CHICAGO – More than 53,000 people will develop pancreatic ductal adenocarcinoma in the United States this year, and upwards of 41,000 will die from the disease, many of them with tumors considered unresectable because they involve adjacent vessels. However, researchers at the University of California, Irvine, have found that careful removal of the tumor around involved veins and arteries, even in borderline cases, can improve outcomes for these patients.

Roy M. Fujitani, MD, updated previously published data on a single-center study he coauthored in 2015 of 270 patients who had undergone a Whipple operation, 183 for pancreatic adenocarcinoma (J Vasc Surg. 2015;61:475-80) at a symposium on vascular surgery sponsored by Northwestern University.

Courtesy Dr. Roy M. Fujitani

CHICAGO – More than 53,000 people will develop pancreatic ductal adenocarcinoma in the United States this year, and upwards of 41,000 will die from the disease, many of them with tumors considered unresectable because they involve adjacent vessels. However, researchers at the University of California, Irvine, have found that careful removal of the tumor around involved veins and arteries, even in borderline cases, can improve outcomes for these patients.

Roy M. Fujitani, MD, updated previously published data on a single-center study he coauthored in 2015 of 270 patients who had undergone a Whipple operation, 183 for pancreatic adenocarcinoma (J Vasc Surg. 2015;61:475-80) at a symposium on vascular surgery sponsored by Northwestern University.

Courtesy Dr. Roy M. Fujitani

CHICAGO – More than 53,000 people will develop pancreatic ductal adenocarcinoma in the United States this year, and upwards of 41,000 will die from the disease, many of them with tumors considered unresectable because they involve adjacent vessels. However, researchers at the University of California, Irvine, have found that careful removal of the tumor around involved veins and arteries, even in borderline cases, can improve outcomes for these patients.

Roy M. Fujitani, MD, updated previously published data on a single-center study he coauthored in 2015 of 270 patients who had undergone a Whipple operation, 183 for pancreatic adenocarcinoma (J Vasc Surg. 2015;61:475-80) at a symposium on vascular surgery sponsored by Northwestern University.

Courtesy Dr. Roy M. Fujitani

Study Overview

Objective. To determine if evolocumab, a PCSK9 inhibitor, affects the progression of coronary artery disease in patients treated with statins.

Design. Multicenter, international, double-blind, placebo-controlled, randomized clinical trial.

Setting and participants. 197 community and academic hospitals worldwide enrolled 978 participants who underwent serial intravascular ultrasounds (IVUS) to measure their burden of coronary atherosclerosis. A total of 2628 patients were screened. Patients were considered for inclusion if they were 18 years of age or older and had at least 1 coronary artery stenosis of at least 20% on a clinically indicated catheterization. Additionally, the target vessel had to meet IVUS imaging quality and visibility standards. Participants were required to have been on stable statin therapy for at least 4 weeks with an LDL level of > 80 mg/dL or between 60–80 mg/dL with either 1 major or 3 minor cardiovascular risk factors. Major risk factors were noncoronary atherosclerotic disease, myocardial infarction (MI) or hospitalization for unstable angina within the past 2 years, or type 2 diabetes. Minor risk factors included current tobacco use, hypertension, low HDL-C levels, family history of early coronary disease, hsCRP level of 2 mg/L or greater, and age older than 50 years for men and 55 years for women. Patients with uncontrolled hypertension, uncontrolled diabetes, heart failure, renal insufficiency, or liver disease were excluded.

Intervention. Patients were randomized to either treatment with monthly subcutaneous injections of 420 mg evolocumab or placebo injections for 76 weeks. Participants attended 7 follow-up visits during the study period and then underwent repeat IVUS imaging at the 78th week. Research staff, who were blinded to both treatment status and imaging sequence, collected and assessed target vessel measurements, including the vessel lumen and external elastic membrane dimensions. IVUS imaging has been used in numerous clinical studies and has been shown to be accurate and reliable [1].

Main outcome measures. The primary outcome was the target artery change in percent atheroma volume (PAV) from baseline to week 78. PAV was calculated from IVUS measurements. Nominal change in PAV was then determined by calculating the difference of the PAV at baseline and at week 78.

