PURLs

ILLUSTRATIVE CASE

A 26-year-old G1P0 at 40w1d presents in spontaneous labor and is dilated to 4 cm. The patient reached complete cervical dilation after artificial rupture of membranes and oxytocin augmentation. After 4 hours of pushing, there has been minimal descent of the fetal vertex beyond +1 station with significant caput succedaneum. Her physician decides to proceed with cesarean delivery.^2,3 What antibiotics should be administered prior to incision to reduce postoperative infection?

The Centers for Disease Control and Prevention (CDC) reports that nearly 1.3 million cesarean deliveries were performed in the United States in 2015, which represents about a third of all births.⁴ C-section is the most common major surgical procedure performed in this country and is associated with an infection rate 5 to 10 times that of vaginal delivery.^5,6 Pregnancy-associated infection, particularly during delivery, is a significant risk and the fourth most common cause of maternal death in the United States.⁵

The current standard of care in cesarean delivery is antibiotic prophylaxis (often a first-generation cephalosporin) prior to skin incision.⁷ The majority of c-sections performed are nonelective, and of these, postoperative infections occur in 12% of women who receive standard prophylaxis.^8,9 A small, single-center design trial suggested azithromycin adjunctive therapy expands antibiotic coverage to Ureaplasma species, resulting in a lower risk of postoperative infection.¹⁰

This study evaluated the use of azithromycin adjunctive therapy, in addition to standard antibiotic prophylaxis, to reduce the risk of postoperative infections in women receiving nonelective c-sections.

STUDY SUMMARY

Azithromycin reduced maternal infections up to 6 weeks post–c-section

A multicenter, randomized double-blind trial conducted in 14 hospitals in the United States evaluated the effect of a one-time dose of 500 mg intravenous (IV) azithromycin on post-cesarean infections. Women with a singleton pregnancy of at least 24 weeks’ gestation were eligible for inclusion if they required nonelective cesarean delivery during labor or at least 4 hours after membrane rupture. Patients were excluded if they had a known azithromycin allergy, subsequent vaginal delivery, azithromycin use within the week prior to randomization, extensive hepatic or renal dysfunction, a known history of prolonged QT interval, or substantial electrolyte abnormalities. Patients were eligible even if they were receiving other antibiotics for a positive group B Streptococcus screening.¹

All patients (N=2013) were treated with standard antibiotic prophylaxis, most often cefazolin, according to individual institution protocols. The women were randomized to receive either an azithromycin 500 mg/250 mL IV infusion (n=1019) or an identical placebo IV infusion (n=994) within one hour of the procedure. The primary outcome was a composite endpoint of endometritis, wound infection, or other infections occurring up to 6 weeks after the c-section. Secondary outcomes included neonatal death, sepsis, and other neonatal and maternal complications.¹

Patients in the placebo group had a higher rate of smoking during pregnancy; the researchers found no other significant differences.¹

Results. The primary composite outcome occurred less frequently in the azithromycin group than in the placebo group (6.1% vs 12.1%; relative risk [RR]=0.51; 95% confidence interval [CI], 0.38-0.68; number needed to treat [NNT]=17). When the researchers looked at the individual elements of the primary composite outcome, 2 had significant reductions vs placebo.

Endometritis (3.8% vs 6.1%; RR=0.62; 95% CI, 0.42-0.92; NNT=44) and wound infections (2.4% vs 6.6%; RR=0.35; 95% CI, 0.22-0.56; NNT=24) occurred significantly less frequently, but there was no difference for other infections (0.3% vs 0.6%; RR=0.49; 95% CI, 0.12-1.94). Serious maternal adverse events were also lower with treatment than in the control group (1.5% vs 2.9%; RR=0.5; 95% CI, 0.27-0.94; NNT=71). There was no difference in composite secondary neonatal outcomes including death and serious complications (14.3% vs 13.6%; RR=1.05; 95% CI, 0.85-1.31).¹

WHAT’S NEW

Azithromycin reduces infections without increasing adverse events

This study showed that adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of maternal or neonatal adverse events.

CAVEATS

Proceed with caution in those with prolonged QT intervals

While azithromycin was efficacious and well tolerated in the study, not every patient can take it. Patients with a previous drug reaction or allergy should avoid it, and experts advise prescribing it with caution for patients who have (or are at increased risk for) a prolonged QT interval, including those on other QT-prolonging medications.

Adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of adverse events.

Of note, women with scheduled c-sections and those with chorioamnionitis or another infection requiring postpartum antibiotics were excluded from this study. Thus, it is unknown if azithromycin use decreases complications in these patients.

CHALLENGES TO IMPLEMENTATION

Speed of procedure is often paramount, so drug availability is key

Nonelective c-sections occur based on many factors that include a non-reassuring fetal heart rate. In many of these cases, speed of cesarean delivery may mean the difference between positive and negative outcomes. Availability of azithromycin on labor and delivery floors for timely administration within one hour of the procedure is important.

Additionally, azithromycin has known QT prolongation risks.¹¹ While the baseline QT interval is not known for many healthy, young women, this should be considered when azithromycin is utilized in combination with other medications that may prolong the QT interval.

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 G1P0 at 40w1d presents in spontaneous labor and is dilated to 4 cm. The patient reached complete cervical dilation after artificial rupture of membranes and oxytocin augmentation. After 4 hours of pushing, there has been minimal descent of the fetal vertex beyond +1 station with significant caput succedaneum. Her physician decides to proceed with cesarean delivery.^2,3 What antibiotics should be administered prior to incision to reduce postoperative infection?

The Centers for Disease Control and Prevention (CDC) reports that nearly 1.3 million cesarean deliveries were performed in the United States in 2015, which represents about a third of all births.⁴ C-section is the most common major surgical procedure performed in this country and is associated with an infection rate 5 to 10 times that of vaginal delivery.^5,6 Pregnancy-associated infection, particularly during delivery, is a significant risk and the fourth most common cause of maternal death in the United States.⁵

The current standard of care in cesarean delivery is antibiotic prophylaxis (often a first-generation cephalosporin) prior to skin incision.⁷ The majority of c-sections performed are nonelective, and of these, postoperative infections occur in 12% of women who receive standard prophylaxis.^8,9 A small, single-center design trial suggested azithromycin adjunctive therapy expands antibiotic coverage to Ureaplasma species, resulting in a lower risk of postoperative infection.¹⁰

This study evaluated the use of azithromycin adjunctive therapy, in addition to standard antibiotic prophylaxis, to reduce the risk of postoperative infections in women receiving nonelective c-sections.

STUDY SUMMARY

Azithromycin reduced maternal infections up to 6 weeks post–c-section

A multicenter, randomized double-blind trial conducted in 14 hospitals in the United States evaluated the effect of a one-time dose of 500 mg intravenous (IV) azithromycin on post-cesarean infections. Women with a singleton pregnancy of at least 24 weeks’ gestation were eligible for inclusion if they required nonelective cesarean delivery during labor or at least 4 hours after membrane rupture. Patients were excluded if they had a known azithromycin allergy, subsequent vaginal delivery, azithromycin use within the week prior to randomization, extensive hepatic or renal dysfunction, a known history of prolonged QT interval, or substantial electrolyte abnormalities. Patients were eligible even if they were receiving other antibiotics for a positive group B Streptococcus screening.¹

All patients (N=2013) were treated with standard antibiotic prophylaxis, most often cefazolin, according to individual institution protocols. The women were randomized to receive either an azithromycin 500 mg/250 mL IV infusion (n=1019) or an identical placebo IV infusion (n=994) within one hour of the procedure. The primary outcome was a composite endpoint of endometritis, wound infection, or other infections occurring up to 6 weeks after the c-section. Secondary outcomes included neonatal death, sepsis, and other neonatal and maternal complications.¹

Patients in the placebo group had a higher rate of smoking during pregnancy; the researchers found no other significant differences.¹

Results. The primary composite outcome occurred less frequently in the azithromycin group than in the placebo group (6.1% vs 12.1%; relative risk [RR]=0.51; 95% confidence interval [CI], 0.38-0.68; number needed to treat [NNT]=17). When the researchers looked at the individual elements of the primary composite outcome, 2 had significant reductions vs placebo.

Endometritis (3.8% vs 6.1%; RR=0.62; 95% CI, 0.42-0.92; NNT=44) and wound infections (2.4% vs 6.6%; RR=0.35; 95% CI, 0.22-0.56; NNT=24) occurred significantly less frequently, but there was no difference for other infections (0.3% vs 0.6%; RR=0.49; 95% CI, 0.12-1.94). Serious maternal adverse events were also lower with treatment than in the control group (1.5% vs 2.9%; RR=0.5; 95% CI, 0.27-0.94; NNT=71). There was no difference in composite secondary neonatal outcomes including death and serious complications (14.3% vs 13.6%; RR=1.05; 95% CI, 0.85-1.31).¹

WHAT’S NEW

Azithromycin reduces infections without increasing adverse events

This study showed that adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of maternal or neonatal adverse events.

CAVEATS

Proceed with caution in those with prolonged QT intervals

While azithromycin was efficacious and well tolerated in the study, not every patient can take it. Patients with a previous drug reaction or allergy should avoid it, and experts advise prescribing it with caution for patients who have (or are at increased risk for) a prolonged QT interval, including those on other QT-prolonging medications.

Adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of adverse events.

Of note, women with scheduled c-sections and those with chorioamnionitis or another infection requiring postpartum antibiotics were excluded from this study. Thus, it is unknown if azithromycin use decreases complications in these patients.

CHALLENGES TO IMPLEMENTATION

Speed of procedure is often paramount, so drug availability is key

Nonelective c-sections occur based on many factors that include a non-reassuring fetal heart rate. In many of these cases, speed of cesarean delivery may mean the difference between positive and negative outcomes. Availability of azithromycin on labor and delivery floors for timely administration within one hour of the procedure is important.

Additionally, azithromycin has known QT prolongation risks.¹¹ While the baseline QT interval is not known for many healthy, young women, this should be considered when azithromycin is utilized in combination with other medications that may prolong the QT interval.

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 G1P0 at 40w1d presents in spontaneous labor and is dilated to 4 cm. The patient reached complete cervical dilation after artificial rupture of membranes and oxytocin augmentation. After 4 hours of pushing, there has been minimal descent of the fetal vertex beyond +1 station with significant caput succedaneum. Her physician decides to proceed with cesarean delivery.^2,3 What antibiotics should be administered prior to incision to reduce postoperative infection?

The Centers for Disease Control and Prevention (CDC) reports that nearly 1.3 million cesarean deliveries were performed in the United States in 2015, which represents about a third of all births.⁴ C-section is the most common major surgical procedure performed in this country and is associated with an infection rate 5 to 10 times that of vaginal delivery.^5,6 Pregnancy-associated infection, particularly during delivery, is a significant risk and the fourth most common cause of maternal death in the United States.⁵

The current standard of care in cesarean delivery is antibiotic prophylaxis (often a first-generation cephalosporin) prior to skin incision.⁷ The majority of c-sections performed are nonelective, and of these, postoperative infections occur in 12% of women who receive standard prophylaxis.^8,9 A small, single-center design trial suggested azithromycin adjunctive therapy expands antibiotic coverage to Ureaplasma species, resulting in a lower risk of postoperative infection.¹⁰

This study evaluated the use of azithromycin adjunctive therapy, in addition to standard antibiotic prophylaxis, to reduce the risk of postoperative infections in women receiving nonelective c-sections.

STUDY SUMMARY

Azithromycin reduced maternal infections up to 6 weeks post–c-section

A multicenter, randomized double-blind trial conducted in 14 hospitals in the United States evaluated the effect of a one-time dose of 500 mg intravenous (IV) azithromycin on post-cesarean infections. Women with a singleton pregnancy of at least 24 weeks’ gestation were eligible for inclusion if they required nonelective cesarean delivery during labor or at least 4 hours after membrane rupture. Patients were excluded if they had a known azithromycin allergy, subsequent vaginal delivery, azithromycin use within the week prior to randomization, extensive hepatic or renal dysfunction, a known history of prolonged QT interval, or substantial electrolyte abnormalities. Patients were eligible even if they were receiving other antibiotics for a positive group B Streptococcus screening.¹

All patients (N=2013) were treated with standard antibiotic prophylaxis, most often cefazolin, according to individual institution protocols. The women were randomized to receive either an azithromycin 500 mg/250 mL IV infusion (n=1019) or an identical placebo IV infusion (n=994) within one hour of the procedure. The primary outcome was a composite endpoint of endometritis, wound infection, or other infections occurring up to 6 weeks after the c-section. Secondary outcomes included neonatal death, sepsis, and other neonatal and maternal complications.¹

Patients in the placebo group had a higher rate of smoking during pregnancy; the researchers found no other significant differences.¹

Results. The primary composite outcome occurred less frequently in the azithromycin group than in the placebo group (6.1% vs 12.1%; relative risk [RR]=0.51; 95% confidence interval [CI], 0.38-0.68; number needed to treat [NNT]=17). When the researchers looked at the individual elements of the primary composite outcome, 2 had significant reductions vs placebo.

