (≥2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (Tivicay plus Truvada). The combination of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvite­gravir/­­cobicistat/tenofovir alafenamide/emtricitabine­­ that was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.

Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵

Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸

Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. There is a once-daily formulation of raltegravir that's expected to be available late in 2017.²⁰

Before starting a regimen with abacavir, screen patients for the HLA-B*5701 allele, which predicts hypersensitivity to the drug.Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-based regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and self-limiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in late 2017, it will provide yet another daily STR option.²³

The addition of fixed-dose tenofovir alafenamide/emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

The DHHS guidelines also include “alternative” (TABLE 3²) and “other” regimens (available at: http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not. These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir- or cobicistat-boosted atazanavir or darunavir.

Consider the new 4-drug, single-tablet formulation for older patients with HIV or those with comorbidities such as hypertension or diabetes.The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The future of ART

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE › At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm³, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

CORRESPONDENCE
Jeffrey T. Kirchner, DO, FAAFP, AAHIVS, Medical Director, LGHP Comprehensive Care, 554 North Duke St., 3rd Floor, Lancaster, PA 1760; [email protected].

CASE › James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 years have changed everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the US Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.¹

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer half-life than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of single-tablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

The US Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see TABLE 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories:²

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently recommended first-line therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (TABLE 2).²

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Most of the newer agents are more potent, less toxic, have a higher genetic barrier to resistance, and a longer half-life than their predecessors.Dolutegravir is generally well-tolerated with minimal adverse effects (≥2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

Dolutegravir plus tenofovir disoproxil fumarate/emtricitabine (Tivicay plus Truvada). The combination of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²

Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvite­gravir/­­cobicistat/tenofovir alafenamide/emtricitabine­­ that was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.

Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵

Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸

Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. There is a once-daily formulation of raltegravir that's expected to be available late in 2017.²⁰

Before starting a regimen with abacavir, screen patients for the HLA-B*5701 allele, which predicts hypersensitivity to the drug.Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-based regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and self-limiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in late 2017, it will provide yet another daily STR option.²³

The addition of fixed-dose tenofovir alafenamide/emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

The DHHS guidelines also include “alternative” (TABLE 3²) and “other” regimens (available at: http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not. These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir- or cobicistat-boosted atazanavir or darunavir.

Consider the new 4-drug, single-tablet formulation for older patients with HIV or those with comorbidities such as hypertension or diabetes.The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The future of ART

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE › At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm³, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

CORRESPONDENCE
Jeffrey T. Kirchner, DO, FAAFP, AAHIVS, Medical Director, LGHP Comprehensive Care, 554 North Duke St., 3rd Floor, Lancaster, PA 1760; [email protected].

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

One of my brothers has adult onset bipolar disorder. As luck would have it, he also has type 2 diabetes mellitus. He struggles constantly with blood sugar control since he needs to take 2 psychotropic medications, both of which cause weight gain.

I mistakenly told a patient that her beta-blocker wasn't interfering with her weight loss.His situation has prompted me to think about the responsibility we have as we care, and advocate, for our patients with major mental illness who require these effective medications. At a minimum, we must be knowledgeable about the adverse metabolic effects of these drugs, avoid prescribing them when possible, and advocate for dose reductions when feasible. Knowing, for example, that these drugs fall on a spectrum, with haloperidol causing the least weight gain and olanzapine causing the most, is important.¹

An eye-opener. The article by Saunders in this issue provides advice on avoiding medications that commonly cause weight gain when prescribing for overweight or obese patients with diabetes, hypertension, and/or depression. I was unaware that some of the drugs on the list contribute to the problem. For example, I saw a new patient last week who has hypertension and is obese; she has been taking the beta-blocker metoprolol for the past 8 years. She has tried unsuccessfully to lose weight. She asked me if the metoprolol could be interfering with weight loss, and I mistakenly told her “No.” Thankfully, we decided to discontinue it anyway. I will admit to her my knowledge gap when I see her next month for follow-up. Errors are great teachers, especially when no harm is done.

The scope of the Saunders article is not meant to be comprehensive, since it focuses on medications for diabetes, hypertension, and depression. I think all of us are aware of the weight gain associated with other commonly prescribed drugs, such as systemic corticosteroids and long-acting progesterone for contraception. Thankfully, combination oral contraceptives do not appear to be associated with weight gain²—answering one of the more common questions I receive from patients about weight and medications.

The bottom line. Avoid prescribing medications that can cause weight gain in overweight and obese patients when possible, use the lowest effective dose when such agents are necessary, and warn patients of this adverse effect so that they can take precautions, such as walking an extra mile a day or giving up that high-calorie latte in the morning.

1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951-962.

2. Gallo MF, Lopez LM, Grimes DA, et al. Combination contraceptives: effects on weight. Cochrane Database Syst Rev. 2011;CD003987.

Separate sampling of the duodenal bulb increased detection of celiac disease by only 0.1% when endoscopy patients had a low pretest probability of celiac disease, according to research published in the November issue of Clinical Gastroenterology and Hepatology.

Duodenal bulb histology did reveal other abnormal findings, such as chronic peptic duodenitis, gastric heterotopia, and Brunner gland hyperplasia, wrote Samantha Stoven, MD, of Mayo Clinic, Rochester, Minn., and her associates. These findings did not seem to impede the identification of celiac disease, but their clinical implications were unclear, the researchers noted.

©Monthian/Thinkstock

Most studies of the diagnostic yield of duodenal bulb specimens have been performed in patients with known celiac disease or positive serology. In past studies of these high-probability cohorts, duodenal bulb sampling increased the diagnostic yield of celiac disease anywhere from 1.8% to 18%, but whether and how that finding translates to low-probability cohorts is unclear, the researchers said. Therefore, they retrospectively analyzed data from 679 endoscopy patients who had both duodenal bulb and small bowel biopsies collected at three Mayo Clinic sites in 2011. These sites are “open access,” meaning that patients can be referred for endoscopy without the approval of a gastroenterologist.