The secondary measure was the normalized total atheroma volume (TAV). TAV addresses variability in the length of vessel segments and the number of images collected during IVUS catheter pullback. The nominal change in TAV was then determined by the difference at baseline and at week 78.

Additional secondary efficacy endpoints included number of patients with regression of plaque and change in lipid parameters. Safety outcomes were investigated through evaluation of the incidence of adjudicated clinical events, including all-cause mortality, cardiovascular death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and heart failure requiring hospitalization. Post-hoc analysis compared baseline LDL-C level and change in PAV and regression of PAV. The association between LDL lowering and plaque progression was also assessed post hoc.

IVUS measurements were evaluated as least squares means. Comparison of treatment groups was conducted using analysis of covariance on rank transformed data that accounted for baseline value and geographic location. Investigators used a step-down statistical procedure to evaluate primary and secondary endpoints. The statistical model accounted for confounders such as baseline LDL-C, baseline PAV, intensity of statin therapy, geographic region, age, and sex.

Main results. 484 participants were randomized to the evolocumab group and 484 to the placebo group, and 423 participants in both groups completed both baseline and follow-up IVUS imaging. Treatment and control groups contained participants matched for age, gender, ethnicity, cardiovascular risk factors, and baseline medication use, including lipid-lowering agents, ACE inhibitors, ARBs, beta-blockers, and antiplatelet therapies. Both groups consisted of a majority of white (93.4% in placebo and 94.2% in treatment) males (72.3% in placebo and 72.1% in treatment). Approximately 80% of participants had hypertension (83.7% in placebo and 82.2% in treatment), about 35% had prior MIs (35.3% in placebo and 34.9% in treatment), and roughly a fifth of participants had diabetes (21.5% in placebo and 20.2% in treatment). At baseline 98.6% of participants were treated with statins, with 58.9% on high-intensity therapy and 39.4% on moderate-intensity. Mean LDL-C level at baseline was 92.5 (SD, 27.2) mg/dL.

After 76 weeks of treatment, mean LDL-C level in the placebo group was 93.0 mg/dL and 36.6 mg/dL in the treatment group, which corresponds to a 0.2 mg/dL increase in the placebo group and a 56.3 mg/dL reduction in the treatment group. The change in LDL-C level was statistically significant (P < 0.001).

Placebo group participants had no significant change in PAV (0.05%, P = 0.78), but the evolocumab group experienced a 0.95% decrease from baseline (P < 0.001). Similarly, the placebo group had no change in TAV from baseline (–0.9 mm³, P = 0.45), but the treatment group had a 5.8 mm³ reduction in TAV from baseline (P < 0.001). The treatment group had a greater proportion of patients who experienced PAV regression (64.3% vs. 47.3%, P < 0.001) and TAV regression (61.5% vs. 48.9%, P < 0.001).

Subgroup analysis did not demonstrate a significant association between change in PAV and specific study participant characteristics (eg, age, gender, ethnicity).

Post-hoc analysis using local regression (LOESS) curve revealed a linear relationship between achieved LDL-C level and change in PAV for LDL-C levels from 110 mg/dL to 20 mg/dL.

The treatment group did not exhibit a significant increase in adverse drug events, which included injection site reactions, myalgias, neurocognitive events, and incidence of diabetes. There was no significant difference in adverse cardiovascular outcomes between groups; however, there were numerically fewer nonfatal MIs and coronary revascularizations in the treatment group.

Conclusion. The use of evolocumab in statin-treated patients resulted in greater reduction of PAV than use of statins alone.

Commentary

Evolocumab is a monoclonal antibody that inhibits pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is involved in LDL-C receptor recycling. By reducing removal of LDL-C receptors, evolocumab amplifies LDL-C clearance and has been shown to reduce LDL-C levels by approximately 61% from baseline with 12 weeks oftreatment [2]. Studies have shown that the lipid-lowering potential of evolocumab is superior to statins alone and to combination therapy with statins and ezetimibe [2]. Furthermore, PCSK9 inhibitors have been effective at LDL-lowering in patients who failed or could not tolerate standard of care therapy with statins and ezetimibe [3,4]. PCSK9 inhibitors hold great promise for reducing morbidity and mortality of cardiovascular disease; however, LDL-lowering is not equivalent to improved clinical outcomes.