Endometritis (3.8% vs 6.1%; RR=0.62; 95% CI, 0.42-0.92; NNT=44) and wound infections (2.4% vs 6.6%; RR=0.35; 95% CI, 0.22-0.56; NNT=24) occurred significantly less frequently, but there was no difference for other infections (0.3% vs 0.6%; RR=0.49; 95% CI, 0.12-1.94). Serious maternal adverse events were also lower with treatment than in the control group (1.5% vs 2.9%; RR=0.5; 95% CI, 0.27-0.94; NNT=71). There was no difference in composite secondary neonatal outcomes including death and serious complications (14.3% vs 13.6%; RR=1.05; 95% CI, 0.85-1.31).¹

WHAT’S NEW

Azithromycin reduces infections without increasing adverse events

This study showed that adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of maternal or neonatal adverse events.

CAVEATS

Proceed with caution in those with prolonged QT intervals

While azithromycin was efficacious and well tolerated in the study, not every patient can take it. Patients with a previous drug reaction or allergy should avoid it, and experts advise prescribing it with caution for patients who have (or are at increased risk for) a prolonged QT interval, including those on other QT-prolonging medications.

Adding azithromycin to standard antibiotic prophylaxis within one hour of a c-section reduces post-cesarean delivery infection rates without increasing the risk of adverse events.

Of note, women with scheduled c-sections and those with chorioamnionitis or another infection requiring postpartum antibiotics were excluded from this study. Thus, it is unknown if azithromycin use decreases complications in these patients.

CHALLENGES TO IMPLEMENTATION

Speed of procedure is often paramount, so drug availability is key

Nonelective c-sections occur based on many factors that include a non-reassuring fetal heart rate. In many of these cases, speed of cesarean delivery may mean the difference between positive and negative outcomes. Availability of azithromycin on labor and delivery floors for timely administration within one hour of the procedure is important.

Additionally, azithromycin has known QT prolongation risks.¹¹ While the baseline QT interval is not known for many healthy, young women, this should be considered when azithromycin is utilized in combination with other medications that may prolong the QT interval.

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.

A 65-year-old woman is admitted to your inpatient service from the family health center. She is diagnosed with community-acquired pneumonia (CAP) based on a five-day history of cough and fever and a positive chest x-ray. She now requires oxygen at rest. She has a history of hypertension and diabetes, both of which have been controlled by oral medications. Antibiotic therapy is initiated—but what treatment duration is ideal?

The World Health Organization estimates that pneumonia is the third most common cause of mortality worldwide, causing 3.2 million deaths per year.² Appropriate prescribing of antibiotics is critical for successful treatment of CAP.

In 2007, the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) created consensus guidelines for the treatment of CAP.³ These guidelines recommend a minimum five-day course of antibiotics if the patient is clinically stable (defined as afebrile for 48 h; heart rate ≤ 100 beats/min; respiratory rate ≤ 24 breaths/min^-1; systolic blood pressure ≥ 90 mm Hg; oxygen saturation ≥ 90%; normal mental status; and able to tolerate oral intake). Longer antibiotic treatment durations are recommended on an individualized basis (eg, if the isolated pathogen is not susceptible to the initial antibiotic or if the infection was caused by an extrapulmonary source).

However, these recommendations are not routinely followed. Practitioners often make it their custom to prescribe longer courses of antibiotics.⁴ Yet, we know that there are several reasons to consider shorter courses of antibiotics, including lower health care costs, fewer adverse effects, and lower rates of bacterial resistance.^5-7

Two meta-analyses were performed to compare the safety and efficacy of short- and long-course antibiotic therapy in CAP (≤ 7 d vs > 7 d, respectively).^8,9 Both meta-analyses found no difference in efficacy or safety between shorter and longer courses of antibiotics for CAP. Secondary outcomes noted a trend toward decreased antibiotic-associated adverse events with shorter courses of therapy.^8,9

However, there are limitations to broad implementation. Studies included in these analyses utilized a variety of antibiotic treatment regimens and longer courses (7 d vs 5 d) that are not recommended by the IDSA/ATS guidelines. Additionally, studies included both inpatient and outpatient treatment groups, so findings may not apply to an exclusively inpatient CAP population.^8,9

This study sought to validate the IDSA/ATS guidelines recommending a five-day course of antibiotics for hospitalized patients with CAP.¹

STUDY SUMMARY

No differences in clinical outcomes

This multicenter, double-blind, noninferiority randomized trial compared short-term antibiotic treatment duration (5 d) to physician-discretion antibiotic treatment duration among 312 patients (ages 18 and older) admitted for CAP to one of four teaching hospitals in Spain.¹ Pneumonia was diagnosed on chest radiograph with at least one symptom: cough, fever, dyspnea, or chest pain. Patients were excluded if, among other things, they had an immunocompromising condition, lived in a nursing home, had a recent hospital stay, used antibiotics within the previous 30 days, or had an uncommon pathogen, such as Pseudomonas aeruginosa or Staphylococcus aureus.¹

After receiving a minimum of five days of antibiotics, patients were randomly assigned to an intervention group (where, if clinically stable, no further antibiotics were given) or a control group (where physicians determined antibiotic duration).¹

Primary outcomes were clinical success rate at days 10 and 30 from admission (defined as resolution of signs and symptoms of CAP without further antibiotics) and improvement of CAP-related symptoms (as determined by an 18-item questionnaire scored 0-90, with higher scores indicative of greater severity). Secondary outcomes included duration of antibiotic use, time to clinical improvement, mortality, hospital readmission, hospital length of stay, and CAP recurrence.¹

Of the 312 participants, 162 were randomized to the intervention group and 150 to the control group. Mean age of patients in the intervention and control groups was 66.2 and 64.7, respectively. Other baseline demographics were similar between the groups. Nearly 80% of patients received quinolone treatment; < 10% received a ß-lactam plus a macrolide.¹

Clinical success rates were similar for the control and intervention groups at day 10 (49% vs 56%, respectively) and day 30 (89% vs 92%). Median antibiotic treatment duration was shorter in the intervention group than in the control group (5 d vs 10 d); the intervention group also had a lower rate of 30-day hospital readmissions (1.4% vs 6.6%). There were no differences for other secondary outcomes.¹

WHAT’S NEW

Clinical support for 2007 guidelines

This is the first study to clinically support the IDSA/ATS guidelines, which state that a five-day course of antibiotic therapy for hospitalized adults with CAP is effective and without increased risk for adverse events.

CAVEATS

Generalizability is unclear

This study focused on antibiotic duration for the treatment of CAP in hospitalized patients and mainly used quinolone antibiotics. It remains unclear if duration of therapy is as effective in the outpatient setting or when using alternative antibiotic regimens.

If patients continued to have symptoms (eg, fever or low oxygen saturation on room air) after five days of antibiotics, treatment was continued in the study. Thus, patients in real life who continue to have symptoms may need individualized therapy and may require more than five days of antibiotics.

CHALLENGES TO IMPLEMENTATION

Antibiotics end before clinical improvement

In this study, it took an average of 12 days in both groups for patients to achieve clinical improvement, and upwards of 15 to 18 days for patients to return to normal activity. Patients and providers may be dissatisfied if the treatment course ends days before clinical improvement of symptoms. This may cause prescribers to lengthen the duration of antibiotic therapy inappropriately.

ACKNOWLEDGEMENT

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

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017; 66[10]:629-631).

A 65-year-old woman is admitted to your inpatient service from the family health center. She is diagnosed with community-acquired pneumonia (CAP) based on a five-day history of cough and fever and a positive chest x-ray. She now requires oxygen at rest. She has a history of hypertension and diabetes, both of which have been controlled by oral medications. Antibiotic therapy is initiated—but what treatment duration is ideal?

The World Health Organization estimates that pneumonia is the third most common cause of mortality worldwide, causing 3.2 million deaths per year.² Appropriate prescribing of antibiotics is critical for successful treatment of CAP.

In 2007, the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) created consensus guidelines for the treatment of CAP.³ These guidelines recommend a minimum five-day course of antibiotics if the patient is clinically stable (defined as afebrile for 48 h; heart rate ≤ 100 beats/min; respiratory rate ≤ 24 breaths/min^-1; systolic blood pressure ≥ 90 mm Hg; oxygen saturation ≥ 90%; normal mental status; and able to tolerate oral intake). Longer antibiotic treatment durations are recommended on an individualized basis (eg, if the isolated pathogen is not susceptible to the initial antibiotic or if the infection was caused by an extrapulmonary source).

However, these recommendations are not routinely followed. Practitioners often make it their custom to prescribe longer courses of antibiotics.⁴ Yet, we know that there are several reasons to consider shorter courses of antibiotics, including lower health care costs, fewer adverse effects, and lower rates of bacterial resistance.^5-7

Two meta-analyses were performed to compare the safety and efficacy of short- and long-course antibiotic therapy in CAP (≤ 7 d vs > 7 d, respectively).^8,9 Both meta-analyses found no difference in efficacy or safety between shorter and longer courses of antibiotics for CAP. Secondary outcomes noted a trend toward decreased antibiotic-associated adverse events with shorter courses of therapy.^8,9

However, there are limitations to broad implementation. Studies included in these analyses utilized a variety of antibiotic treatment regimens and longer courses (7 d vs 5 d) that are not recommended by the IDSA/ATS guidelines. Additionally, studies included both inpatient and outpatient treatment groups, so findings may not apply to an exclusively inpatient CAP population.^8,9

This study sought to validate the IDSA/ATS guidelines recommending a five-day course of antibiotics for hospitalized patients with CAP.¹

STUDY SUMMARY

No differences in clinical outcomes

This multicenter, double-blind, noninferiority randomized trial compared short-term antibiotic treatment duration (5 d) to physician-discretion antibiotic treatment duration among 312 patients (ages 18 and older) admitted for CAP to one of four teaching hospitals in Spain.¹ Pneumonia was diagnosed on chest radiograph with at least one symptom: cough, fever, dyspnea, or chest pain. Patients were excluded if, among other things, they had an immunocompromising condition, lived in a nursing home, had a recent hospital stay, used antibiotics within the previous 30 days, or had an uncommon pathogen, such as Pseudomonas aeruginosa or Staphylococcus aureus.¹

After receiving a minimum of five days of antibiotics, patients were randomly assigned to an intervention group (where, if clinically stable, no further antibiotics were given) or a control group (where physicians determined antibiotic duration).¹

Primary outcomes were clinical success rate at days 10 and 30 from admission (defined as resolution of signs and symptoms of CAP without further antibiotics) and improvement of CAP-related symptoms (as determined by an 18-item questionnaire scored 0-90, with higher scores indicative of greater severity). Secondary outcomes included duration of antibiotic use, time to clinical improvement, mortality, hospital readmission, hospital length of stay, and CAP recurrence.¹

Of the 312 participants, 162 were randomized to the intervention group and 150 to the control group. Mean age of patients in the intervention and control groups was 66.2 and 64.7, respectively. Other baseline demographics were similar between the groups. Nearly 80% of patients received quinolone treatment; < 10% received a ß-lactam plus a macrolide.¹

Clinical success rates were similar for the control and intervention groups at day 10 (49% vs 56%, respectively) and day 30 (89% vs 92%). Median antibiotic treatment duration was shorter in the intervention group than in the control group (5 d vs 10 d); the intervention group also had a lower rate of 30-day hospital readmissions (1.4% vs 6.6%). There were no differences for other secondary outcomes.¹

WHAT’S NEW

Clinical support for 2007 guidelines

This is the first study to clinically support the IDSA/ATS guidelines, which state that a five-day course of antibiotic therapy for hospitalized adults with CAP is effective and without increased risk for adverse events.

CAVEATS

Generalizability is unclear

This study focused on antibiotic duration for the treatment of CAP in hospitalized patients and mainly used quinolone antibiotics. It remains unclear if duration of therapy is as effective in the outpatient setting or when using alternative antibiotic regimens.

If patients continued to have symptoms (eg, fever or low oxygen saturation on room air) after five days of antibiotics, treatment was continued in the study. Thus, patients in real life who continue to have symptoms may need individualized therapy and may require more than five days of antibiotics.

CHALLENGES TO IMPLEMENTATION

Antibiotics end before clinical improvement

In this study, it took an average of 12 days in both groups for patients to achieve clinical improvement, and upwards of 15 to 18 days for patients to return to normal activity. Patients and providers may be dissatisfied if the treatment course ends days before clinical improvement of symptoms. This may cause prescribers to lengthen the duration of antibiotic therapy inappropriately.

ACKNOWLEDGEMENT

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

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017; 66[10]:629-631).

A 65-year-old woman is admitted to your inpatient service from the family health center. She is diagnosed with community-acquired pneumonia (CAP) based on a five-day history of cough and fever and a positive chest x-ray. She now requires oxygen at rest. She has a history of hypertension and diabetes, both of which have been controlled by oral medications. Antibiotic therapy is initiated—but what treatment duration is ideal?

The World Health Organization estimates that pneumonia is the third most common cause of mortality worldwide, causing 3.2 million deaths per year.² Appropriate prescribing of antibiotics is critical for successful treatment of CAP.