The average age of the patients was 50 years, and 63% were female. They were most commonly referred for duodenal biopsy because of chronic dyspepsia (46% of patients), diarrhea (35%), or nausea (17%). Patients with either known celiac disease or positive serology were excluded from the study (Clin Gastroenterol Hepatol. 2016 Mar 7. doi: 10.1016/j.cgh.2016.02.026). A total of 265 patients (39%) had abnormal duodenal histology, which was most often diagnosed as chronic peptic duodenitis, the researchers said. Histologic abnormalities usually involved the duodenal bulb (36% of cases), not the distal duodenum (15%; P less than .0001). However, among the 16 patients (2%) found to have celiac disease, just one patient had disease only in the duodenal bulb. Thus, duodenal bulb sampling increased the diagnostic yield of celiac disease by only 0.1% when considering the overall cohort. The patient with celiac disease limited to the bulb was a 46-year-old female presenting with diarrhea and anemia who had normal serologies but a permissive human leukocyte antigen test. Her duodenal bulb had villous atrophy and more than 25 intraepithelial lymphocytes per 100 epithelial cells, while her distal duodenum was normal.

Among the 85% of patients who had normal distal duodenums, 28% had abnormal bulb histology, most often chronic peptic duodenitis, active chronic peptic duodenitis, or gastric heterotopia, the researchers said. Among the 59% of patients whose celiac serology before endoscopy was truly unknown, only two (0.5%) had histologic changes consistent with celiac disease, which in both cases were located in the distal duodenum.

SOURCE: American Gastroenterological Association

“Individual sampling of the duodenal bulb in patients with either negative or unknown celiac serologic status can be considered in practices where expert gastrointestinal pathologists are present and there is agreement that both samples can be submitted in the same bottle, or there is not a separate charge for the additional container. Further studies may be needed to assess the diagnostic yield of separate bulb biopsies for celiac detection in all comers.”

An American College of Gastroenterology Junior Faculty Development Award helped support the work. Senior author Joseph A. Murray, MD, disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, AMAG Pharmaceuticals, and several other corporate entities. The remaining authors had no disclosures.

Separate sampling of the duodenal bulb increased detection of celiac disease by only 0.1% when endoscopy patients had a low pretest probability of celiac disease, according to research published in the November issue of Clinical Gastroenterology and Hepatology.

Duodenal bulb histology did reveal other abnormal findings, such as chronic peptic duodenitis, gastric heterotopia, and Brunner gland hyperplasia, wrote Samantha Stoven, MD, of Mayo Clinic, Rochester, Minn., and her associates. These findings did not seem to impede the identification of celiac disease, but their clinical implications were unclear, the researchers noted.

©Monthian/Thinkstock

Most studies of the diagnostic yield of duodenal bulb specimens have been performed in patients with known celiac disease or positive serology. In past studies of these high-probability cohorts, duodenal bulb sampling increased the diagnostic yield of celiac disease anywhere from 1.8% to 18%, but whether and how that finding translates to low-probability cohorts is unclear, the researchers said. Therefore, they retrospectively analyzed data from 679 endoscopy patients who had both duodenal bulb and small bowel biopsies collected at three Mayo Clinic sites in 2011. These sites are “open access,” meaning that patients can be referred for endoscopy without the approval of a gastroenterologist.

The average age of the patients was 50 years, and 63% were female. They were most commonly referred for duodenal biopsy because of chronic dyspepsia (46% of patients), diarrhea (35%), or nausea (17%). Patients with either known celiac disease or positive serology were excluded from the study (Clin Gastroenterol Hepatol. 2016 Mar 7. doi: 10.1016/j.cgh.2016.02.026). A total of 265 patients (39%) had abnormal duodenal histology, which was most often diagnosed as chronic peptic duodenitis, the researchers said. Histologic abnormalities usually involved the duodenal bulb (36% of cases), not the distal duodenum (15%; P less than .0001). However, among the 16 patients (2%) found to have celiac disease, just one patient had disease only in the duodenal bulb. Thus, duodenal bulb sampling increased the diagnostic yield of celiac disease by only 0.1% when considering the overall cohort. The patient with celiac disease limited to the bulb was a 46-year-old female presenting with diarrhea and anemia who had normal serologies but a permissive human leukocyte antigen test. Her duodenal bulb had villous atrophy and more than 25 intraepithelial lymphocytes per 100 epithelial cells, while her distal duodenum was normal.

Among the 85% of patients who had normal distal duodenums, 28% had abnormal bulb histology, most often chronic peptic duodenitis, active chronic peptic duodenitis, or gastric heterotopia, the researchers said. Among the 59% of patients whose celiac serology before endoscopy was truly unknown, only two (0.5%) had histologic changes consistent with celiac disease, which in both cases were located in the distal duodenum.

SOURCE: American Gastroenterological Association

“Individual sampling of the duodenal bulb in patients with either negative or unknown celiac serologic status can be considered in practices where expert gastrointestinal pathologists are present and there is agreement that both samples can be submitted in the same bottle, or there is not a separate charge for the additional container. Further studies may be needed to assess the diagnostic yield of separate bulb biopsies for celiac detection in all comers.”

An American College of Gastroenterology Junior Faculty Development Award helped support the work. Senior author Joseph A. Murray, MD, disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, AMAG Pharmaceuticals, and several other corporate entities. The remaining authors had no disclosures.

Separate sampling of the duodenal bulb increased detection of celiac disease by only 0.1% when endoscopy patients had a low pretest probability of celiac disease, according to research published in the November issue of Clinical Gastroenterology and Hepatology.

Duodenal bulb histology did reveal other abnormal findings, such as chronic peptic duodenitis, gastric heterotopia, and Brunner gland hyperplasia, wrote Samantha Stoven, MD, of Mayo Clinic, Rochester, Minn., and her associates. These findings did not seem to impede the identification of celiac disease, but their clinical implications were unclear, the researchers noted.

©Monthian/Thinkstock

Most studies of the diagnostic yield of duodenal bulb specimens have been performed in patients with known celiac disease or positive serology. In past studies of these high-probability cohorts, duodenal bulb sampling increased the diagnostic yield of celiac disease anywhere from 1.8% to 18%, but whether and how that finding translates to low-probability cohorts is unclear, the researchers said. Therefore, they retrospectively analyzed data from 679 endoscopy patients who had both duodenal bulb and small bowel biopsies collected at three Mayo Clinic sites in 2011. These sites are “open access,” meaning that patients can be referred for endoscopy without the approval of a gastroenterologist.