The GLAGOV study moves toward demonstration of the clinical benefit of evolocumab. The study shows that combined therapy with statins and evolocumab, versus statins alone, not only achieves better stability of atherosclerotic plaque dimensions but actually results in regression of plaque size. In the study, plaque burden is extrapolated from vessel measurements obtained through IVUS, and nominal changes in PAV and TAV serve as markers for atherosclerosis, but these surrogates cannot be equated to a reduction in cardiovascular events. The GLAGOV trial does explore clinical outcomes such as MI, stroke, unstable angina, coronary revascularization, and death; however, the study is not powered to evaluate the statistical significance of these events. We await sufficiently powered phase 3 clinical trials to determine the clinical benefits of PCSK9 inhibitors on cardiovascular disease.

The GLAGOV trial has several strengths, including its design as an international, double-blind, placebo-controlled, randomized clinical trial. The intervention is simple and the outcomes are clearly defined. The statistical assessment yields significant results. Nonetheless, there are multiple limitations to the study. The lead author has received research support from Amgen, the maker of evolocumab. Amgen also participated in study design and maintenance of trial databases; however, data analysis was conducted by an independent statistician. Additionally, the majority of study participants were white males with very few minority patients despite inclusion of study sites around the globe. The homogeneity of the study cohort makes the data difficult to generalize to a larger population. Similarly, patients who lacked a clinical indication for coronary catheterization and those with uncontrolled diabetes, hypertension, and heart failure were excluded, which further limits application of this study to many patients with atherosclerosis. Another limitation is study attrition; only 87% of participants completed the 78-week IVUS and were included in the data analysis, and results may have differed if those lost to follow-up had completed the trial. Furthermore, study duration was limited to 76 weeks and the magnitude and durability of study outcomes after this time point remain unknown.

Applications for Clinical Practice

Reduction in PAV and TAV are surrogate endpoints and are not indicative of a clinical benefit. Nonetheless, the GLAGOV study demonstrates that evolocumab, when used in conjunction with statins, can promote regression of atherosclerosis greater than treatment with statins alone. More studies are needed to evaluate a clinical benefit of adding evolocumab to the regularly used arsenal of lipid-lowering therapies for the treatment of atherosclerosis. Furthermore, cost-effectiveness of evolocumab has not been shown. In 2015 the yearly wholesale price of evolcumab was $14,350. A cost-effectiveness analysis based on this price estimates that treatment of atherosclerotic coronary vascular disease with evolocumab has a cost of $414,000 per quality-adjusted life year [5]. Evolocumab is well tolerated, but additional studies for cardiovascular and mortality outcomes are needed before it can be considered part of the standard of treatment for coronary artery disease.

—Lauren Brooks, MD, University of Maryland School of Medicine, Baltimore, MD

Study Overview

Objective. To determine if evolocumab, a PCSK9 inhibitor, affects the progression of coronary artery disease in patients treated with statins.

Design. Multicenter, international, double-blind, placebo-controlled, randomized clinical trial.

Setting and participants. 197 community and academic hospitals worldwide enrolled 978 participants who underwent serial intravascular ultrasounds (IVUS) to measure their burden of coronary atherosclerosis. A total of 2628 patients were screened. Patients were considered for inclusion if they were 18 years of age or older and had at least 1 coronary artery stenosis of at least 20% on a clinically indicated catheterization. Additionally, the target vessel had to meet IVUS imaging quality and visibility standards. Participants were required to have been on stable statin therapy for at least 4 weeks with an LDL level of > 80 mg/dL or between 60–80 mg/dL with either 1 major or 3 minor cardiovascular risk factors. Major risk factors were noncoronary atherosclerotic disease, myocardial infarction (MI) or hospitalization for unstable angina within the past 2 years, or type 2 diabetes. Minor risk factors included current tobacco use, hypertension, low HDL-C levels, family history of early coronary disease, hsCRP level of 2 mg/L or greater, and age older than 50 years for men and 55 years for women. Patients with uncontrolled hypertension, uncontrolled diabetes, heart failure, renal insufficiency, or liver disease were excluded.