In 2007, the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) created consensus guidelines for the treatment of CAP.³ These guidelines recommend a minimum five-day course of antibiotics if the patient is clinically stable (defined as afebrile for 48 h; heart rate ≤ 100 beats/min; respiratory rate ≤ 24 breaths/min^-1; systolic blood pressure ≥ 90 mm Hg; oxygen saturation ≥ 90%; normal mental status; and able to tolerate oral intake). Longer antibiotic treatment durations are recommended on an individualized basis (eg, if the isolated pathogen is not susceptible to the initial antibiotic or if the infection was caused by an extrapulmonary source).

However, these recommendations are not routinely followed. Practitioners often make it their custom to prescribe longer courses of antibiotics.⁴ Yet, we know that there are several reasons to consider shorter courses of antibiotics, including lower health care costs, fewer adverse effects, and lower rates of bacterial resistance.^5-7

Two meta-analyses were performed to compare the safety and efficacy of short- and long-course antibiotic therapy in CAP (≤ 7 d vs > 7 d, respectively).^8,9 Both meta-analyses found no difference in efficacy or safety between shorter and longer courses of antibiotics for CAP. Secondary outcomes noted a trend toward decreased antibiotic-associated adverse events with shorter courses of therapy.^8,9

However, there are limitations to broad implementation. Studies included in these analyses utilized a variety of antibiotic treatment regimens and longer courses (7 d vs 5 d) that are not recommended by the IDSA/ATS guidelines. Additionally, studies included both inpatient and outpatient treatment groups, so findings may not apply to an exclusively inpatient CAP population.^8,9

This study sought to validate the IDSA/ATS guidelines recommending a five-day course of antibiotics for hospitalized patients with CAP.¹

STUDY SUMMARY

No differences in clinical outcomes

This multicenter, double-blind, noninferiority randomized trial compared short-term antibiotic treatment duration (5 d) to physician-discretion antibiotic treatment duration among 312 patients (ages 18 and older) admitted for CAP to one of four teaching hospitals in Spain.¹ Pneumonia was diagnosed on chest radiograph with at least one symptom: cough, fever, dyspnea, or chest pain. Patients were excluded if, among other things, they had an immunocompromising condition, lived in a nursing home, had a recent hospital stay, used antibiotics within the previous 30 days, or had an uncommon pathogen, such as Pseudomonas aeruginosa or Staphylococcus aureus.¹

After receiving a minimum of five days of antibiotics, patients were randomly assigned to an intervention group (where, if clinically stable, no further antibiotics were given) or a control group (where physicians determined antibiotic duration).¹

Primary outcomes were clinical success rate at days 10 and 30 from admission (defined as resolution of signs and symptoms of CAP without further antibiotics) and improvement of CAP-related symptoms (as determined by an 18-item questionnaire scored 0-90, with higher scores indicative of greater severity). Secondary outcomes included duration of antibiotic use, time to clinical improvement, mortality, hospital readmission, hospital length of stay, and CAP recurrence.¹

Of the 312 participants, 162 were randomized to the intervention group and 150 to the control group. Mean age of patients in the intervention and control groups was 66.2 and 64.7, respectively. Other baseline demographics were similar between the groups. Nearly 80% of patients received quinolone treatment; < 10% received a ß-lactam plus a macrolide.¹

Clinical success rates were similar for the control and intervention groups at day 10 (49% vs 56%, respectively) and day 30 (89% vs 92%). Median antibiotic treatment duration was shorter in the intervention group than in the control group (5 d vs 10 d); the intervention group also had a lower rate of 30-day hospital readmissions (1.4% vs 6.6%). There were no differences for other secondary outcomes.¹

WHAT’S NEW

Clinical support for 2007 guidelines

This is the first study to clinically support the IDSA/ATS guidelines, which state that a five-day course of antibiotic therapy for hospitalized adults with CAP is effective and without increased risk for adverse events.

CAVEATS

Generalizability is unclear

This study focused on antibiotic duration for the treatment of CAP in hospitalized patients and mainly used quinolone antibiotics. It remains unclear if duration of therapy is as effective in the outpatient setting or when using alternative antibiotic regimens.

If patients continued to have symptoms (eg, fever or low oxygen saturation on room air) after five days of antibiotics, treatment was continued in the study. Thus, patients in real life who continue to have symptoms may need individualized therapy and may require more than five days of antibiotics.

CHALLENGES TO IMPLEMENTATION

Antibiotics end before clinical improvement

In this study, it took an average of 12 days in both groups for patients to achieve clinical improvement, and upwards of 15 to 18 days for patients to return to normal activity. Patients and providers may be dissatisfied if the treatment course ends days before clinical improvement of symptoms. This may cause prescribers to lengthen the duration of antibiotic therapy inappropriately.

ACKNOWLEDGEMENT

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

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017; 66[10]:629-631).

ILLUSTRATIVE CASE

A 60-year-old man establishes care with you. He has well-controlled osteoarthritis (as long as he takes his low-dose daily aspirin) and chronic atrial fibrillation, for which he takes warfarin. His international normalized ratio (INR) is consistently within the recommended target range of 2 to 3. He feels well and has never had gastroesophageal reflux disease (GERD) or a gastrointestinal (GI) bleed. Should you recommend a proton pump inhibitor (PPI) to decrease the likelihood of a future upper GI bleed?

Anticoagulation therapy creates a dilemma—the need to balance the benefits of preventing embolization with the risks of serious bleeding. Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and other antiplatelet agents further increases the risk of the latter.²

Physicians have long used PPIs to treat upper GI bleeds. They prevent acid secretion and are the most efficacious drugs for healing peptic ulcers.^3,4 However, while previous case-control studies show that PPIs reduce the risk of upper GI bleeds in patients taking antiplatelet agents or NSAIDs, they do not show a statistically significant benefit for patients taking warfarin.^5,6 Further reflecting the confusion and uncertainty surrounding this issue is that while one expert consensus report recommends that patients taking dual warfarin and antiplatelet agent/NSAID therapy take a PPI to decrease the risk of upper GI bleeding,² other guidelines regarding anticoagulant therapy do not address this clinical question.^2,7,8

[polldaddy:9860876]

STUDY SUMMARY

Study lends support to PPI use in a high-risk group

This retrospective cohort study sought to answer the question: “Does PPI co-therapy decrease the rate of serious upper GI bleeds in patients taking warfarin?” Researchers examined rates of hospitalization for upper GI bleeding for Medicare and Medicaid patients taking warfarin with and without PPI co-therapy (tracked via prescription fill dates). They also evaluated concomitant use of NSAIDs and antiplatelet agents.

The authors excluded patients with a recent history of a severe bleed or certain illnesses that would predispose a patient to GI bleeding (such as esophageal varices). Patients with risk factors for an upper GI bleed (such as abdominal pain, peptic ulcer disease, anemia, etc.) were more likely to be taking PPI co-therapy. Researchers analyzed the effect of PPI co-therapy in patients with and without these additional risk factors.

Results. The study followed over 75,000 person-years of active warfarin therapy (more than 52,000 person-years in the Medicaid cohort and more than 23,000 person-years in the Medicare cohort). Hospitalizations due to upper GI bleeding occurred at a rate of 127/10,000 person-years (incidence was similar in both the Medicaid and Medicare groups).

Looking at all patients taking warfarin (regardless of whether or not they were also taking an NSAID or antiplatelet agent), PPI co-therapy reduced the risk of hospitalization for upper GI bleeding by 24% (adjusted hazard ratio [HR]=0.76; 95% confidence interval [CI], 0.63 to 0.91), which translates into 29 fewer hospitalizations per 10,000 person-years. The number needed to treat (NNT) was 345 person-years, meaning 345 patients taking warfarin would have to take a PPI for one year to prevent one hospitalization for an upper GI bleed. As one might expect, PPI co-therapy did not significantly reduce the risk of lower GI, other GI, or non-GI bleeding.

Further research is warranted to determine if PPI therapy is beneficial to patients taking direct oral anticoagulants.

In patients taking both warfarin and concurrent antiplatelet agents or NSAIDs, PPI co-therapy reduced the risk of hospitalization for upper GI bleeding by about half (HR=0.55; 95% CI, 0.39-0.77). Hospitalizations decreased by 128/10,000 person-years (95% CI, -66 to -173), yielding an NNT of 78 person-years. For patients taking warfarin but not antiplatelet agents or NSAIDs, PPI co-therapy did not significantly decrease the risk of hospitalization for upper GI bleeding (HR=0.86; 95% CI, 0.70-1.06).

Additional risk factors for GI bleeds. Researchers also looked at patients who had additional risk factors for GI bleeds (other than the exclusion criteria). For patients taking both warfarin and an antiplatelet agent/NSAID, PPI co-therapy decreased the risk of upper GI bleeding whether or not the patients had other bleeding risk factors. Again, for patients who had additional bleeding risk factors, but were not taking an antiplatelet agent or NSAID, PPI therapy showed no statistically significant effect.

WHAT’S NEW

PPIs offer benefits, but not to patients taking warfarin alone

The statistically significant results in this large observational study suggest that PPI co-therapy is beneficial in reducing the risk of upper GI bleeding in patients taking warfarin plus an antiplatelet agent/NSAID, but that PPI co-therapy provides no benefit to patients taking warfarin exclusively.

CAVEATS

Study was good, but it wasn’t a randomized controlled trial

This study is observational, and not a randomized control trial (RCT). Therefore, unknown confounding variables may have skewed results. For example, patients could have taken over-the-counter medications that influenced or obscured results, but were not included in the data analysis (misclassification bias).

At best, we can infer a correlation between PPIs and decreased risk of upper GI bleeds. We need RCTs to determine whether PPIs cause a lower risk.

Don’t overlook the risk of PPIs. This study assessed the ability of PPIs to prevent bleeds, but did not address the risks of long-term PPI therapy. Adverse effects of PPIs include an increased risk of pneumonia, infection with Clostridium difficile, hip and spine fractures, anemia, and possibly chronic kidney disease and dementia.^9-11 In addition, cost-analysis studies of PPI therapy are limited and inconsistent.¹² Therefore, it’s best to make decisions regarding PPIs after discussing other risks and benefits.

What about DOACs? Another consideration is the option to prescribe a direct oral anticoagulant (DOAC), such as dabigatran, rivaroxaban, or apixaban, instead of warfarin. DOACs are at least as effective as warfarin at preventing stroke in patients with atrial fibrillation and may even be safer.¹³ Dabigatran 110 mg causes fewer “major bleeding” events than warfarin.¹³ Rivaroxaban has been shown to result in fewer fatal bleeding events than warfarin due to fatal intracranial bleeds, although it is associated with more GI bleedding.¹³ Compared with warfarin, apixaban is associated with fewer GI bleeds and lower bleeding rates overall.¹³ Further research is warranted to determine if PPI therapy is beneficial to patients taking DOACs.

CHALLENGES TO IMPLEMENTATION

It’s still a balancing act

When chronic anticoagulation is necessary, physicians and patients must attempt to prevent thrombotic events while minimizing the risk of GI bleeds. PPIs may be beneficial in preventing upper GI bleeds in patients taking dual warfarin and antiplatelet therapy, but the long-term consequences of PPI therapy should not be ignored.

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 60-year-old man establishes care with you. He has well-controlled osteoarthritis (as long as he takes his low-dose daily aspirin) and chronic atrial fibrillation, for which he takes warfarin. His international normalized ratio (INR) is consistently within the recommended target range of 2 to 3. He feels well and has never had gastroesophageal reflux disease (GERD) or a gastrointestinal (GI) bleed. Should you recommend a proton pump inhibitor (PPI) to decrease the likelihood of a future upper GI bleed?

Anticoagulation therapy creates a dilemma—the need to balance the benefits of preventing embolization with the risks of serious bleeding. Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and other antiplatelet agents further increases the risk of the latter.²

Physicians have long used PPIs to treat upper GI bleeds. They prevent acid secretion and are the most efficacious drugs for healing peptic ulcers.^3,4 However, while previous case-control studies show that PPIs reduce the risk of upper GI bleeds in patients taking antiplatelet agents or NSAIDs, they do not show a statistically significant benefit for patients taking warfarin.^5,6 Further reflecting the confusion and uncertainty surrounding this issue is that while one expert consensus report recommends that patients taking dual warfarin and antiplatelet agent/NSAID therapy take a PPI to decrease the risk of upper GI bleeding,² other guidelines regarding anticoagulant therapy do not address this clinical question.^2,7,8

[polldaddy:9860876]

STUDY SUMMARY

Study lends support to PPI use in a high-risk group

This retrospective cohort study sought to answer the question: “Does PPI co-therapy decrease the rate of serious upper GI bleeds in patients taking warfarin?” Researchers examined rates of hospitalization for upper GI bleeding for Medicare and Medicaid patients taking warfarin with and without PPI co-therapy (tracked via prescription fill dates). They also evaluated concomitant use of NSAIDs and antiplatelet agents.

The authors excluded patients with a recent history of a severe bleed or certain illnesses that would predispose a patient to GI bleeding (such as esophageal varices). Patients with risk factors for an upper GI bleed (such as abdominal pain, peptic ulcer disease, anemia, etc.) were more likely to be taking PPI co-therapy. Researchers analyzed the effect of PPI co-therapy in patients with and without these additional risk factors.