The average age of the patients was 50 years, and 63% were female. They were most commonly referred for duodenal biopsy because of chronic dyspepsia (46% of patients), diarrhea (35%), or nausea (17%). Patients with either known celiac disease or positive serology were excluded from the study (Clin Gastroenterol Hepatol. 2016 Mar 7. doi: 10.1016/j.cgh.2016.02.026). A total of 265 patients (39%) had abnormal duodenal histology, which was most often diagnosed as chronic peptic duodenitis, the researchers said. Histologic abnormalities usually involved the duodenal bulb (36% of cases), not the distal duodenum (15%; P less than .0001). However, among the 16 patients (2%) found to have celiac disease, just one patient had disease only in the duodenal bulb. Thus, duodenal bulb sampling increased the diagnostic yield of celiac disease by only 0.1% when considering the overall cohort. The patient with celiac disease limited to the bulb was a 46-year-old female presenting with diarrhea and anemia who had normal serologies but a permissive human leukocyte antigen test. Her duodenal bulb had villous atrophy and more than 25 intraepithelial lymphocytes per 100 epithelial cells, while her distal duodenum was normal.

Among the 85% of patients who had normal distal duodenums, 28% had abnormal bulb histology, most often chronic peptic duodenitis, active chronic peptic duodenitis, or gastric heterotopia, the researchers said. Among the 59% of patients whose celiac serology before endoscopy was truly unknown, only two (0.5%) had histologic changes consistent with celiac disease, which in both cases were located in the distal duodenum.

SOURCE: American Gastroenterological Association

“Individual sampling of the duodenal bulb in patients with either negative or unknown celiac serologic status can be considered in practices where expert gastrointestinal pathologists are present and there is agreement that both samples can be submitted in the same bottle, or there is not a separate charge for the additional container. Further studies may be needed to assess the diagnostic yield of separate bulb biopsies for celiac detection in all comers.”

An American College of Gastroenterology Junior Faculty Development Award helped support the work. Senior author Joseph A. Murray, MD, disclosed ties to Alba Therapeutics, Alvine Pharmaceuticals, AMAG Pharmaceuticals, and several other corporate entities. The remaining authors had no disclosures.

A 62-year-old man with hypertension, type 2 diabetes mellitus, and hypercholesterolemia presented to the emergency department with substernal chest pain that started about 15 hours earlier while he was at rest watching television.

On examination, his pulse was 92 beats per minute and regular, his blood pressure was 160/88 mm Hg, and he had no evidence of jugular venous distention or pedal edema. Lung examination was positive for bibasilar crackles.

Electrocardiography revealed Q waves with ST elevation in leads I, aVL, V₄, V₅, and V₆ with reciprocal ST depression in leads II, III, and aVF.

His troponin T level on presentation was markedly elevated.

Image

He underwent heart catheterization and was found to have 100% occlusion of the proximal left anterior descending artery. He underwent successful percutaneous coronary intervention with placement of a drug-eluting stent, and afterward had grade 3 flow on the Thrombolysis in Myocardial Infarction (TIMI) scale.

Echocardiography the next day revealed a mobile echo-dense mass in the left ventricular apex (Figure 1) and a left ventricular ejection fraction of 35%.

THE INCIDENCE OF LEFT VENTRICULAR THROMBOSIS IN ACUTE MI

1. What is the incidence of left ventricular thrombosis after acute myocardial infarction (MI), now that primary percutaneous coronary intervention is common?

• 0.1%
• 2%
• 20%
• 40%

Left ventricular thrombosis is a serious complication of acute MI that can cause systemic thromboembolism, including stroke.¹ Before thrombolytic therapy was available, this complication occurred in 20% to 60% of patients with acute MI.^2,3 But early reperfusion strategies, anticoagulation for the first 48 hours, and dual antiplatelet therapy have reduced the incidence of this complication significantly.

In the thrombolytic era, the incidence of left ventricular thrombosis was 5.1% in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) 3 study, which had 8,326 patients. A subset of patients who had an anterior MI had almost double the incidence (11.5%).³

Image

The incidence has further declined with the advent of primary percutaneous coronary intervention, likely thanks to enhanced myocardial salvage, and now ranges from 2.5% to 15% (Table 1).^4–11 The largest observational study, with 2,911 patients undergoing percutaneous coronary intervention, reported an incidence of 2.5% within 3 to 5 days of the MI.⁷ At our center, the incidence was found to be even lower, 1.8% in 1,700 patients presenting with ST-elevation MI undergoing primary percutaneous coronary intervention. Hence, of the answers to the question above, 2% would be closest.

Large infarct size with a low left ventricular ejection fraction (< 40%), anterior wall MI, hypertension, and delay in time from symptom onset to intervention were independent predictors of left ventricular thrombus formation in most studies.^7,12 The risk is highest during the first 2 weeks after MI, and thrombosis almost never occurs more than 3 months after the index event.^5,13–16

WHAT IS THE PATHOGENESIS OF LEFT VENTRICULAR THROMBOSIS?

A large transmural infarct results in loss of contractile function, which causes stagnation and pooling of blood adjacent to the infarcted ventricular segment. In addition, endocardial injury exposes tissue factor, which then initiates the coagulation cascade. To make matters worse, MI results in a hypercoagulable state through unclear mechanisms, which completes the Virchow triad for thrombus formation. Elevations of D-dimer, fibrinogen, anticardiolipin antibodies (IgM and IgG), and tissue factor have also been reported after acute MI.¹⁷

Thrombus formation begins with platelet aggregation at the site of endocardial damage, forming a platelet plug, followed by activation of clotting factors. These thrombi are referred to as “mural,” as they adhere to the chamber wall (endocardium). They are composed of fibrin and entrapped red and white blood cells (Figure 2).

The natural course of thrombus evolution is established but variable. A left ventricular thrombus may dislodge and embolize, resulting in stroke or other thromboembolic complications. Alternately, it can dissolve over time, aided by intrinsic fibrinolytic mechanisms. On other occasions, the thrombus may organize, a process characterized by ingrowth of smooth muscle cells, fibroblasts, and endothelium.

HOW IS LEFT VENTRICULAR THROMBOSIS DIAGNOSED?

2. What is the best imaging test for detecting a thrombus?

• Transesophageal echocardiography
• Transthoracic echocardiography
• Cardiac magnetic resonance imaging (MRI) without gadolinium contrast
• Cardiac MRI with gadolinium contrast

Evaluation of left ventricular function after acute MI carries a class I indication (ie, it should be performed).¹⁸ 

Echocardiography is commonly used, and it has a 60% sensitivity to detect a thrombus.¹⁹ In patients with poorer transthoracic echocardiographic windows, contrast can be used to better delineate the left ventricular cavity and show the thrombus. Transesophageal echocardiography is seldom useful, as the left ventricular apex is foreshortened and in the far field.