Intervention. Patients were randomized to either treatment with monthly subcutaneous injections of 420 mg evolocumab or placebo injections for 76 weeks. Participants attended 7 follow-up visits during the study period and then underwent repeat IVUS imaging at the 78th week. Research staff, who were blinded to both treatment status and imaging sequence, collected and assessed target vessel measurements, including the vessel lumen and external elastic membrane dimensions. IVUS imaging has been used in numerous clinical studies and has been shown to be accurate and reliable [1].

Main outcome measures. The primary outcome was the target artery change in percent atheroma volume (PAV) from baseline to week 78. PAV was calculated from IVUS measurements. Nominal change in PAV was then determined by calculating the difference of the PAV at baseline and at week 78.

The secondary measure was the normalized total atheroma volume (TAV). TAV addresses variability in the length of vessel segments and the number of images collected during IVUS catheter pullback. The nominal change in TAV was then determined by the difference at baseline and at week 78.

Additional secondary efficacy endpoints included number of patients with regression of plaque and change in lipid parameters. Safety outcomes were investigated through evaluation of the incidence of adjudicated clinical events, including all-cause mortality, cardiovascular death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and heart failure requiring hospitalization. Post-hoc analysis compared baseline LDL-C level and change in PAV and regression of PAV. The association between LDL lowering and plaque progression was also assessed post hoc.

IVUS measurements were evaluated as least squares means. Comparison of treatment groups was conducted using analysis of covariance on rank transformed data that accounted for baseline value and geographic location. Investigators used a step-down statistical procedure to evaluate primary and secondary endpoints. The statistical model accounted for confounders such as baseline LDL-C, baseline PAV, intensity of statin therapy, geographic region, age, and sex.

Main results. 484 participants were randomized to the evolocumab group and 484 to the placebo group, and 423 participants in both groups completed both baseline and follow-up IVUS imaging. Treatment and control groups contained participants matched for age, gender, ethnicity, cardiovascular risk factors, and baseline medication use, including lipid-lowering agents, ACE inhibitors, ARBs, beta-blockers, and antiplatelet therapies. Both groups consisted of a majority of white (93.4% in placebo and 94.2% in treatment) males (72.3% in placebo and 72.1% in treatment). Approximately 80% of participants had hypertension (83.7% in placebo and 82.2% in treatment), about 35% had prior MIs (35.3% in placebo and 34.9% in treatment), and roughly a fifth of participants had diabetes (21.5% in placebo and 20.2% in treatment). At baseline 98.6% of participants were treated with statins, with 58.9% on high-intensity therapy and 39.4% on moderate-intensity. Mean LDL-C level at baseline was 92.5 (SD, 27.2) mg/dL.

After 76 weeks of treatment, mean LDL-C level in the placebo group was 93.0 mg/dL and 36.6 mg/dL in the treatment group, which corresponds to a 0.2 mg/dL increase in the placebo group and a 56.3 mg/dL reduction in the treatment group. The change in LDL-C level was statistically significant (P < 0.001).

Placebo group participants had no significant change in PAV (0.05%, P = 0.78), but the evolocumab group experienced a 0.95% decrease from baseline (P < 0.001). Similarly, the placebo group had no change in TAV from baseline (–0.9 mm³, P = 0.45), but the treatment group had a 5.8 mm³ reduction in TAV from baseline (P < 0.001). The treatment group had a greater proportion of patients who experienced PAV regression (64.3% vs. 47.3%, P < 0.001) and TAV regression (61.5% vs. 48.9%, P < 0.001).

Subgroup analysis did not demonstrate a significant association between change in PAV and specific study participant characteristics (eg, age, gender, ethnicity).

Post-hoc analysis using local regression (LOESS) curve revealed a linear relationship between achieved LDL-C level and change in PAV for LDL-C levels from 110 mg/dL to 20 mg/dL.

The treatment group did not exhibit a significant increase in adverse drug events, which included injection site reactions, myalgias, neurocognitive events, and incidence of diabetes. There was no significant difference in adverse cardiovascular outcomes between groups; however, there were numerically fewer nonfatal MIs and coronary revascularizations in the treatment group.

Conclusion. The use of evolocumab in statin-treated patients resulted in greater reduction of PAV than use of statins alone.