Results. The study followed over 75,000 person-years of active warfarin therapy (more than 52,000 person-years in the Medicaid cohort and more than 23,000 person-years in the Medicare cohort). Hospitalizations due to upper GI bleeding occurred at a rate of 127/10,000 person-years (incidence was similar in both the Medicaid and Medicare groups).

Looking at all patients taking warfarin (regardless of whether or not they were also taking an NSAID or antiplatelet agent), PPI co-therapy reduced the risk of hospitalization for upper GI bleeding by 24% (adjusted hazard ratio [HR]=0.76; 95% confidence interval [CI], 0.63 to 0.91), which translates into 29 fewer hospitalizations per 10,000 person-years. The number needed to treat (NNT) was 345 person-years, meaning 345 patients taking warfarin would have to take a PPI for one year to prevent one hospitalization for an upper GI bleed. As one might expect, PPI co-therapy did not significantly reduce the risk of lower GI, other GI, or non-GI bleeding.

Further research is warranted to determine if PPI therapy is beneficial to patients taking direct oral anticoagulants.

In patients taking both warfarin and concurrent antiplatelet agents or NSAIDs, PPI co-therapy reduced the risk of hospitalization for upper GI bleeding by about half (HR=0.55; 95% CI, 0.39-0.77). Hospitalizations decreased by 128/10,000 person-years (95% CI, -66 to -173), yielding an NNT of 78 person-years. For patients taking warfarin but not antiplatelet agents or NSAIDs, PPI co-therapy did not significantly decrease the risk of hospitalization for upper GI bleeding (HR=0.86; 95% CI, 0.70-1.06).

Additional risk factors for GI bleeds. Researchers also looked at patients who had additional risk factors for GI bleeds (other than the exclusion criteria). For patients taking both warfarin and an antiplatelet agent/NSAID, PPI co-therapy decreased the risk of upper GI bleeding whether or not the patients had other bleeding risk factors. Again, for patients who had additional bleeding risk factors, but were not taking an antiplatelet agent or NSAID, PPI therapy showed no statistically significant effect.

WHAT’S NEW

PPIs offer benefits, but not to patients taking warfarin alone

The statistically significant results in this large observational study suggest that PPI co-therapy is beneficial in reducing the risk of upper GI bleeding in patients taking warfarin plus an antiplatelet agent/NSAID, but that PPI co-therapy provides no benefit to patients taking warfarin exclusively.

CAVEATS

Study was good, but it wasn’t a randomized controlled trial

This study is observational, and not a randomized control trial (RCT). Therefore, unknown confounding variables may have skewed results. For example, patients could have taken over-the-counter medications that influenced or obscured results, but were not included in the data analysis (misclassification bias).

At best, we can infer a correlation between PPIs and decreased risk of upper GI bleeds. We need RCTs to determine whether PPIs cause a lower risk.

Don’t overlook the risk of PPIs. This study assessed the ability of PPIs to prevent bleeds, but did not address the risks of long-term PPI therapy. Adverse effects of PPIs include an increased risk of pneumonia, infection with Clostridium difficile, hip and spine fractures, anemia, and possibly chronic kidney disease and dementia.^9-11 In addition, cost-analysis studies of PPI therapy are limited and inconsistent.¹² Therefore, it’s best to make decisions regarding PPIs after discussing other risks and benefits.

What about DOACs? Another consideration is the option to prescribe a direct oral anticoagulant (DOAC), such as dabigatran, rivaroxaban, or apixaban, instead of warfarin. DOACs are at least as effective as warfarin at preventing stroke in patients with atrial fibrillation and may even be safer.¹³ Dabigatran 110 mg causes fewer “major bleeding” events than warfarin.¹³ Rivaroxaban has been shown to result in fewer fatal bleeding events than warfarin due to fatal intracranial bleeds, although it is associated with more GI bleedding.¹³ Compared with warfarin, apixaban is associated with fewer GI bleeds and lower bleeding rates overall.¹³ Further research is warranted to determine if PPI therapy is beneficial to patients taking DOACs.

CHALLENGES TO IMPLEMENTATION

It’s still a balancing act

When chronic anticoagulation is necessary, physicians and patients must attempt to prevent thrombotic events while minimizing the risk of GI bleeds. PPIs may be beneficial in preventing upper GI bleeds in patients taking dual warfarin and antiplatelet therapy, but the long-term consequences of PPI therapy should not be ignored.

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 60-year-old man establishes care with you. He has well-controlled osteoarthritis (as long as he takes his low-dose daily aspirin) and chronic atrial fibrillation, for which he takes warfarin. His international normalized ratio (INR) is consistently within the recommended target range of 2 to 3. He feels well and has never had gastroesophageal reflux disease (GERD) or a gastrointestinal (GI) bleed. Should you recommend a proton pump inhibitor (PPI) to decrease the likelihood of a future upper GI bleed?

Anticoagulation therapy creates a dilemma—the need to balance the benefits of preventing embolization with the risks of serious bleeding. Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and other antiplatelet agents further increases the risk of the latter.²

Physicians have long used PPIs to treat upper GI bleeds. They prevent acid secretion and are the most efficacious drugs for healing peptic ulcers.^3,4 However, while previous case-control studies show that PPIs reduce the risk of upper GI bleeds in patients taking antiplatelet agents or NSAIDs, they do not show a statistically significant benefit for patients taking warfarin.^5,6 Further reflecting the confusion and uncertainty surrounding this issue is that while one expert consensus report recommends that patients taking dual warfarin and antiplatelet agent/NSAID therapy take a PPI to decrease the risk of upper GI bleeding,² other guidelines regarding anticoagulant therapy do not address this clinical question.^2,7,8

[polldaddy:9860876]

STUDY SUMMARY

Study lends support to PPI use in a high-risk group

This retrospective cohort study sought to answer the question: “Does PPI co-therapy decrease the rate of serious upper GI bleeds in patients taking warfarin?” Researchers examined rates of hospitalization for upper GI bleeding for Medicare and Medicaid patients taking warfarin with and without PPI co-therapy (tracked via prescription fill dates). They also evaluated concomitant use of NSAIDs and antiplatelet agents.

The authors excluded patients with a recent history of a severe bleed or certain illnesses that would predispose a patient to GI bleeding (such as esophageal varices). Patients with risk factors for an upper GI bleed (such as abdominal pain, peptic ulcer disease, anemia, etc.) were more likely to be taking PPI co-therapy. Researchers analyzed the effect of PPI co-therapy in patients with and without these additional risk factors.

Results. The study followed over 75,000 person-years of active warfarin therapy (more than 52,000 person-years in the Medicaid cohort and more than 23,000 person-years in the Medicare cohort). Hospitalizations due to upper GI bleeding occurred at a rate of 127/10,000 person-years (incidence was similar in both the Medicaid and Medicare groups).

Looking at all patients taking warfarin (regardless of whether or not they were also taking an NSAID or antiplatelet agent), PPI co-therapy reduced the risk of hospitalization for upper GI bleeding by 24% (adjusted hazard ratio [HR]=0.76; 95% confidence interval [CI], 0.63 to 0.91), which translates into 29 fewer hospitalizations per 10,000 person-years. The number needed to treat (NNT) was 345 person-years, meaning 345 patients taking warfarin would have to take a PPI for one year to prevent one hospitalization for an upper GI bleed. As one might expect, PPI co-therapy did not significantly reduce the risk of lower GI, other GI, or non-GI bleeding.

Further research is warranted to determine if PPI therapy is beneficial to patients taking direct oral anticoagulants.

In patients taking both warfarin and concurrent antiplatelet agents or NSAIDs, PPI co-therapy reduced the risk of hospitalization for upper GI bleeding by about half (HR=0.55; 95% CI, 0.39-0.77). Hospitalizations decreased by 128/10,000 person-years (95% CI, -66 to -173), yielding an NNT of 78 person-years. For patients taking warfarin but not antiplatelet agents or NSAIDs, PPI co-therapy did not significantly decrease the risk of hospitalization for upper GI bleeding (HR=0.86; 95% CI, 0.70-1.06).

Additional risk factors for GI bleeds. Researchers also looked at patients who had additional risk factors for GI bleeds (other than the exclusion criteria). For patients taking both warfarin and an antiplatelet agent/NSAID, PPI co-therapy decreased the risk of upper GI bleeding whether or not the patients had other bleeding risk factors. Again, for patients who had additional bleeding risk factors, but were not taking an antiplatelet agent or NSAID, PPI therapy showed no statistically significant effect.

WHAT’S NEW

PPIs offer benefits, but not to patients taking warfarin alone

The statistically significant results in this large observational study suggest that PPI co-therapy is beneficial in reducing the risk of upper GI bleeding in patients taking warfarin plus an antiplatelet agent/NSAID, but that PPI co-therapy provides no benefit to patients taking warfarin exclusively.

CAVEATS

Study was good, but it wasn’t a randomized controlled trial

This study is observational, and not a randomized control trial (RCT). Therefore, unknown confounding variables may have skewed results. For example, patients could have taken over-the-counter medications that influenced or obscured results, but were not included in the data analysis (misclassification bias).

At best, we can infer a correlation between PPIs and decreased risk of upper GI bleeds. We need RCTs to determine whether PPIs cause a lower risk.

Don’t overlook the risk of PPIs. This study assessed the ability of PPIs to prevent bleeds, but did not address the risks of long-term PPI therapy. Adverse effects of PPIs include an increased risk of pneumonia, infection with Clostridium difficile, hip and spine fractures, anemia, and possibly chronic kidney disease and dementia.^9-11 In addition, cost-analysis studies of PPI therapy are limited and inconsistent.¹² Therefore, it’s best to make decisions regarding PPIs after discussing other risks and benefits.

What about DOACs? Another consideration is the option to prescribe a direct oral anticoagulant (DOAC), such as dabigatran, rivaroxaban, or apixaban, instead of warfarin. DOACs are at least as effective as warfarin at preventing stroke in patients with atrial fibrillation and may even be safer.¹³ Dabigatran 110 mg causes fewer “major bleeding” events than warfarin.¹³ Rivaroxaban has been shown to result in fewer fatal bleeding events than warfarin due to fatal intracranial bleeds, although it is associated with more GI bleedding.¹³ Compared with warfarin, apixaban is associated with fewer GI bleeds and lower bleeding rates overall.¹³ Further research is warranted to determine if PPI therapy is beneficial to patients taking DOACs.

CHALLENGES TO IMPLEMENTATION

It’s still a balancing act

When chronic anticoagulation is necessary, physicians and patients must attempt to prevent thrombotic events while minimizing the risk of GI bleeds. PPIs may be beneficial in preventing upper GI bleeds in patients taking dual warfarin and antiplatelet therapy, but the long-term consequences of PPI therapy should not be ignored.

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.

A 60-year-old man presents for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association class 3 heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and based on his self-administered 9-item Patient Health Questionnaire (PHQ-9) score of 17, you determine that he is having a concomitant major depressive episode. Should you start him on an SSRI?

Depression is widely recognized as an independent risk factor for cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying link between depression and CVD risk.^2,6 Conversely, a recent systematic review found that positive constructs, mediated primarily through lifestyle behaviors, may have a protective effect on outcomes.⁷

Recently, researchers have focused on treating depression to simultaneously improve CVD outcomes. While some studies have shown SSRIs to be a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD trial did suggest that SSRI treatment may improve mortality and morbidity post-MI.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with lower quality of life (QoL), poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure; it is an independent predictor of mortality in this patient population.¹ Until recently, only one RCT (the SADHART-CHF study) looked at SSRI treatment in patients with heart failure and depression.¹² In that 12-week trial, sertraline did not improve depression or CVD outcomes when compared with placebo—but the study period may have been too short to capture long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 mo).¹ Specifically, this RCT assessed whether treatment with escitalopram could reduce morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients with New York Heart Association class 2 to 4 heart failure and left ventricular ejection fractions < 45% were screened for depression using the PHQ-9. Patients with PHQ-9 scores ≥ 12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist, and those diagnosed with major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months, in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every six months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The study used a composite endpoint of all-cause death or hospitalization; the primary outcome was time to first event of this composite. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale, and health-related QoL as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 escitalopram, 187 placebo). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR], 0.99).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean MADRS score changed from 20.2 at baseline to 11.2 at 12 weeks with escitalopram, and from 21.4 to 12.5 in the placebo group (between-group difference, –0.9).¹⁰ Overall, the two treatment groups had comparable daily medication doses and mean treatment duration (18 mo), and both groups demonstrated partial remission of depression symptoms, improved health status, and improved QoL over the study period.

Interestingly, the placebo group experienced significantly improved QoL at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by conducting the study over a much longer duration (up to 24 mo vs 12 wk). Also, in contrast to SADHART-CHF, this trial studied escitalopram rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: SSRI treatment for patients with heart failure and depression did not reduce the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram versus placebo. Given that this high-quality trial replicated the findings of SADHART-CHF with a longer treatment period and a potentially more effective SSRI, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating severe depression has an impact on cardiovascular outcomes.

Lastly, and most importantly, this study only looked at initiating SSRIs for depression in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to mitigate the elevated risk for adverse clinical outcomes remains nuanced and elusive. The same can be said of non-CVD chronic conditions (eg, diabetes) based on recent systematic reviews.¹³ In sum, these studies suggest that a traditional screen-and-treat approach using SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

A recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought.¹⁴ Nevertheless, this area of research should continue to be explored, given the worsened chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change, we expect that it will be a challenge to convince providers to stop initiating SSRI treatment to affect cardiovascular outcomes in patients with depression and heart failure—especially given the body of evidence denoting depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

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

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[9]:564-567).