A left ventricular thrombus is confirmed if an echo-dense mass with well-demarcated margins distinct from the endocardium is seen throughout the cardiac cycle. It should be evident in at least two different views (apical and short-axis) and should be adjacent to a hypokinetic or akinetic left ventricular wall. False-positive findings can occur due to misidentified false tendons, papillary muscles, and trabeculae.

Cardiac MRI with late gadolinium enhancement is now the gold standard for diagnostic imaging, as it accurately characterizes the shape, size, and location of the thrombus (Figure 3). Gadolinium contrast increases the enhancement of the ventricular cavity, thus allowing easy detection of thrombus, which appears dark. Cardiac MRI with delayed enhancement has 88% to 91% sensitivity and 99% specificity to detect left ventricular thrombosis.^20,21 However, compared with echocardiography, routine cardiac MRI is time-intensive, costly, and not routinely available. As a result, it should be performed only in patients with poor acoustic windows and a high clinical suspicion of left ventricular thrombosis.

Delayed-contrast cardiac computed tomography can be used to identify left ventricular thrombosis, using absence of contrast uptake. The need to use contrast is a disadvantage, but computed tomography can be an alternative in patients with contraindications to cardiac MRI.

WHAT COMPLICATIONS ARISE FROM LEFT VENTRICULAR THROMBOSIS?

The most feared complication of left ventricular thrombosis is thromboembolism. Cardioembolic stroke is generally severe, prone to early and long-term recurrence, and associated with a higher death rate than noncardioembolic ischemic stroke.^22,23 Thrombi associated with thromboembolism are often acute and mobile rather than organized and immobile.²⁴ They may embolize to the brain,  spleen, kidneys, and bowel.²⁵ In a meta-analysis of 11 studies, the pooled odds ratio for risk of embolization was 5.45 (95% confidence interval [CI] 3.02–9.83) with left ventricular thrombi vs without.²⁶ Before systemic thrombolysis and antiplatelet therapy became available, stroke rates ranged from 1.5% to 10%.^27–29

In a meta-analysis of 22 studies from 1978 to 2004, the incidence of ischemic stroke after MI during hospitalization was around 11.1 per 1,000 MIs.³⁰ This study found that anterior MI was associated with a higher risk of stroke, but reported no difference in the incidence of stroke with percutaneous coronary intervention, systemic thrombolysis, or no reperfusion.

In a large prospective cohort study of 2,160 patients,³¹ 259 (12%) had a stroke after MI. In multivariable analysis, age, diabetes, and previous stroke were predictors of stroke after MI. This study reported significantly fewer strokes in patients who underwent percutaneous coronary intervention than with other or no reperfusion therapies.³¹

ANTICOAGULATION TREATMENT

3. How would you treat a patient who has a drug-eluting stent in the left anterior descending artery and a new diagnosis of left ventricular thrombosis?

• Warfarin
• Aspirin and clopidogrel
• Aspirin, clopidogrel, and warfarin
• Aspirin and warfarin

The management of left ventricular thrombosis has been summarized in guidelines from the American College of Chest Physicians (ACCP) in 2012,³² and from the American College of Cardiology/American Heart Association in 2013,¹⁸ which recommend anticoagulation for at least 3 months, or indefinitely if bleeding risk is low, for all patients developing a left ventricular thrombus.

For patients with acute MI and left ventricular thrombosis, the ACCP guidelines recommend warfarin with a target international normalized ratio of 2.0 to 3.0 plus dual antiplatelet therapy (eg, aspirin plus clopidogrel)  for 3 months, after which warfarin is discontinued but dual antiplatelet therapy is continued for up to 12 months.³²

The European Society of Cardiology guidelines³³ recommend 6 months of anticoagulation. However, if the patient is receiving dual antiplatelet therapy, they recommend repeated imaging of the left ventricle after 3 months of anticoagulation, which may allow for earlier discontinuation of anticoagulation if the thrombus has resolved and apical wall motion has recovered. Therefore, most experts recommend 3 months of anticoagulation when used in combination with dual antiplatelet therapy and repeating echocardiography at 3 months to safely discontinue anticoagulation. The best answer to the question posed here is aspirin, clopidogrel, and warfarin.

Decisions about antithrombotic therapy may also depend on stent type and the patient’s bleeding risk. With bare-metal stents, dual antiplatelet therapy along with anticoagulation should be used for 1 month, after which anticoagulation should be used with a single antiplatelet agent for another 2 months; after this, the anticoagulant can be discontinued and dual antiplatelet therapy can be resumed for a total of 12 months. Newer anticoagulants such as rivaroxaban, dabigatran, edoxaban, and apixaban may also have a role, but they have not yet been studied for this indication.

Surgical thrombectomy is rarely considered now, given the known efficacy of anticoagulants in dissolving the thrombus. It was done in the past for large, mobile, or protruding left ventricular thrombi, which have a higher potential for embolization.³⁴ Currently, it can be done under very special circumstances, such as before placement of a left ventricular assist device or if the thrombus is large, to prevent embolism.^35,36

BLEEDING COMPLICATIONS WITH TRIPLE ANTITHROMBOTIC THERAPY

After stent placement, almost all patients need to be on dual antiplatelet therapy for a specified duration depending on the type and generation of stent used. Such patients end up on “triple” antithrombotic therapy (two antiplatelet drugs plus an anticoagulant), which poses a high risk of bleeding.³⁷ Consideration needs to be given to the risks of stroke, stent thrombosis, and major bleeding when selecting the antithrombotic regimen.³⁸ Triple antithrombotic therapy has been associated with a risk of fatal and nonfatal bleeding of 4% to 16% when used for indications such as atrial fibrillation.^39–41

Risks of triple antithrombotic therapy (aspirin 80–100 mg, clopidogrel 75 mg, and warfarin) were compared with those of clopidogrel plus warfarin in the What Is the Optimal Antiplatelet and Anticoagulant therapy in Patients With Oral Anticoagulation and Coronary Stenting Trial,³⁷ which reported a significantly lower risk of  major and minor bleeding with clopidogrel-plus-warfarin therapy than with triple antithrombotic therapy, 14.3% vs 31.7% (hazard ratio 0.40, 95% CI 0.28–0.58, P < .0001).

Additionally, the increased risk of major and minor bleeding associated with triple antithrombotic therapy has been confirmed in many observational studies; other studies found a trend toward lower risk with triple therapy, but this was not statistically significant (Table 2).^{38,40,42–55} A large multicenter European trial is being conducted to compare dual antiplatelet therapy vs triple antithrombotic therapy in patients with left ventricular thrombosis.