Commentary

Evolocumab is a monoclonal antibody that inhibits pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is involved in LDL-C receptor recycling. By reducing removal of LDL-C receptors, evolocumab amplifies LDL-C clearance and has been shown to reduce LDL-C levels by approximately 61% from baseline with 12 weeks oftreatment [2]. Studies have shown that the lipid-lowering potential of evolocumab is superior to statins alone and to combination therapy with statins and ezetimibe [2]. Furthermore, PCSK9 inhibitors have been effective at LDL-lowering in patients who failed or could not tolerate standard of care therapy with statins and ezetimibe [3,4]. PCSK9 inhibitors hold great promise for reducing morbidity and mortality of cardiovascular disease; however, LDL-lowering is not equivalent to improved clinical outcomes.

The GLAGOV study moves toward demonstration of the clinical benefit of evolocumab. The study shows that combined therapy with statins and evolocumab, versus statins alone, not only achieves better stability of atherosclerotic plaque dimensions but actually results in regression of plaque size. In the study, plaque burden is extrapolated from vessel measurements obtained through IVUS, and nominal changes in PAV and TAV serve as markers for atherosclerosis, but these surrogates cannot be equated to a reduction in cardiovascular events. The GLAGOV trial does explore clinical outcomes such as MI, stroke, unstable angina, coronary revascularization, and death; however, the study is not powered to evaluate the statistical significance of these events. We await sufficiently powered phase 3 clinical trials to determine the clinical benefits of PCSK9 inhibitors on cardiovascular disease.

The GLAGOV trial has several strengths, including its design as an international, double-blind, placebo-controlled, randomized clinical trial. The intervention is simple and the outcomes are clearly defined. The statistical assessment yields significant results. Nonetheless, there are multiple limitations to the study. The lead author has received research support from Amgen, the maker of evolocumab. Amgen also participated in study design and maintenance of trial databases; however, data analysis was conducted by an independent statistician. Additionally, the majority of study participants were white males with very few minority patients despite inclusion of study sites around the globe. The homogeneity of the study cohort makes the data difficult to generalize to a larger population. Similarly, patients who lacked a clinical indication for coronary catheterization and those with uncontrolled diabetes, hypertension, and heart failure were excluded, which further limits application of this study to many patients with atherosclerosis. Another limitation is study attrition; only 87% of participants completed the 78-week IVUS and were included in the data analysis, and results may have differed if those lost to follow-up had completed the trial. Furthermore, study duration was limited to 76 weeks and the magnitude and durability of study outcomes after this time point remain unknown.

Applications for Clinical Practice

Reduction in PAV and TAV are surrogate endpoints and are not indicative of a clinical benefit. Nonetheless, the GLAGOV study demonstrates that evolocumab, when used in conjunction with statins, can promote regression of atherosclerosis greater than treatment with statins alone. More studies are needed to evaluate a clinical benefit of adding evolocumab to the regularly used arsenal of lipid-lowering therapies for the treatment of atherosclerosis. Furthermore, cost-effectiveness of evolocumab has not been shown. In 2015 the yearly wholesale price of evolcumab was $14,350. A cost-effectiveness analysis based on this price estimates that treatment of atherosclerotic coronary vascular disease with evolocumab has a cost of $414,000 per quality-adjusted life year [5]. Evolocumab is well tolerated, but additional studies for cardiovascular and mortality outcomes are needed before it can be considered part of the standard of treatment for coronary artery disease.

—Lauren Brooks, MD, University of Maryland School of Medicine, Baltimore, MD

Study Overview

Objective. To determine if evolocumab, a PCSK9 inhibitor, affects the progression of coronary artery disease in patients treated with statins.

Design. Multicenter, international, double-blind, placebo-controlled, randomized clinical trial.

Setting and participants. 197 community and academic hospitals worldwide enrolled 978 participants who underwent serial intravascular ultrasounds (IVUS) to measure their burden of coronary atherosclerosis. A total of 2628 patients were screened. Patients were considered for inclusion if they were 18 years of age or older and had at least 1 coronary artery stenosis of at least 20% on a clinically indicated catheterization. Additionally, the target vessel had to meet IVUS imaging quality and visibility standards. Participants were required to have been on stable statin therapy for at least 4 weeks with an LDL level of > 80 mg/dL or between 60–80 mg/dL with either 1 major or 3 minor cardiovascular risk factors. Major risk factors were noncoronary atherosclerotic disease, myocardial infarction (MI) or hospitalization for unstable angina within the past 2 years, or type 2 diabetes. Minor risk factors included current tobacco use, hypertension, low HDL-C levels, family history of early coronary disease, hsCRP level of 2 mg/L or greater, and age older than 50 years for men and 55 years for women. Patients with uncontrolled hypertension, uncontrolled diabetes, heart failure, renal insufficiency, or liver disease were excluded.