A 60-year-old man presents for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association class 3 heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and based on his self-administered 9-item Patient Health Questionnaire (PHQ-9) score of 17, you determine that he is having a concomitant major depressive episode. Should you start him on an SSRI?

Depression is widely recognized as an independent risk factor for cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying link between depression and CVD risk.^2,6 Conversely, a recent systematic review found that positive constructs, mediated primarily through lifestyle behaviors, may have a protective effect on outcomes.⁷

Recently, researchers have focused on treating depression to simultaneously improve CVD outcomes. While some studies have shown SSRIs to be a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD trial did suggest that SSRI treatment may improve mortality and morbidity post-MI.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with lower quality of life (QoL), poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure; it is an independent predictor of mortality in this patient population.¹ Until recently, only one RCT (the SADHART-CHF study) looked at SSRI treatment in patients with heart failure and depression.¹² In that 12-week trial, sertraline did not improve depression or CVD outcomes when compared with placebo—but the study period may have been too short to capture long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 mo).¹ Specifically, this RCT assessed whether treatment with escitalopram could reduce morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients with New York Heart Association class 2 to 4 heart failure and left ventricular ejection fractions < 45% were screened for depression using the PHQ-9. Patients with PHQ-9 scores ≥ 12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist, and those diagnosed with major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months, in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every six months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The study used a composite endpoint of all-cause death or hospitalization; the primary outcome was time to first event of this composite. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale, and health-related QoL as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 escitalopram, 187 placebo). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR], 0.99).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean MADRS score changed from 20.2 at baseline to 11.2 at 12 weeks with escitalopram, and from 21.4 to 12.5 in the placebo group (between-group difference, –0.9).¹⁰ Overall, the two treatment groups had comparable daily medication doses and mean treatment duration (18 mo), and both groups demonstrated partial remission of depression symptoms, improved health status, and improved QoL over the study period.

Interestingly, the placebo group experienced significantly improved QoL at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by conducting the study over a much longer duration (up to 24 mo vs 12 wk). Also, in contrast to SADHART-CHF, this trial studied escitalopram rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: SSRI treatment for patients with heart failure and depression did not reduce the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram versus placebo. Given that this high-quality trial replicated the findings of SADHART-CHF with a longer treatment period and a potentially more effective SSRI, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating severe depression has an impact on cardiovascular outcomes.

Lastly, and most importantly, this study only looked at initiating SSRIs for depression in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to mitigate the elevated risk for adverse clinical outcomes remains nuanced and elusive. The same can be said of non-CVD chronic conditions (eg, diabetes) based on recent systematic reviews.¹³ In sum, these studies suggest that a traditional screen-and-treat approach using SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

A recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought.¹⁴ Nevertheless, this area of research should continue to be explored, given the worsened chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change, we expect that it will be a challenge to convince providers to stop initiating SSRI treatment to affect cardiovascular outcomes in patients with depression and heart failure—especially given the body of evidence denoting depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

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

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[9]:564-567).

A 60-year-old man presents for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association class 3 heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and based on his self-administered 9-item Patient Health Questionnaire (PHQ-9) score of 17, you determine that he is having a concomitant major depressive episode. Should you start him on an SSRI?

Depression is widely recognized as an independent risk factor for cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying link between depression and CVD risk.^2,6 Conversely, a recent systematic review found that positive constructs, mediated primarily through lifestyle behaviors, may have a protective effect on outcomes.⁷

Recently, researchers have focused on treating depression to simultaneously improve CVD outcomes. While some studies have shown SSRIs to be a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD trial did suggest that SSRI treatment may improve mortality and morbidity post-MI.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with lower quality of life (QoL), poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure; it is an independent predictor of mortality in this patient population.¹ Until recently, only one RCT (the SADHART-CHF study) looked at SSRI treatment in patients with heart failure and depression.¹² In that 12-week trial, sertraline did not improve depression or CVD outcomes when compared with placebo—but the study period may have been too short to capture long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 mo).¹ Specifically, this RCT assessed whether treatment with escitalopram could reduce morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients with New York Heart Association class 2 to 4 heart failure and left ventricular ejection fractions < 45% were screened for depression using the PHQ-9. Patients with PHQ-9 scores ≥ 12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist, and those diagnosed with major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months, in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every six months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The study used a composite endpoint of all-cause death or hospitalization; the primary outcome was time to first event of this composite. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale, and health-related QoL as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 escitalopram, 187 placebo). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR], 0.99).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean MADRS score changed from 20.2 at baseline to 11.2 at 12 weeks with escitalopram, and from 21.4 to 12.5 in the placebo group (between-group difference, –0.9).¹⁰ Overall, the two treatment groups had comparable daily medication doses and mean treatment duration (18 mo), and both groups demonstrated partial remission of depression symptoms, improved health status, and improved QoL over the study period.

Interestingly, the placebo group experienced significantly improved QoL at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by conducting the study over a much longer duration (up to 24 mo vs 12 wk). Also, in contrast to SADHART-CHF, this trial studied escitalopram rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: SSRI treatment for patients with heart failure and depression did not reduce the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram versus placebo. Given that this high-quality trial replicated the findings of SADHART-CHF with a longer treatment period and a potentially more effective SSRI, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating severe depression has an impact on cardiovascular outcomes.

Lastly, and most importantly, this study only looked at initiating SSRIs for depression in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to mitigate the elevated risk for adverse clinical outcomes remains nuanced and elusive. The same can be said of non-CVD chronic conditions (eg, diabetes) based on recent systematic reviews.¹³ In sum, these studies suggest that a traditional screen-and-treat approach using SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

A recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought.¹⁴ Nevertheless, this area of research should continue to be explored, given the worsened chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change, we expect that it will be a challenge to convince providers to stop initiating SSRI treatment to affect cardiovascular outcomes in patients with depression and heart failure—especially given the body of evidence denoting depression as a risk factor for increased morbidity and mortality in this population.

ACKNOWLEDGEMENT

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

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[9]:564-567).

ILLUSTRATIVE CASE

A 65-year-old woman is admitted to your inpatient service from your family health center. She is diagnosed with community-acquired pneumonia (CAP) based on a 5-day history of cough and fever and a positive chest x-ray. She now requires oxygen at rest. She has a past medical history of hypertension and diabetes, both of which have been controlled on oral medications. Antibiotic therapy is initiated for the treatment of the pneumonia, but what treatment duration is ideal?

The World Health Organization estimates that pneumonia is the third most common cause of mortality worldwide, causing 3.2 million deaths per year.² Appropriate prescribing of antibiotics is critical for the successful treatment of CAP.

The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) created consensus guidelines, published in 2007, for the treatment of CAP.³ These guidelines recommend a minimum 5-day course of antibiotics if the patient is clinically stable, which is defined as: afebrile for 48 hours, heart rate ≤100 beats/minute, respiratory rate ≤24 respirations/minute, systolic blood pressure ≥90 mm Hg, oxygen saturation ≥90%, normal mental status, and able to tolerate oral intake. Longer antibiotic treatment durations are recommended on an individualized basis, if, for example, the isolated pathogen is not susceptible to the initial antibiotic or if the infection was caused by an extrapulmonary source.

However, these recommendations are not routinely followed. Practitioners often make it their custom to prescribe longer courses of antibiotics.⁴ And yet we know that there are several reasons to consider shorter courses of antibiotics, including lower health care costs, fewer adverse effects, and lower rates of bacterial resistance.^5-7

Two meta-analyses were performed to compare the safety and efficacy of short- (≤7 days) vs long-course (>7 days) antibiotic therapy in CAP.^8,9 Both meta-analyses found no difference in efficacy or safety between shorter and longer courses of antibiotic treatment regimens for CAP. Secondary outcomes noted a trend toward decreased antibiotic-associated adverse events with shorter courses of therapy.^8,9

While these meta-analyses supported shorter courses of antibiotics for CAP, there are limitations to the broad implementation of their findings. Studies included in these analyses utilized a variety of antibiotic treatment regimens and longer courses (7 days vs 5 days) that are not recommended by the IDSA/ATS guidelines. Additionally, studies included both inpatient and outpatient treatment groups, so findings may not apply to an exclusively inpatient CAP population.^8,9

This study sought to validate the IDSA/ATS guidelines recommending a 5-day course of antibiotics for hospitalized patients with CAP.¹

STUDY SUMMARY

No differences in clinical outcomes between 5 days of Tx—and longer

This multicenter, double-blind, noninferiority randomized trial compared short-term antibiotic treatment duration (5 days) to physician-discretion antibiotic treatment duration among 312 patients ≥18 years of age admitted for CAP to one of 4 teaching hospitals in Spain.¹ Pneumonia was diagnosed on chest radiograph with at least one symptom: cough, fever, dyspnea, or chest pain. Patients were excluded if, among other things, they had an immunocompromising condition, lived in a nursing home, had a recent hospital stay, used antibiotics within the previous 30 days, or had an uncommon pathogen, such as Pseudomonas aeruginosa or Staphylococcus aureus.¹

This is the first study to support the efficacy of the 5-day course of antibiotics for hospitalized CAP patients recommended by IDSA/ATS guidelines.

Patients were randomized after receiving a minimum of 5 days of antibiotics to an intervention group (where, if clinically stable, no further antibiotics were given) or a control group (where physicians determined antibiotic duration).¹ Primary outcomes were clinical success rate at Days 10 and 30 from admission, defined as resolution of signs and symptoms of CAP without further antibiotics, and improvement of CAP-related symptoms as determined by an 18-item CAP symptom questionnaire. This questionnaire was scored 0 to 90, where higher scores indicated greater severity. Secondary outcomes included: duration of antibiotic use, time to clinical improvement, mortality, hospital readmission, hospital length of stay, and CAP recurrence.¹A total of 312 patients were randomized with 162 patients in the intervention group and 150 patients in the control group. The mean age of patients in the intervention and control groups was 66.2 and 64.7 years, respectively. Other baseline demographics were similar between the groups. Nearly 80% of patients received quinolone treatment; <10% received a beta-lactam plus a macrolide.¹

Clinical success rates were similar for the control and intervention groups, respectively, at Day 10 (49% vs 56%; P=.18) and Day 30 (89% vs 92%; P=.33). There was shorter median treatment duration with antibiotics in the intervention group compared with the control group (5 days vs 10 days; P<.001) and fewer 30-day hospital readmissions (1.4% vs 6.6%; P=.02). There were no differences for other secondary outcomes.¹

WHAT’S NEW

Clinical support for 2007 guidelines

This is the first study to clinically support the IDSA/ATS guidelines, which state that a 5-day course of antibiotic therapy for hospitalized adults with CAP is effective and without increased risk of adverse events.

CAVEATS

Generalizability to other meds and settings is unclear

This study focused on antibiotic duration for the treatment of CAP in hospitalized patients and mainly used quinolone antibiotics. It remains unclear if duration of therapy is as effective in the outpatient setting or when using alternative antibiotic regimens.

If patients continued to have symptoms (such as fever or low oxygen saturation on room air) after 5 days of antibiotic treatment, antibiotic treatment was continued in the study. Thus, patients in real life who continue to have symptoms may need individualized therapy and may require more than 5 days of antibiotics.

CHALLENGES TO IMPLEMENTATION

Antibiotics end before clinical improvement occurs

This study noted an average of 12 days in both groups for patients to achieve clinical improvement, with upwards of 15 to 18 days for patients to return to normal activity. Patients and providers may be dissatisfied if the treatment course ends days before clinical improvement of symptoms. This may cause prescribers to lengthen the duration of antibiotic therapy inappropriately.

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 65-year-old woman is admitted to your inpatient service from your family health center. She is diagnosed with community-acquired pneumonia (CAP) based on a 5-day history of cough and fever and a positive chest x-ray. She now requires oxygen at rest. She has a past medical history of hypertension and diabetes, both of which have been controlled on oral medications. Antibiotic therapy is initiated for the treatment of the pneumonia, but what treatment duration is ideal?

The World Health Organization estimates that pneumonia is the third most common cause of mortality worldwide, causing 3.2 million deaths per year.² Appropriate prescribing of antibiotics is critical for the successful treatment of CAP.

The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) created consensus guidelines, published in 2007, for the treatment of CAP.³ These guidelines recommend a minimum 5-day course of antibiotics if the patient is clinically stable, which is defined as: afebrile for 48 hours, heart rate ≤100 beats/minute, respiratory rate ≤24 respirations/minute, systolic blood pressure ≥90 mm Hg, oxygen saturation ≥90%, normal mental status, and able to tolerate oral intake. Longer antibiotic treatment durations are recommended on an individualized basis, if, for example, the isolated pathogen is not susceptible to the initial antibiotic or if the infection was caused by an extrapulmonary source.