CASE FOLLOW-UP

Our patient was started on warfarin, clopidogrel 75 mg, and aspirin 75 mg at the time of discharge. He was continued on warfarin for 3 months, at which time a follow-up echocardiogram showed no thrombus in the left ventricle. Warfarin was discontinued, and he had no thromboembolic complications.

TAKE-HOME POINTS

Left ventricular thrombosis after an acute MI is very important to detect, as it can lead to serious complications through arterial embolism.

The incidence of left ventricular thrombosis has declined significantly with the use of percutaneous coronary intervention. However, it may still occur in a small number of patients with larger infarcts owing to delay in revascularization or proximal (left main or left anterior descending) occlusions with larger infarct size.

Echocardiography, which is routinely performed after acute MI to assess myocardial function, uncovers most left ventricular thrombi. In high-risk cases, MRI with late gadolinium enhancement can increase the diagnostic yield.

Anticoagulation with warfarin is recommended for at least 3 months. Post-MI patients undergoing stent implantation may need triple antithrombotic therapy, which, however, increases the bleeding risk significantly. Large randomized trials are needed to guide physicians in risk stratification of such patients.

A 62-year-old man with hypertension, type 2 diabetes mellitus, and hypercholesterolemia presented to the emergency department with substernal chest pain that started about 15 hours earlier while he was at rest watching television.

On examination, his pulse was 92 beats per minute and regular, his blood pressure was 160/88 mm Hg, and he had no evidence of jugular venous distention or pedal edema. Lung examination was positive for bibasilar crackles.

Electrocardiography revealed Q waves with ST elevation in leads I, aVL, V₄, V₅, and V₆ with reciprocal ST depression in leads II, III, and aVF.

His troponin T level on presentation was markedly elevated.

Image

He underwent heart catheterization and was found to have 100% occlusion of the proximal left anterior descending artery. He underwent successful percutaneous coronary intervention with placement of a drug-eluting stent, and afterward had grade 3 flow on the Thrombolysis in Myocardial Infarction (TIMI) scale.

Echocardiography the next day revealed a mobile echo-dense mass in the left ventricular apex (Figure 1) and a left ventricular ejection fraction of 35%.

THE INCIDENCE OF LEFT VENTRICULAR THROMBOSIS IN ACUTE MI

1. What is the incidence of left ventricular thrombosis after acute myocardial infarction (MI), now that primary percutaneous coronary intervention is common?

• 0.1%
• 2%
• 20%
• 40%

Left ventricular thrombosis is a serious complication of acute MI that can cause systemic thromboembolism, including stroke.¹ Before thrombolytic therapy was available, this complication occurred in 20% to 60% of patients with acute MI.^2,3 But early reperfusion strategies, anticoagulation for the first 48 hours, and dual antiplatelet therapy have reduced the incidence of this complication significantly.

In the thrombolytic era, the incidence of left ventricular thrombosis was 5.1% in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) 3 study, which had 8,326 patients. A subset of patients who had an anterior MI had almost double the incidence (11.5%).³

Image

The incidence has further declined with the advent of primary percutaneous coronary intervention, likely thanks to enhanced myocardial salvage, and now ranges from 2.5% to 15% (Table 1).^4–11 The largest observational study, with 2,911 patients undergoing percutaneous coronary intervention, reported an incidence of 2.5% within 3 to 5 days of the MI.⁷ At our center, the incidence was found to be even lower, 1.8% in 1,700 patients presenting with ST-elevation MI undergoing primary percutaneous coronary intervention. Hence, of the answers to the question above, 2% would be closest.

Large infarct size with a low left ventricular ejection fraction (< 40%), anterior wall MI, hypertension, and delay in time from symptom onset to intervention were independent predictors of left ventricular thrombus formation in most studies.^7,12 The risk is highest during the first 2 weeks after MI, and thrombosis almost never occurs more than 3 months after the index event.^5,13–16

WHAT IS THE PATHOGENESIS OF LEFT VENTRICULAR THROMBOSIS?

A large transmural infarct results in loss of contractile function, which causes stagnation and pooling of blood adjacent to the infarcted ventricular segment. In addition, endocardial injury exposes tissue factor, which then initiates the coagulation cascade. To make matters worse, MI results in a hypercoagulable state through unclear mechanisms, which completes the Virchow triad for thrombus formation. Elevations of D-dimer, fibrinogen, anticardiolipin antibodies (IgM and IgG), and tissue factor have also been reported after acute MI.¹⁷

Thrombus formation begins with platelet aggregation at the site of endocardial damage, forming a platelet plug, followed by activation of clotting factors. These thrombi are referred to as “mural,” as they adhere to the chamber wall (endocardium). They are composed of fibrin and entrapped red and white blood cells (Figure 2).

The natural course of thrombus evolution is established but variable. A left ventricular thrombus may dislodge and embolize, resulting in stroke or other thromboembolic complications. Alternately, it can dissolve over time, aided by intrinsic fibrinolytic mechanisms. On other occasions, the thrombus may organize, a process characterized by ingrowth of smooth muscle cells, fibroblasts, and endothelium.

HOW IS LEFT VENTRICULAR THROMBOSIS DIAGNOSED?

2. What is the best imaging test for detecting a thrombus?

• Transesophageal echocardiography
• Transthoracic echocardiography
• Cardiac magnetic resonance imaging (MRI) without gadolinium contrast
• Cardiac MRI with gadolinium contrast

Evaluation of left ventricular function after acute MI carries a class I indication (ie, it should be performed).¹⁸ 

Echocardiography is commonly used, and it has a 60% sensitivity to detect a thrombus.¹⁹ In patients with poorer transthoracic echocardiographic windows, contrast can be used to better delineate the left ventricular cavity and show the thrombus. Transesophageal echocardiography is seldom useful, as the left ventricular apex is foreshortened and in the far field.

A left ventricular thrombus is confirmed if an echo-dense mass with well-demarcated margins distinct from the endocardium is seen throughout the cardiac cycle. It should be evident in at least two different views (apical and short-axis) and should be adjacent to a hypokinetic or akinetic left ventricular wall. False-positive findings can occur due to misidentified false tendons, papillary muscles, and trabeculae.

Cardiac MRI with late gadolinium enhancement is now the gold standard for diagnostic imaging, as it accurately characterizes the shape, size, and location of the thrombus (Figure 3). Gadolinium contrast increases the enhancement of the ventricular cavity, thus allowing easy detection of thrombus, which appears dark. Cardiac MRI with delayed enhancement has 88% to 91% sensitivity and 99% specificity to detect left ventricular thrombosis.^20,21 However, compared with echocardiography, routine cardiac MRI is time-intensive, costly, and not routinely available. As a result, it should be performed only in patients with poor acoustic windows and a high clinical suspicion of left ventricular thrombosis.