Intervention. Patients were randomized to either treatment with monthly subcutaneous injections of 420 mg evolocumab or placebo injections for 76 weeks. Participants attended 7 follow-up visits during the study period and then underwent repeat IVUS imaging at the 78th week. Research staff, who were blinded to both treatment status and imaging sequence, collected and assessed target vessel measurements, including the vessel lumen and external elastic membrane dimensions. IVUS imaging has been used in numerous clinical studies and has been shown to be accurate and reliable [1].

Main outcome measures. The primary outcome was the target artery change in percent atheroma volume (PAV) from baseline to week 78. PAV was calculated from IVUS measurements. Nominal change in PAV was then determined by calculating the difference of the PAV at baseline and at week 78.

The secondary measure was the normalized total atheroma volume (TAV). TAV addresses variability in the length of vessel segments and the number of images collected during IVUS catheter pullback. The nominal change in TAV was then determined by the difference at baseline and at week 78.

Additional secondary efficacy endpoints included number of patients with regression of plaque and change in lipid parameters. Safety outcomes were investigated through evaluation of the incidence of adjudicated clinical events, including all-cause mortality, cardiovascular death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and heart failure requiring hospitalization. Post-hoc analysis compared baseline LDL-C level and change in PAV and regression of PAV. The association between LDL lowering and plaque progression was also assessed post hoc.

IVUS measurements were evaluated as least squares means. Comparison of treatment groups was conducted using analysis of covariance on rank transformed data that accounted for baseline value and geographic location. Investigators used a step-down statistical procedure to evaluate primary and secondary endpoints. The statistical model accounted for confounders such as baseline LDL-C, baseline PAV, intensity of statin therapy, geographic region, age, and sex.

Main results. 484 participants were randomized to the evolocumab group and 484 to the placebo group, and 423 participants in both groups completed both baseline and follow-up IVUS imaging. Treatment and control groups contained participants matched for age, gender, ethnicity, cardiovascular risk factors, and baseline medication use, including lipid-lowering agents, ACE inhibitors, ARBs, beta-blockers, and antiplatelet therapies. Both groups consisted of a majority of white (93.4% in placebo and 94.2% in treatment) males (72.3% in placebo and 72.1% in treatment). Approximately 80% of participants had hypertension (83.7% in placebo and 82.2% in treatment), about 35% had prior MIs (35.3% in placebo and 34.9% in treatment), and roughly a fifth of participants had diabetes (21.5% in placebo and 20.2% in treatment). At baseline 98.6% of participants were treated with statins, with 58.9% on high-intensity therapy and 39.4% on moderate-intensity. Mean LDL-C level at baseline was 92.5 (SD, 27.2) mg/dL.

After 76 weeks of treatment, mean LDL-C level in the placebo group was 93.0 mg/dL and 36.6 mg/dL in the treatment group, which corresponds to a 0.2 mg/dL increase in the placebo group and a 56.3 mg/dL reduction in the treatment group. The change in LDL-C level was statistically significant (P < 0.001).

Placebo group participants had no significant change in PAV (0.05%, P = 0.78), but the evolocumab group experienced a 0.95% decrease from baseline (P < 0.001). Similarly, the placebo group had no change in TAV from baseline (–0.9 mm³, P = 0.45), but the treatment group had a 5.8 mm³ reduction in TAV from baseline (P < 0.001). The treatment group had a greater proportion of patients who experienced PAV regression (64.3% vs. 47.3%, P < 0.001) and TAV regression (61.5% vs. 48.9%, P < 0.001).

Subgroup analysis did not demonstrate a significant association between change in PAV and specific study participant characteristics (eg, age, gender, ethnicity).