However, these recommendations are not routinely followed. Practitioners often make it their custom to prescribe longer courses of antibiotics.⁴ And yet we know that there are several reasons to consider shorter courses of antibiotics, including lower health care costs, fewer adverse effects, and lower rates of bacterial resistance.^5-7

Two meta-analyses were performed to compare the safety and efficacy of short- (≤7 days) vs long-course (>7 days) antibiotic therapy in CAP.^8,9 Both meta-analyses found no difference in efficacy or safety between shorter and longer courses of antibiotic treatment regimens for CAP. Secondary outcomes noted a trend toward decreased antibiotic-associated adverse events with shorter courses of therapy.^8,9

While these meta-analyses supported shorter courses of antibiotics for CAP, there are limitations to the broad implementation of their findings. Studies included in these analyses utilized a variety of antibiotic treatment regimens and longer courses (7 days vs 5 days) that are not recommended by the IDSA/ATS guidelines. Additionally, studies included both inpatient and outpatient treatment groups, so findings may not apply to an exclusively inpatient CAP population.^8,9

This study sought to validate the IDSA/ATS guidelines recommending a 5-day course of antibiotics for hospitalized patients with CAP.¹

STUDY SUMMARY

No differences in clinical outcomes between 5 days of Tx—and longer

This multicenter, double-blind, noninferiority randomized trial compared short-term antibiotic treatment duration (5 days) to physician-discretion antibiotic treatment duration among 312 patients ≥18 years of age admitted for CAP to one of 4 teaching hospitals in Spain.¹ Pneumonia was diagnosed on chest radiograph with at least one symptom: cough, fever, dyspnea, or chest pain. Patients were excluded if, among other things, they had an immunocompromising condition, lived in a nursing home, had a recent hospital stay, used antibiotics within the previous 30 days, or had an uncommon pathogen, such as Pseudomonas aeruginosa or Staphylococcus aureus.¹

This is the first study to support the efficacy of the 5-day course of antibiotics for hospitalized CAP patients recommended by IDSA/ATS guidelines.

Patients were randomized after receiving a minimum of 5 days of antibiotics to an intervention group (where, if clinically stable, no further antibiotics were given) or a control group (where physicians determined antibiotic duration).¹ Primary outcomes were clinical success rate at Days 10 and 30 from admission, defined as resolution of signs and symptoms of CAP without further antibiotics, and improvement of CAP-related symptoms as determined by an 18-item CAP symptom questionnaire. This questionnaire was scored 0 to 90, where higher scores indicated greater severity. Secondary outcomes included: duration of antibiotic use, time to clinical improvement, mortality, hospital readmission, hospital length of stay, and CAP recurrence.¹A total of 312 patients were randomized with 162 patients in the intervention group and 150 patients in the control group. The mean age of patients in the intervention and control groups was 66.2 and 64.7 years, respectively. Other baseline demographics were similar between the groups. Nearly 80% of patients received quinolone treatment; <10% received a beta-lactam plus a macrolide.¹

Clinical success rates were similar for the control and intervention groups, respectively, at Day 10 (49% vs 56%; P=.18) and Day 30 (89% vs 92%; P=.33). There was shorter median treatment duration with antibiotics in the intervention group compared with the control group (5 days vs 10 days; P<.001) and fewer 30-day hospital readmissions (1.4% vs 6.6%; P=.02). There were no differences for other secondary outcomes.¹

WHAT’S NEW

Clinical support for 2007 guidelines

This is the first study to clinically support the IDSA/ATS guidelines, which state that a 5-day course of antibiotic therapy for hospitalized adults with CAP is effective and without increased risk of adverse events.

CAVEATS

Generalizability to other meds and settings is unclear

This study focused on antibiotic duration for the treatment of CAP in hospitalized patients and mainly used quinolone antibiotics. It remains unclear if duration of therapy is as effective in the outpatient setting or when using alternative antibiotic regimens.

If patients continued to have symptoms (such as fever or low oxygen saturation on room air) after 5 days of antibiotic treatment, antibiotic treatment was continued in the study. Thus, patients in real life who continue to have symptoms may need individualized therapy and may require more than 5 days of antibiotics.

CHALLENGES TO IMPLEMENTATION

Antibiotics end before clinical improvement occurs

This study noted an average of 12 days in both groups for patients to achieve clinical improvement, with upwards of 15 to 18 days for patients to return to normal activity. Patients and providers may be dissatisfied if the treatment course ends days before clinical improvement of symptoms. This may cause prescribers to lengthen the duration of antibiotic therapy inappropriately.

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 65-year-old woman is admitted to your inpatient service from your family health center. She is diagnosed with community-acquired pneumonia (CAP) based on a 5-day history of cough and fever and a positive chest x-ray. She now requires oxygen at rest. She has a past medical history of hypertension and diabetes, both of which have been controlled on oral medications. Antibiotic therapy is initiated for the treatment of the pneumonia, but what treatment duration is ideal?

The World Health Organization estimates that pneumonia is the third most common cause of mortality worldwide, causing 3.2 million deaths per year.² Appropriate prescribing of antibiotics is critical for the successful treatment of CAP.

The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) created consensus guidelines, published in 2007, for the treatment of CAP.³ These guidelines recommend a minimum 5-day course of antibiotics if the patient is clinically stable, which is defined as: afebrile for 48 hours, heart rate ≤100 beats/minute, respiratory rate ≤24 respirations/minute, systolic blood pressure ≥90 mm Hg, oxygen saturation ≥90%, normal mental status, and able to tolerate oral intake. Longer antibiotic treatment durations are recommended on an individualized basis, if, for example, the isolated pathogen is not susceptible to the initial antibiotic or if the infection was caused by an extrapulmonary source.

However, these recommendations are not routinely followed. Practitioners often make it their custom to prescribe longer courses of antibiotics.⁴ And yet we know that there are several reasons to consider shorter courses of antibiotics, including lower health care costs, fewer adverse effects, and lower rates of bacterial resistance.^5-7

Two meta-analyses were performed to compare the safety and efficacy of short- (≤7 days) vs long-course (>7 days) antibiotic therapy in CAP.^8,9 Both meta-analyses found no difference in efficacy or safety between shorter and longer courses of antibiotic treatment regimens for CAP. Secondary outcomes noted a trend toward decreased antibiotic-associated adverse events with shorter courses of therapy.^8,9

While these meta-analyses supported shorter courses of antibiotics for CAP, there are limitations to the broad implementation of their findings. Studies included in these analyses utilized a variety of antibiotic treatment regimens and longer courses (7 days vs 5 days) that are not recommended by the IDSA/ATS guidelines. Additionally, studies included both inpatient and outpatient treatment groups, so findings may not apply to an exclusively inpatient CAP population.^8,9

This study sought to validate the IDSA/ATS guidelines recommending a 5-day course of antibiotics for hospitalized patients with CAP.¹

STUDY SUMMARY

No differences in clinical outcomes between 5 days of Tx—and longer

This multicenter, double-blind, noninferiority randomized trial compared short-term antibiotic treatment duration (5 days) to physician-discretion antibiotic treatment duration among 312 patients ≥18 years of age admitted for CAP to one of 4 teaching hospitals in Spain.¹ Pneumonia was diagnosed on chest radiograph with at least one symptom: cough, fever, dyspnea, or chest pain. Patients were excluded if, among other things, they had an immunocompromising condition, lived in a nursing home, had a recent hospital stay, used antibiotics within the previous 30 days, or had an uncommon pathogen, such as Pseudomonas aeruginosa or Staphylococcus aureus.¹

This is the first study to support the efficacy of the 5-day course of antibiotics for hospitalized CAP patients recommended by IDSA/ATS guidelines.

Patients were randomized after receiving a minimum of 5 days of antibiotics to an intervention group (where, if clinically stable, no further antibiotics were given) or a control group (where physicians determined antibiotic duration).¹ Primary outcomes were clinical success rate at Days 10 and 30 from admission, defined as resolution of signs and symptoms of CAP without further antibiotics, and improvement of CAP-related symptoms as determined by an 18-item CAP symptom questionnaire. This questionnaire was scored 0 to 90, where higher scores indicated greater severity. Secondary outcomes included: duration of antibiotic use, time to clinical improvement, mortality, hospital readmission, hospital length of stay, and CAP recurrence.¹A total of 312 patients were randomized with 162 patients in the intervention group and 150 patients in the control group. The mean age of patients in the intervention and control groups was 66.2 and 64.7 years, respectively. Other baseline demographics were similar between the groups. Nearly 80% of patients received quinolone treatment; <10% received a beta-lactam plus a macrolide.¹

Clinical success rates were similar for the control and intervention groups, respectively, at Day 10 (49% vs 56%; P=.18) and Day 30 (89% vs 92%; P=.33). There was shorter median treatment duration with antibiotics in the intervention group compared with the control group (5 days vs 10 days; P<.001) and fewer 30-day hospital readmissions (1.4% vs 6.6%; P=.02). There were no differences for other secondary outcomes.¹

WHAT’S NEW

Clinical support for 2007 guidelines

This is the first study to clinically support the IDSA/ATS guidelines, which state that a 5-day course of antibiotic therapy for hospitalized adults with CAP is effective and without increased risk of adverse events.

CAVEATS

Generalizability to other meds and settings is unclear

This study focused on antibiotic duration for the treatment of CAP in hospitalized patients and mainly used quinolone antibiotics. It remains unclear if duration of therapy is as effective in the outpatient setting or when using alternative antibiotic regimens.

If patients continued to have symptoms (such as fever or low oxygen saturation on room air) after 5 days of antibiotic treatment, antibiotic treatment was continued in the study. Thus, patients in real life who continue to have symptoms may need individualized therapy and may require more than 5 days of antibiotics.

CHALLENGES TO IMPLEMENTATION

Antibiotics end before clinical improvement occurs

This study noted an average of 12 days in both groups for patients to achieve clinical improvement, with upwards of 15 to 18 days for patients to return to normal activity. Patients and providers may be dissatisfied if the treatment course ends days before clinical improvement of symptoms. This may cause prescribers to lengthen the duration of antibiotic therapy inappropriately.

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.

A 66-year-old man with a history of hypertension and type 2 diabetes is hospitalized for palpitations and dizziness and is diagnosed with atrial fibrillation (A-fib). His heart rate is successfully regulated with a ß-blocker. He has a CHA₂DS₂-VASc score of 3, making him a candidate for anticoagulation. Which agent should you start?

Thromboembolism in patients with A-fib often results in stroke and death, but appropriate use of antithrombotic therapy can reduce risk. Evidence-based guidelines recommend that patients with A-fib at intermediate or high risk for stroke (CHADS₂ score ≥ 2, or prior history of cardioembolic stroke or transient ischemic attack) receive antithrombotic therapy with oral anticoagulation, rather than receive no therapy or therapy with antiplatelets.^2,3

The American College of Chest Physicians also recommends use of the direct oral anticoagulant (DOAC) dabigatran instead of warfarin for those patients with nonvalvular A-fib with an estimated glomerular filtration rate ≥ 15 mL/min/1.73 m².³

A meta-analysis of large randomized controlled trials (RCTs) investigated individual DOACs: dabigatran (a direct thrombin inhibitor) and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. The results revealed similar or lower rates of ischemic stroke and major bleeding (except gastrointestinal bleeds; relative risk, 1.25) when compared with warfarin (at an international normalized ratio [INR] goal of 2-3).⁴ In addition, three separate meta-analyses that pooled results from large RCTs involving dabigatran, apixaban, and rivaroxaban also concluded that these medications significantly reduced incidence of embolic stroke and risk for major bleeds and hemorrhagic stroke, compared with warfarin.^5-7

However, less is known about the comparative effectiveness and safety of the ­DOACs when they are used in clinical practice, and it is not clear which, if any, of these agents is superior to others. Moreover, only about half of the patients in the United States with A-fib who are eligible to take DOACs are currently managed with them.⁸

STUDY SUMMARY

Different DOACs, different benefits

This large cohort study used data from three Danish national databases to assess the effectiveness of three DOACs compared with warfarin. The nearly 62,000 patients had been recently diagnosed with A-fib without valvular disease or venous thromboembolism. Subjects were prescribed either standard doses of dabigatran (150 bid; N = 12,701), rivaroxaban (20 mg/d; N = 7,192), or apixaban (5 mg bid; N = 6,349) or dose-adjusted warfarin to an INR goal of 2 to 3 (N = 35,436). Patients were followed for an average of 1.9 years.

Ischemic stroke, systemic emboli. In the first year of observation, there were 1,702 reports of ischemic stroke or systemic emboli. The incidence of ischemic stroke or systemic embolism was the same or better for each of the three DOAC treatments than for warfarin (2.9-3.9 vs 3.3 events per 100 person-years, respectively). Ischemic stroke or systemic emboli events occurred less frequently in the rivaroxaban group than in the warfarin group at one year (hazard ratio [HR], 0.83) and after 2.5 years (HR, 0.80). The rates of ischemic stroke and systemic emboli for both apixaban and dabigatran were not significantly different than that for warfarin at either end-point.

Bleeding events (defined as intracranial, major gastrointestinal, and traumatic intracranial) were lower in the apixaban group (HR, 0.63) and dabigatran group (HR, 0.61) than in the warfarin group at one year. Significant reductions remained after 2.5 years. There was no difference in bleeding events between rivaroxaban and warfarin.