Delayed-contrast cardiac computed tomography can be used to identify left ventricular thrombosis, using absence of contrast uptake. The need to use contrast is a disadvantage, but computed tomography can be an alternative in patients with contraindications to cardiac MRI.

WHAT COMPLICATIONS ARISE FROM LEFT VENTRICULAR THROMBOSIS?

The most feared complication of left ventricular thrombosis is thromboembolism. Cardioembolic stroke is generally severe, prone to early and long-term recurrence, and associated with a higher death rate than noncardioembolic ischemic stroke.^22,23 Thrombi associated with thromboembolism are often acute and mobile rather than organized and immobile.²⁴ They may embolize to the brain,  spleen, kidneys, and bowel.²⁵ In a meta-analysis of 11 studies, the pooled odds ratio for risk of embolization was 5.45 (95% confidence interval [CI] 3.02–9.83) with left ventricular thrombi vs without.²⁶ Before systemic thrombolysis and antiplatelet therapy became available, stroke rates ranged from 1.5% to 10%.^27–29

In a meta-analysis of 22 studies from 1978 to 2004, the incidence of ischemic stroke after MI during hospitalization was around 11.1 per 1,000 MIs.³⁰ This study found that anterior MI was associated with a higher risk of stroke, but reported no difference in the incidence of stroke with percutaneous coronary intervention, systemic thrombolysis, or no reperfusion.

In a large prospective cohort study of 2,160 patients,³¹ 259 (12%) had a stroke after MI. In multivariable analysis, age, diabetes, and previous stroke were predictors of stroke after MI. This study reported significantly fewer strokes in patients who underwent percutaneous coronary intervention than with other or no reperfusion therapies.³¹

ANTICOAGULATION TREATMENT

3. How would you treat a patient who has a drug-eluting stent in the left anterior descending artery and a new diagnosis of left ventricular thrombosis?

• Warfarin
• Aspirin and clopidogrel
• Aspirin, clopidogrel, and warfarin
• Aspirin and warfarin

The management of left ventricular thrombosis has been summarized in guidelines from the American College of Chest Physicians (ACCP) in 2012,³² and from the American College of Cardiology/American Heart Association in 2013,¹⁸ which recommend anticoagulation for at least 3 months, or indefinitely if bleeding risk is low, for all patients developing a left ventricular thrombus.

For patients with acute MI and left ventricular thrombosis, the ACCP guidelines recommend warfarin with a target international normalized ratio of 2.0 to 3.0 plus dual antiplatelet therapy (eg, aspirin plus clopidogrel)  for 3 months, after which warfarin is discontinued but dual antiplatelet therapy is continued for up to 12 months.³²

The European Society of Cardiology guidelines³³ recommend 6 months of anticoagulation. However, if the patient is receiving dual antiplatelet therapy, they recommend repeated imaging of the left ventricle after 3 months of anticoagulation, which may allow for earlier discontinuation of anticoagulation if the thrombus has resolved and apical wall motion has recovered. Therefore, most experts recommend 3 months of anticoagulation when used in combination with dual antiplatelet therapy and repeating echocardiography at 3 months to safely discontinue anticoagulation. The best answer to the question posed here is aspirin, clopidogrel, and warfarin.

Decisions about antithrombotic therapy may also depend on stent type and the patient’s bleeding risk. With bare-metal stents, dual antiplatelet therapy along with anticoagulation should be used for 1 month, after which anticoagulation should be used with a single antiplatelet agent for another 2 months; after this, the anticoagulant can be discontinued and dual antiplatelet therapy can be resumed for a total of 12 months. Newer anticoagulants such as rivaroxaban, dabigatran, edoxaban, and apixaban may also have a role, but they have not yet been studied for this indication.

Surgical thrombectomy is rarely considered now, given the known efficacy of anticoagulants in dissolving the thrombus. It was done in the past for large, mobile, or protruding left ventricular thrombi, which have a higher potential for embolization.³⁴ Currently, it can be done under very special circumstances, such as before placement of a left ventricular assist device or if the thrombus is large, to prevent embolism.^35,36

BLEEDING COMPLICATIONS WITH TRIPLE ANTITHROMBOTIC THERAPY

After stent placement, almost all patients need to be on dual antiplatelet therapy for a specified duration depending on the type and generation of stent used. Such patients end up on “triple” antithrombotic therapy (two antiplatelet drugs plus an anticoagulant), which poses a high risk of bleeding.³⁷ Consideration needs to be given to the risks of stroke, stent thrombosis, and major bleeding when selecting the antithrombotic regimen.³⁸ Triple antithrombotic therapy has been associated with a risk of fatal and nonfatal bleeding of 4% to 16% when used for indications such as atrial fibrillation.^39–41

Risks of triple antithrombotic therapy (aspirin 80–100 mg, clopidogrel 75 mg, and warfarin) were compared with those of clopidogrel plus warfarin in the What Is the Optimal Antiplatelet and Anticoagulant therapy in Patients With Oral Anticoagulation and Coronary Stenting Trial,³⁷ which reported a significantly lower risk of  major and minor bleeding with clopidogrel-plus-warfarin therapy than with triple antithrombotic therapy, 14.3% vs 31.7% (hazard ratio 0.40, 95% CI 0.28–0.58, P < .0001).

Additionally, the increased risk of major and minor bleeding associated with triple antithrombotic therapy has been confirmed in many observational studies; other studies found a trend toward lower risk with triple therapy, but this was not statistically significant (Table 2).^{38,40,42–55} A large multicenter European trial is being conducted to compare dual antiplatelet therapy vs triple antithrombotic therapy in patients with left ventricular thrombosis.

CASE FOLLOW-UP

Our patient was started on warfarin, clopidogrel 75 mg, and aspirin 75 mg at the time of discharge. He was continued on warfarin for 3 months, at which time a follow-up echocardiogram showed no thrombus in the left ventricle. Warfarin was discontinued, and he had no thromboembolic complications.

TAKE-HOME POINTS

Left ventricular thrombosis after an acute MI is very important to detect, as it can lead to serious complications through arterial embolism.

The incidence of left ventricular thrombosis has declined significantly with the use of percutaneous coronary intervention. However, it may still occur in a small number of patients with larger infarcts owing to delay in revascularization or proximal (left main or left anterior descending) occlusions with larger infarct size.