Risk for death. Compared with warfarin, the risk for death after one year of treatment was lower in the apixaban (HR, 0.65) and dabigatran (HR, 0.63) groups, and there was no significant difference in the rivaroxaban group (HR, 0.92).

WHAT’S NEW

No agent “has it all,” but DOACs have advantages

This comparative effectiveness and safety analysis reveals that all of the DOACs are at least as effective as warfarin in preventing ischemic stroke and systemic emboli, that rivaroxaban may be more effective, and that apixaban and dabigatran have a lower risk for bleeding than warfarin.

CAVEATS

Lacking INR data

This study was a nonrandomized cohort trial. And, while propensity weighting helps, the researchers were unable to completely control for underlying risk factors or unknown confounders.

INR data for patients on warfarin were not provided, so it is not clear how often patients were out of therapeutic range, which could affect the stroke and bleeding results in the warfarin group. This, however, is seen with routine use of warfarin. This study reflects the challenge of maintaining patients in warfarin’s narrow therapeutic range.

CHALLENGES TO IMPLEMENTATION

It comes down to cost

Cost could be a barrier, as health insurance coverage for DOACs varies. Patients with high-deductible health insurance plans, or who find themselves in the Medicare “donut hole,” may be at a particular disadvantage.

ACKNOWLEDGEMENT

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

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[8]:518-519).

A 66-year-old man with a history of hypertension and type 2 diabetes is hospitalized for palpitations and dizziness and is diagnosed with atrial fibrillation (A-fib). His heart rate is successfully regulated with a ß-blocker. He has a CHA₂DS₂-VASc score of 3, making him a candidate for anticoagulation. Which agent should you start?

Thromboembolism in patients with A-fib often results in stroke and death, but appropriate use of antithrombotic therapy can reduce risk. Evidence-based guidelines recommend that patients with A-fib at intermediate or high risk for stroke (CHADS₂ score ≥ 2, or prior history of cardioembolic stroke or transient ischemic attack) receive antithrombotic therapy with oral anticoagulation, rather than receive no therapy or therapy with antiplatelets.^2,3

The American College of Chest Physicians also recommends use of the direct oral anticoagulant (DOAC) dabigatran instead of warfarin for those patients with nonvalvular A-fib with an estimated glomerular filtration rate ≥ 15 mL/min/1.73 m².³

A meta-analysis of large randomized controlled trials (RCTs) investigated individual DOACs: dabigatran (a direct thrombin inhibitor) and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. The results revealed similar or lower rates of ischemic stroke and major bleeding (except gastrointestinal bleeds; relative risk, 1.25) when compared with warfarin (at an international normalized ratio [INR] goal of 2-3).⁴ In addition, three separate meta-analyses that pooled results from large RCTs involving dabigatran, apixaban, and rivaroxaban also concluded that these medications significantly reduced incidence of embolic stroke and risk for major bleeds and hemorrhagic stroke, compared with warfarin.^5-7

However, less is known about the comparative effectiveness and safety of the ­DOACs when they are used in clinical practice, and it is not clear which, if any, of these agents is superior to others. Moreover, only about half of the patients in the United States with A-fib who are eligible to take DOACs are currently managed with them.⁸

STUDY SUMMARY

Different DOACs, different benefits

This large cohort study used data from three Danish national databases to assess the effectiveness of three DOACs compared with warfarin. The nearly 62,000 patients had been recently diagnosed with A-fib without valvular disease or venous thromboembolism. Subjects were prescribed either standard doses of dabigatran (150 bid; N = 12,701), rivaroxaban (20 mg/d; N = 7,192), or apixaban (5 mg bid; N = 6,349) or dose-adjusted warfarin to an INR goal of 2 to 3 (N = 35,436). Patients were followed for an average of 1.9 years.

Ischemic stroke, systemic emboli. In the first year of observation, there were 1,702 reports of ischemic stroke or systemic emboli. The incidence of ischemic stroke or systemic embolism was the same or better for each of the three DOAC treatments than for warfarin (2.9-3.9 vs 3.3 events per 100 person-years, respectively). Ischemic stroke or systemic emboli events occurred less frequently in the rivaroxaban group than in the warfarin group at one year (hazard ratio [HR], 0.83) and after 2.5 years (HR, 0.80). The rates of ischemic stroke and systemic emboli for both apixaban and dabigatran were not significantly different than that for warfarin at either end-point.

Bleeding events (defined as intracranial, major gastrointestinal, and traumatic intracranial) were lower in the apixaban group (HR, 0.63) and dabigatran group (HR, 0.61) than in the warfarin group at one year. Significant reductions remained after 2.5 years. There was no difference in bleeding events between rivaroxaban and warfarin.

Risk for death. Compared with warfarin, the risk for death after one year of treatment was lower in the apixaban (HR, 0.65) and dabigatran (HR, 0.63) groups, and there was no significant difference in the rivaroxaban group (HR, 0.92).

WHAT’S NEW

No agent “has it all,” but DOACs have advantages

This comparative effectiveness and safety analysis reveals that all of the DOACs are at least as effective as warfarin in preventing ischemic stroke and systemic emboli, that rivaroxaban may be more effective, and that apixaban and dabigatran have a lower risk for bleeding than warfarin.

CAVEATS

Lacking INR data

This study was a nonrandomized cohort trial. And, while propensity weighting helps, the researchers were unable to completely control for underlying risk factors or unknown confounders.

INR data for patients on warfarin were not provided, so it is not clear how often patients were out of therapeutic range, which could affect the stroke and bleeding results in the warfarin group. This, however, is seen with routine use of warfarin. This study reflects the challenge of maintaining patients in warfarin’s narrow therapeutic range.

CHALLENGES TO IMPLEMENTATION

It comes down to cost

Cost could be a barrier, as health insurance coverage for DOACs varies. Patients with high-deductible health insurance plans, or who find themselves in the Medicare “donut hole,” may be at a particular disadvantage.

ACKNOWLEDGEMENT

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

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[8]:518-519).

A 66-year-old man with a history of hypertension and type 2 diabetes is hospitalized for palpitations and dizziness and is diagnosed with atrial fibrillation (A-fib). His heart rate is successfully regulated with a ß-blocker. He has a CHA₂DS₂-VASc score of 3, making him a candidate for anticoagulation. Which agent should you start?

Thromboembolism in patients with A-fib often results in stroke and death, but appropriate use of antithrombotic therapy can reduce risk. Evidence-based guidelines recommend that patients with A-fib at intermediate or high risk for stroke (CHADS₂ score ≥ 2, or prior history of cardioembolic stroke or transient ischemic attack) receive antithrombotic therapy with oral anticoagulation, rather than receive no therapy or therapy with antiplatelets.^2,3

The American College of Chest Physicians also recommends use of the direct oral anticoagulant (DOAC) dabigatran instead of warfarin for those patients with nonvalvular A-fib with an estimated glomerular filtration rate ≥ 15 mL/min/1.73 m².³

A meta-analysis of large randomized controlled trials (RCTs) investigated individual DOACs: dabigatran (a direct thrombin inhibitor) and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. The results revealed similar or lower rates of ischemic stroke and major bleeding (except gastrointestinal bleeds; relative risk, 1.25) when compared with warfarin (at an international normalized ratio [INR] goal of 2-3).⁴ In addition, three separate meta-analyses that pooled results from large RCTs involving dabigatran, apixaban, and rivaroxaban also concluded that these medications significantly reduced incidence of embolic stroke and risk for major bleeds and hemorrhagic stroke, compared with warfarin.^5-7

However, less is known about the comparative effectiveness and safety of the ­DOACs when they are used in clinical practice, and it is not clear which, if any, of these agents is superior to others. Moreover, only about half of the patients in the United States with A-fib who are eligible to take DOACs are currently managed with them.⁸

STUDY SUMMARY

Different DOACs, different benefits

This large cohort study used data from three Danish national databases to assess the effectiveness of three DOACs compared with warfarin. The nearly 62,000 patients had been recently diagnosed with A-fib without valvular disease or venous thromboembolism. Subjects were prescribed either standard doses of dabigatran (150 bid; N = 12,701), rivaroxaban (20 mg/d; N = 7,192), or apixaban (5 mg bid; N = 6,349) or dose-adjusted warfarin to an INR goal of 2 to 3 (N = 35,436). Patients were followed for an average of 1.9 years.

Ischemic stroke, systemic emboli. In the first year of observation, there were 1,702 reports of ischemic stroke or systemic emboli. The incidence of ischemic stroke or systemic embolism was the same or better for each of the three DOAC treatments than for warfarin (2.9-3.9 vs 3.3 events per 100 person-years, respectively). Ischemic stroke or systemic emboli events occurred less frequently in the rivaroxaban group than in the warfarin group at one year (hazard ratio [HR], 0.83) and after 2.5 years (HR, 0.80). The rates of ischemic stroke and systemic emboli for both apixaban and dabigatran were not significantly different than that for warfarin at either end-point.

Bleeding events (defined as intracranial, major gastrointestinal, and traumatic intracranial) were lower in the apixaban group (HR, 0.63) and dabigatran group (HR, 0.61) than in the warfarin group at one year. Significant reductions remained after 2.5 years. There was no difference in bleeding events between rivaroxaban and warfarin.

Risk for death. Compared with warfarin, the risk for death after one year of treatment was lower in the apixaban (HR, 0.65) and dabigatran (HR, 0.63) groups, and there was no significant difference in the rivaroxaban group (HR, 0.92).

WHAT’S NEW

No agent “has it all,” but DOACs have advantages

This comparative effectiveness and safety analysis reveals that all of the DOACs are at least as effective as warfarin in preventing ischemic stroke and systemic emboli, that rivaroxaban may be more effective, and that apixaban and dabigatran have a lower risk for bleeding than warfarin.

CAVEATS

Lacking INR data

This study was a nonrandomized cohort trial. And, while propensity weighting helps, the researchers were unable to completely control for underlying risk factors or unknown confounders.

INR data for patients on warfarin were not provided, so it is not clear how often patients were out of therapeutic range, which could affect the stroke and bleeding results in the warfarin group. This, however, is seen with routine use of warfarin. This study reflects the challenge of maintaining patients in warfarin’s narrow therapeutic range.

CHALLENGES TO IMPLEMENTATION

It comes down to cost

Cost could be a barrier, as health insurance coverage for DOACs varies. Patients with high-deductible health insurance plans, or who find themselves in the Medicare “donut hole,” may be at a particular disadvantage.

ACKNOWLEDGEMENT

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

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2017;66[8]:518-519).

ILLUSTRATIVE CASE

A 60-year-old man comes to your office for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association Class III heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and after evaluation, including a score of 17 on a self-administered 9-item Patient Health Questionnaire (PHQ-9), you determine that he is having a concomitant major depressive episode. Should you start him on a selective serotonin reuptake inhibitor (SSRI)?

Depression is widely recognized as an independent risk factor for both the development of cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying mechanisms linking depression and the risk of CVD.^2,6 Conversely, a recent systematic review suggests that positive constructs—mediated primarily through lifestyle behaviors—may have a protective effect on CVD outcomes.⁷

As a result, researchers have focused on the treatment of depression to improve CVD outcomes in recent years, including in patients with heart failure. While some randomized studies have shown that SSRIs are a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial did suggest that SSRI treatment may improve mortality and morbidity post-myocardial infarction.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with worse quality of life, poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure, and is an independent predictor of mortality in this patient population.¹ Until recently, only one randomized controlled trial (RCT), the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) study, looked at treatment with SSRIs in patients with heart failure and depression.¹² In this trial, sertraline, when compared with placebo, did not improve depression or CVD outcomes over 12 weeks, but the study period may have been insufficiently long to capture the impact on long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF (The effects of selective serotonin re-uptake inhibition on morbidity, mortality, and mood in depressed heart failure patients) study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 months).¹ Specifically, this RCT assessed whether treatment with escitalopram vs placebo could reduce the increased morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

Using SSRIs for depression treatment to affect chronic disease outcomes that are likely lifestyle-related may not be cost-effective or patient-centered.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients established at heart failure clinics with New York Heart Association class II to IV heart failure and left ventricular ejection fractions <45% were screened for depression using the PHQ-9. Individuals with PHQ-9 scores ≥12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist. Those who received a diagnosis of major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded from participation.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every 6 months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The primary study outcome was time to a first event of the composite of all-cause death or hospitalization. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale (GAD-7), and health-related quality of life (QoL) as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 in the escitalopram group and 187 in the placebo group). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR]=0.99; 95% confidence interval [CI], 0.76 to 1.27]; P=.92).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean (SD) MADRS score changed from 20.2 (8.6) at baseline to 11.2 (8.1) at 12 weeks with escitalopram and from 21.4 (8.8) to 12.5 (7.6) in the placebo group (between-group difference = -0.9; 95% CI, -2.6 to 0.7; P =.26).¹⁰ Overall, participants in the 2 treatment groups had comparable daily doses of study medications, as well as mean treatment duration (18 months), and both groups demonstrated partial remission of depression symptoms over the study period, as well as improved health status and QoL as measured by KCCQ.