Echocardiography, which is routinely performed after acute MI to assess myocardial function, uncovers most left ventricular thrombi. In high-risk cases, MRI with late gadolinium enhancement can increase the diagnostic yield.

Anticoagulation with warfarin is recommended for at least 3 months. Post-MI patients undergoing stent implantation may need triple antithrombotic therapy, which, however, increases the bleeding risk significantly. Large randomized trials are needed to guide physicians in risk stratification of such patients.

A 62-year-old man with hypertension, type 2 diabetes mellitus, and hypercholesterolemia presented to the emergency department with substernal chest pain that started about 15 hours earlier while he was at rest watching television.

On examination, his pulse was 92 beats per minute and regular, his blood pressure was 160/88 mm Hg, and he had no evidence of jugular venous distention or pedal edema. Lung examination was positive for bibasilar crackles.

Electrocardiography revealed Q waves with ST elevation in leads I, aVL, V₄, V₅, and V₆ with reciprocal ST depression in leads II, III, and aVF.

His troponin T level on presentation was markedly elevated.

Image

He underwent heart catheterization and was found to have 100% occlusion of the proximal left anterior descending artery. He underwent successful percutaneous coronary intervention with placement of a drug-eluting stent, and afterward had grade 3 flow on the Thrombolysis in Myocardial Infarction (TIMI) scale.

Echocardiography the next day revealed a mobile echo-dense mass in the left ventricular apex (Figure 1) and a left ventricular ejection fraction of 35%.

THE INCIDENCE OF LEFT VENTRICULAR THROMBOSIS IN ACUTE MI

1. What is the incidence of left ventricular thrombosis after acute myocardial infarction (MI), now that primary percutaneous coronary intervention is common?

• 0.1%
• 2%
• 20%
• 40%

Left ventricular thrombosis is a serious complication of acute MI that can cause systemic thromboembolism, including stroke.¹ Before thrombolytic therapy was available, this complication occurred in 20% to 60% of patients with acute MI.^2,3 But early reperfusion strategies, anticoagulation for the first 48 hours, and dual antiplatelet therapy have reduced the incidence of this complication significantly.

In the thrombolytic era, the incidence of left ventricular thrombosis was 5.1% in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) 3 study, which had 8,326 patients. A subset of patients who had an anterior MI had almost double the incidence (11.5%).³

Image

The incidence has further declined with the advent of primary percutaneous coronary intervention, likely thanks to enhanced myocardial salvage, and now ranges from 2.5% to 15% (Table 1).^4–11 The largest observational study, with 2,911 patients undergoing percutaneous coronary intervention, reported an incidence of 2.5% within 3 to 5 days of the MI.⁷ At our center, the incidence was found to be even lower, 1.8% in 1,700 patients presenting with ST-elevation MI undergoing primary percutaneous coronary intervention. Hence, of the answers to the question above, 2% would be closest.

Large infarct size with a low left ventricular ejection fraction (< 40%), anterior wall MI, hypertension, and delay in time from symptom onset to intervention were independent predictors of left ventricular thrombus formation in most studies.^7,12 The risk is highest during the first 2 weeks after MI, and thrombosis almost never occurs more than 3 months after the index event.^5,13–16

WHAT IS THE PATHOGENESIS OF LEFT VENTRICULAR THROMBOSIS?

A large transmural infarct results in loss of contractile function, which causes stagnation and pooling of blood adjacent to the infarcted ventricular segment. In addition, endocardial injury exposes tissue factor, which then initiates the coagulation cascade. To make matters worse, MI results in a hypercoagulable state through unclear mechanisms, which completes the Virchow triad for thrombus formation. Elevations of D-dimer, fibrinogen, anticardiolipin antibodies (IgM and IgG), and tissue factor have also been reported after acute MI.¹⁷

Thrombus formation begins with platelet aggregation at the site of endocardial damage, forming a platelet plug, followed by activation of clotting factors. These thrombi are referred to as “mural,” as they adhere to the chamber wall (endocardium). They are composed of fibrin and entrapped red and white blood cells (Figure 2).

The natural course of thrombus evolution is established but variable. A left ventricular thrombus may dislodge and embolize, resulting in stroke or other thromboembolic complications. Alternately, it can dissolve over time, aided by intrinsic fibrinolytic mechanisms. On other occasions, the thrombus may organize, a process characterized by ingrowth of smooth muscle cells, fibroblasts, and endothelium.

HOW IS LEFT VENTRICULAR THROMBOSIS DIAGNOSED?

2. What is the best imaging test for detecting a thrombus?

• Transesophageal echocardiography
• Transthoracic echocardiography
• Cardiac magnetic resonance imaging (MRI) without gadolinium contrast
• Cardiac MRI with gadolinium contrast

Evaluation of left ventricular function after acute MI carries a class I indication (ie, it should be performed).¹⁸ 

Echocardiography is commonly used, and it has a 60% sensitivity to detect a thrombus.¹⁹ In patients with poorer transthoracic echocardiographic windows, contrast can be used to better delineate the left ventricular cavity and show the thrombus. Transesophageal echocardiography is seldom useful, as the left ventricular apex is foreshortened and in the far field.

A left ventricular thrombus is confirmed if an echo-dense mass with well-demarcated margins distinct from the endocardium is seen throughout the cardiac cycle. It should be evident in at least two different views (apical and short-axis) and should be adjacent to a hypokinetic or akinetic left ventricular wall. False-positive findings can occur due to misidentified false tendons, papillary muscles, and trabeculae.

Cardiac MRI with late gadolinium enhancement is now the gold standard for diagnostic imaging, as it accurately characterizes the shape, size, and location of the thrombus (Figure 3). Gadolinium contrast increases the enhancement of the ventricular cavity, thus allowing easy detection of thrombus, which appears dark. Cardiac MRI with delayed enhancement has 88% to 91% sensitivity and 99% specificity to detect left ventricular thrombosis.^20,21 However, compared with echocardiography, routine cardiac MRI is time-intensive, costly, and not routinely available. As a result, it should be performed only in patients with poor acoustic windows and a high clinical suspicion of left ventricular thrombosis.

Delayed-contrast cardiac computed tomography can be used to identify left ventricular thrombosis, using absence of contrast uptake. The need to use contrast is a disadvantage, but computed tomography can be an alternative in patients with contraindications to cardiac MRI.