Interestingly, QoL as assessed by the KCCQ symptom score was significantly improved in the placebo group at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely on February 28, 2014, based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI doesn’t change earlier finding

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by looking at SSRI treatment of patients with heart failure and depression over a much longer study duration (up to 24 months vs 12 weeks). Also, in contrast to SADHART-CHF, this trial studied escitalopram, rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: treating patients with both heart failure and depression with an SSRI did not improve the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram vs placebo. Given that this high-quality trial, with a much longer treatment period and a possibly more effective SSRI, replicated the findings of SADHART-CHF, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating patients with severe depression has an impact on cardiovascular outcomes.

Although there are other SSRIs besides escitalopram and sertraline, it is likely that this is a class effect.

Lastly, and most importantly, this study only looked at screening patients for depression and initiating SSRIs in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to improve the elevated risk for adverse clinical outcomes remains nuanced and elusive. In fact, the same can be said of non-CVD chronic conditions—such as diabetes—based on recent systematic reviews.¹³ The summation of these studies suggests that a traditional screen-and-treat approach utilizing SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

The publication of a recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions¹⁴ reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought. Nevertheless, this is an area of research that should continue to be explored, given the obvious increased risk for poorer chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change among providers, we expect that it will be a challenge to convince providers to stop screening for depression and initiating treatment with an SSRI to affect CV outcomes in patients with heart failure. This is especially so given the body of evidence for depression as a risk factor for increased morbidity and mortality in this population.

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 60-year-old man comes to your office for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association Class III heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and after evaluation, including a score of 17 on a self-administered 9-item Patient Health Questionnaire (PHQ-9), you determine that he is having a concomitant major depressive episode. Should you start him on a selective serotonin reuptake inhibitor (SSRI)?

Depression is widely recognized as an independent risk factor for both the development of cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying mechanisms linking depression and the risk of CVD.^2,6 Conversely, a recent systematic review suggests that positive constructs—mediated primarily through lifestyle behaviors—may have a protective effect on CVD outcomes.⁷

As a result, researchers have focused on the treatment of depression to improve CVD outcomes in recent years, including in patients with heart failure. While some randomized studies have shown that SSRIs are a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial did suggest that SSRI treatment may improve mortality and morbidity post-myocardial infarction.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with worse quality of life, poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure, and is an independent predictor of mortality in this patient population.¹ Until recently, only one randomized controlled trial (RCT), the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) study, looked at treatment with SSRIs in patients with heart failure and depression.¹² In this trial, sertraline, when compared with placebo, did not improve depression or CVD outcomes over 12 weeks, but the study period may have been insufficiently long to capture the impact on long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF (The effects of selective serotonin re-uptake inhibition on morbidity, mortality, and mood in depressed heart failure patients) study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 months).¹ Specifically, this RCT assessed whether treatment with escitalopram vs placebo could reduce the increased morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

Using SSRIs for depression treatment to affect chronic disease outcomes that are likely lifestyle-related may not be cost-effective or patient-centered.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients established at heart failure clinics with New York Heart Association class II to IV heart failure and left ventricular ejection fractions <45% were screened for depression using the PHQ-9. Individuals with PHQ-9 scores ≥12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist. Those who received a diagnosis of major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded from participation.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every 6 months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The primary study outcome was time to a first event of the composite of all-cause death or hospitalization. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale (GAD-7), and health-related quality of life (QoL) as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 in the escitalopram group and 187 in the placebo group). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR]=0.99; 95% confidence interval [CI], 0.76 to 1.27]; P=.92).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean (SD) MADRS score changed from 20.2 (8.6) at baseline to 11.2 (8.1) at 12 weeks with escitalopram and from 21.4 (8.8) to 12.5 (7.6) in the placebo group (between-group difference = -0.9; 95% CI, -2.6 to 0.7; P =.26).¹⁰ Overall, participants in the 2 treatment groups had comparable daily doses of study medications, as well as mean treatment duration (18 months), and both groups demonstrated partial remission of depression symptoms over the study period, as well as improved health status and QoL as measured by KCCQ.

Interestingly, QoL as assessed by the KCCQ symptom score was significantly improved in the placebo group at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely on February 28, 2014, based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI doesn’t change earlier finding

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by looking at SSRI treatment of patients with heart failure and depression over a much longer study duration (up to 24 months vs 12 weeks). Also, in contrast to SADHART-CHF, this trial studied escitalopram, rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: treating patients with both heart failure and depression with an SSRI did not improve the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram vs placebo. Given that this high-quality trial, with a much longer treatment period and a possibly more effective SSRI, replicated the findings of SADHART-CHF, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating patients with severe depression has an impact on cardiovascular outcomes.

Although there are other SSRIs besides escitalopram and sertraline, it is likely that this is a class effect.

Lastly, and most importantly, this study only looked at screening patients for depression and initiating SSRIs in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to improve the elevated risk for adverse clinical outcomes remains nuanced and elusive. In fact, the same can be said of non-CVD chronic conditions—such as diabetes—based on recent systematic reviews.¹³ The summation of these studies suggests that a traditional screen-and-treat approach utilizing SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

The publication of a recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions¹⁴ reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought. Nevertheless, this is an area of research that should continue to be explored, given the obvious increased risk for poorer chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change among providers, we expect that it will be a challenge to convince providers to stop screening for depression and initiating treatment with an SSRI to affect CV outcomes in patients with heart failure. This is especially so given the body of evidence for depression as a risk factor for increased morbidity and mortality in this population.

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 60-year-old man comes to your office for a follow-up visit to talk about his congestive heart failure. He has New York Heart Association Class III heart failure with a left ventricular ejection fraction of 30%. You notice that he is downcast, and after evaluation, including a score of 17 on a self-administered 9-item Patient Health Questionnaire (PHQ-9), you determine that he is having a concomitant major depressive episode. Should you start him on a selective serotonin reuptake inhibitor (SSRI)?

Depression is widely recognized as an independent risk factor for both the development of cardiovascular disease (CVD), as well as adverse outcomes in patients with known CVD.^2-5 Previous studies have identified poor health behaviors as the primary underlying mechanisms linking depression and the risk of CVD.^2,6 Conversely, a recent systematic review suggests that positive constructs—mediated primarily through lifestyle behaviors—may have a protective effect on CVD outcomes.⁷

As a result, researchers have focused on the treatment of depression to improve CVD outcomes in recent years, including in patients with heart failure. While some randomized studies have shown that SSRIs are a safe and effective treatment for depression in patients with coronary disease, they have not demonstrated improvement in CVD outcomes.^8,9 However, a post hoc analysis of the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial did suggest that SSRI treatment may improve mortality and morbidity post-myocardial infarction.¹⁰

The prevalence of depression among patients with heart failure ranges from 10% to 40%, depending on disease severity.¹¹ Depression is associated with worse quality of life, poorer treatment adherence, and higher rates of rehospitalization among patients with heart failure, and is an independent predictor of mortality in this patient population.¹ Until recently, only one randomized controlled trial (RCT), the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) study, looked at treatment with SSRIs in patients with heart failure and depression.¹² In this trial, sertraline, when compared with placebo, did not improve depression or CVD outcomes over 12 weeks, but the study period may have been insufficiently long to capture the impact on long-term outcomes.

STUDY SUMMARY

SADHART-CHF, but better

In the MOOD-HF (The effects of selective serotonin re-uptake inhibition on morbidity, mortality, and mood in depressed heart failure patients) study, investigators sought to determine whether SSRI treatment for depression in patients with heart failure could improve CVD outcomes over a longer study period (up to 24 months).¹ Specifically, this RCT assessed whether treatment with escitalopram vs placebo could reduce the increased morbidity and mortality risk in patients with comorbid chronic systolic heart failure and depression.

Using SSRIs for depression treatment to affect chronic disease outcomes that are likely lifestyle-related may not be cost-effective or patient-centered.

This double-blind, placebo-controlled trial was conducted at 16 tertiary medical centers in Germany between 2009 and 2014. Adult patients established at heart failure clinics with New York Heart Association class II to IV heart failure and left ventricular ejection fractions <45% were screened for depression using the PHQ-9. Individuals with PHQ-9 scores ≥12 underwent a structured psychiatric interview with a psychiatrist or psychosomatic specialist. Those who received a diagnosis of major depression were invited to participate in the trial. Patients with recent SSRI use and/or psychotherapy were excluded from participation.

Eligible participants were randomized to receive either escitalopram (10-20 mg/d) or placebo for up to 24 months in addition to standard heart failure care. The starting dose of 5 mg was increased to 10 to 20 mg as tolerated until week 12 of the study; the dose at 12 weeks was considered the maintenance dose. Psychiatric and medical assessments were performed every 6 months during the study period. Depression severity was assessed using the 10-item Montgomery-Åsberg Depression Rating Scale (MADRS).

Outcomes. The primary study outcome was time to a first event of the composite of all-cause death or hospitalization. Secondary outcomes included MADRS score at 12 weeks, anxiety as assessed by the Generalized Anxiety Disorder 7-item scale (GAD-7), and health-related quality of life (QoL) as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The sample size was calculated to achieve 80% power for the primary outcome. Baseline characteristics between the intervention and placebo groups were balanced after randomization, and the modified intention-to-treat study population included participants who took at least one dose of the study medication.¹

Results. Ultimately, 372 participants were included in the analysis (185 in the escitalopram group and 187 in the placebo group). A primary endpoint event occurred in 116 participants (63%) in the escitalopram group and in 119 participants (64%) in the placebo group (hazard ratio [HR]=0.99; 95% confidence interval [CI], 0.76 to 1.27]; P=.92).¹ No differences were found between treatment groups for the primary endpoints in either adjusted or unadjusted analyses.

The mean (SD) MADRS score changed from 20.2 (8.6) at baseline to 11.2 (8.1) at 12 weeks with escitalopram and from 21.4 (8.8) to 12.5 (7.6) in the placebo group (between-group difference = -0.9; 95% CI, -2.6 to 0.7; P =.26).¹⁰ Overall, participants in the 2 treatment groups had comparable daily doses of study medications, as well as mean treatment duration (18 months), and both groups demonstrated partial remission of depression symptoms over the study period, as well as improved health status and QoL as measured by KCCQ.

Interestingly, QoL as assessed by the KCCQ symptom score was significantly improved in the placebo group at 12 months.¹ There were no between-group differences in adverse events or safety measures.¹ The trial was discontinued prematurely on February 28, 2014, based on futility after a recommendation from the data and safety monitoring committee.

WHAT’S NEW

Longer study period/different SSRI doesn’t change earlier finding

The MOOD-HF trial directly addresses the major criticism of the SADHART-CHF trial by looking at SSRI treatment of patients with heart failure and depression over a much longer study duration (up to 24 months vs 12 weeks). Also, in contrast to SADHART-CHF, this trial studied escitalopram, rather than sertraline, because some evidence indicates that escitalopram is superior at treating primary depression.¹³ Despite these differences, the results of MOOD-HF are consistent with the findings of SADHART-CHF: treating patients with both heart failure and depression with an SSRI did not improve the elevated morbidity and mortality risk seen with these comorbid conditions.

Also consistent with SADHART-CHF findings, participants in both groups in the MOOD-HF trial had partial remission of depressive symptoms over the study period, with no significant difference between those treated with escitalopram vs placebo. Given that this high-quality trial, with a much longer treatment period and a possibly more effective SSRI, replicated the findings of SADHART-CHF, the results of MOOD-HF should put to rest the practice of initiating SSRI treatment in depressed patients with heart failure in an attempt to affect CVD outcomes.

CAVEATS

There are other SSRI fish in the sea

There are other SSRIs, besides escitalopram and sertraline, available for use. However, it is likely that this is a class effect.

Additionally, none of the patients in this trial had severe depression, as their PHQ-9 scores were all below 19. Therefore, it remains to be determined if treating patients with severe depression has an impact on cardiovascular outcomes.

Although there are other SSRIs besides escitalopram and sertraline, it is likely that this is a class effect.

Lastly, and most importantly, this study only looked at screening patients for depression and initiating SSRIs in the setting of heart failure. The trial did not include patients already taking SSRIs for pre-existing depression. Thus, the results do not imply evidence for discontinuing SSRIs in patients with heart failure.

Treating comorbid depression and CVD to improve the elevated risk for adverse clinical outcomes remains nuanced and elusive. In fact, the same can be said of non-CVD chronic conditions—such as diabetes—based on recent systematic reviews.¹³ The summation of these studies suggests that a traditional screen-and-treat approach utilizing SSRIs for depression treatment to affect chronic disease outcomes (that are likely lifestyle-related) may not be cost-effective or patient-centered.

The publication of a recent study showing that cognitive behavioral therapy did improve depression—but not heart failure—among patients with both conditions¹⁴ reaffirms that teasing out the impact of depression on lifestyle behaviors and chronic disease outcomes among multimorbid patients is more complex than previously thought. Nevertheless, this is an area of research that should continue to be explored, given the obvious increased risk for poorer chronic disease outcomes in the presence of depression.

CHALLENGES TO IMPLEMENTATION

Changing the tide can be difficult

As with any behavior change among providers, we expect that it will be a challenge to convince providers to stop screening for depression and initiating treatment with an SSRI to affect CV outcomes in patients with heart failure. This is especially so given the body of evidence for depression as a risk factor for increased morbidity and mortality in this population.

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.