WHAT COMPLICATIONS ARISE FROM LEFT VENTRICULAR THROMBOSIS?

The most feared complication of left ventricular thrombosis is thromboembolism. Cardioembolic stroke is generally severe, prone to early and long-term recurrence, and associated with a higher death rate than noncardioembolic ischemic stroke.^22,23 Thrombi associated with thromboembolism are often acute and mobile rather than organized and immobile.²⁴ They may embolize to the brain,  spleen, kidneys, and bowel.²⁵ In a meta-analysis of 11 studies, the pooled odds ratio for risk of embolization was 5.45 (95% confidence interval [CI] 3.02–9.83) with left ventricular thrombi vs without.²⁶ Before systemic thrombolysis and antiplatelet therapy became available, stroke rates ranged from 1.5% to 10%.^27–29

In a meta-analysis of 22 studies from 1978 to 2004, the incidence of ischemic stroke after MI during hospitalization was around 11.1 per 1,000 MIs.³⁰ This study found that anterior MI was associated with a higher risk of stroke, but reported no difference in the incidence of stroke with percutaneous coronary intervention, systemic thrombolysis, or no reperfusion.

In a large prospective cohort study of 2,160 patients,³¹ 259 (12%) had a stroke after MI. In multivariable analysis, age, diabetes, and previous stroke were predictors of stroke after MI. This study reported significantly fewer strokes in patients who underwent percutaneous coronary intervention than with other or no reperfusion therapies.³¹

ANTICOAGULATION TREATMENT

3. How would you treat a patient who has a drug-eluting stent in the left anterior descending artery and a new diagnosis of left ventricular thrombosis?

• Warfarin
• Aspirin and clopidogrel
• Aspirin, clopidogrel, and warfarin
• Aspirin and warfarin

The management of left ventricular thrombosis has been summarized in guidelines from the American College of Chest Physicians (ACCP) in 2012,³² and from the American College of Cardiology/American Heart Association in 2013,¹⁸ which recommend anticoagulation for at least 3 months, or indefinitely if bleeding risk is low, for all patients developing a left ventricular thrombus.

For patients with acute MI and left ventricular thrombosis, the ACCP guidelines recommend warfarin with a target international normalized ratio of 2.0 to 3.0 plus dual antiplatelet therapy (eg, aspirin plus clopidogrel)  for 3 months, after which warfarin is discontinued but dual antiplatelet therapy is continued for up to 12 months.³²

The European Society of Cardiology guidelines³³ recommend 6 months of anticoagulation. However, if the patient is receiving dual antiplatelet therapy, they recommend repeated imaging of the left ventricle after 3 months of anticoagulation, which may allow for earlier discontinuation of anticoagulation if the thrombus has resolved and apical wall motion has recovered. Therefore, most experts recommend 3 months of anticoagulation when used in combination with dual antiplatelet therapy and repeating echocardiography at 3 months to safely discontinue anticoagulation. The best answer to the question posed here is aspirin, clopidogrel, and warfarin.

Decisions about antithrombotic therapy may also depend on stent type and the patient’s bleeding risk. With bare-metal stents, dual antiplatelet therapy along with anticoagulation should be used for 1 month, after which anticoagulation should be used with a single antiplatelet agent for another 2 months; after this, the anticoagulant can be discontinued and dual antiplatelet therapy can be resumed for a total of 12 months. Newer anticoagulants such as rivaroxaban, dabigatran, edoxaban, and apixaban may also have a role, but they have not yet been studied for this indication.

Surgical thrombectomy is rarely considered now, given the known efficacy of anticoagulants in dissolving the thrombus. It was done in the past for large, mobile, or protruding left ventricular thrombi, which have a higher potential for embolization.³⁴ Currently, it can be done under very special circumstances, such as before placement of a left ventricular assist device or if the thrombus is large, to prevent embolism.^35,36

BLEEDING COMPLICATIONS WITH TRIPLE ANTITHROMBOTIC THERAPY

After stent placement, almost all patients need to be on dual antiplatelet therapy for a specified duration depending on the type and generation of stent used. Such patients end up on “triple” antithrombotic therapy (two antiplatelet drugs plus an anticoagulant), which poses a high risk of bleeding.³⁷ Consideration needs to be given to the risks of stroke, stent thrombosis, and major bleeding when selecting the antithrombotic regimen.³⁸ Triple antithrombotic therapy has been associated with a risk of fatal and nonfatal bleeding of 4% to 16% when used for indications such as atrial fibrillation.^39–41

Risks of triple antithrombotic therapy (aspirin 80–100 mg, clopidogrel 75 mg, and warfarin) were compared with those of clopidogrel plus warfarin in the What Is the Optimal Antiplatelet and Anticoagulant therapy in Patients With Oral Anticoagulation and Coronary Stenting Trial,³⁷ which reported a significantly lower risk of  major and minor bleeding with clopidogrel-plus-warfarin therapy than with triple antithrombotic therapy, 14.3% vs 31.7% (hazard ratio 0.40, 95% CI 0.28–0.58, P < .0001).

Additionally, the increased risk of major and minor bleeding associated with triple antithrombotic therapy has been confirmed in many observational studies; other studies found a trend toward lower risk with triple therapy, but this was not statistically significant (Table 2).^{38,40,42–55} A large multicenter European trial is being conducted to compare dual antiplatelet therapy vs triple antithrombotic therapy in patients with left ventricular thrombosis.

CASE FOLLOW-UP

Our patient was started on warfarin, clopidogrel 75 mg, and aspirin 75 mg at the time of discharge. He was continued on warfarin for 3 months, at which time a follow-up echocardiogram showed no thrombus in the left ventricle. Warfarin was discontinued, and he had no thromboembolic complications.

TAKE-HOME POINTS

Left ventricular thrombosis after an acute MI is very important to detect, as it can lead to serious complications through arterial embolism.

The incidence of left ventricular thrombosis has declined significantly with the use of percutaneous coronary intervention. However, it may still occur in a small number of patients with larger infarcts owing to delay in revascularization or proximal (left main or left anterior descending) occlusions with larger infarct size.

Echocardiography, which is routinely performed after acute MI to assess myocardial function, uncovers most left ventricular thrombi. In high-risk cases, MRI with late gadolinium enhancement can increase the diagnostic yield.

Anticoagulation with warfarin is recommended for at least 3 months. Post-MI patients undergoing stent implantation may need triple antithrombotic therapy, which, however, increases the bleeding risk significantly. Large randomized trials are needed to guide physicians in risk stratification of such patients.