Post-hoc analysis using local regression (LOESS) curve revealed a linear relationship between achieved LDL-C level and change in PAV for LDL-C levels from 110 mg/dL to 20 mg/dL.

The treatment group did not exhibit a significant increase in adverse drug events, which included injection site reactions, myalgias, neurocognitive events, and incidence of diabetes. There was no significant difference in adverse cardiovascular outcomes between groups; however, there were numerically fewer nonfatal MIs and coronary revascularizations in the treatment group.

Conclusion. The use of evolocumab in statin-treated patients resulted in greater reduction of PAV than use of statins alone.

Commentary

Evolocumab is a monoclonal antibody that inhibits pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is involved in LDL-C receptor recycling. By reducing removal of LDL-C receptors, evolocumab amplifies LDL-C clearance and has been shown to reduce LDL-C levels by approximately 61% from baseline with 12 weeks oftreatment [2]. Studies have shown that the lipid-lowering potential of evolocumab is superior to statins alone and to combination therapy with statins and ezetimibe [2]. Furthermore, PCSK9 inhibitors have been effective at LDL-lowering in patients who failed or could not tolerate standard of care therapy with statins and ezetimibe [3,4]. PCSK9 inhibitors hold great promise for reducing morbidity and mortality of cardiovascular disease; however, LDL-lowering is not equivalent to improved clinical outcomes.

The GLAGOV study moves toward demonstration of the clinical benefit of evolocumab. The study shows that combined therapy with statins and evolocumab, versus statins alone, not only achieves better stability of atherosclerotic plaque dimensions but actually results in regression of plaque size. In the study, plaque burden is extrapolated from vessel measurements obtained through IVUS, and nominal changes in PAV and TAV serve as markers for atherosclerosis, but these surrogates cannot be equated to a reduction in cardiovascular events. The GLAGOV trial does explore clinical outcomes such as MI, stroke, unstable angina, coronary revascularization, and death; however, the study is not powered to evaluate the statistical significance of these events. We await sufficiently powered phase 3 clinical trials to determine the clinical benefits of PCSK9 inhibitors on cardiovascular disease.

The GLAGOV trial has several strengths, including its design as an international, double-blind, placebo-controlled, randomized clinical trial. The intervention is simple and the outcomes are clearly defined. The statistical assessment yields significant results. Nonetheless, there are multiple limitations to the study. The lead author has received research support from Amgen, the maker of evolocumab. Amgen also participated in study design and maintenance of trial databases; however, data analysis was conducted by an independent statistician. Additionally, the majority of study participants were white males with very few minority patients despite inclusion of study sites around the globe. The homogeneity of the study cohort makes the data difficult to generalize to a larger population. Similarly, patients who lacked a clinical indication for coronary catheterization and those with uncontrolled diabetes, hypertension, and heart failure were excluded, which further limits application of this study to many patients with atherosclerosis. Another limitation is study attrition; only 87% of participants completed the 78-week IVUS and were included in the data analysis, and results may have differed if those lost to follow-up had completed the trial. Furthermore, study duration was limited to 76 weeks and the magnitude and durability of study outcomes after this time point remain unknown.

Applications for Clinical Practice

Reduction in PAV and TAV are surrogate endpoints and are not indicative of a clinical benefit. Nonetheless, the GLAGOV study demonstrates that evolocumab, when used in conjunction with statins, can promote regression of atherosclerosis greater than treatment with statins alone. More studies are needed to evaluate a clinical benefit of adding evolocumab to the regularly used arsenal of lipid-lowering therapies for the treatment of atherosclerosis. Furthermore, cost-effectiveness of evolocumab has not been shown. In 2015 the yearly wholesale price of evolcumab was $14,350. A cost-effectiveness analysis based on this price estimates that treatment of atherosclerotic coronary vascular disease with evolocumab has a cost of $414,000 per quality-adjusted life year [5]. Evolocumab is well tolerated, but additional studies for cardiovascular and mortality outcomes are needed before it can be considered part of the standard of treatment for coronary artery disease.

—Lauren Brooks, MD, University of Maryland School of Medicine, Baltimore, MD

SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.

Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.

No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.

Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.

Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m² on day 1 and oxaliplatin 85 mg/m² on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.

In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.

The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.

The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.

“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”

Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.

“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.

“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.

Dr. Edeline reported having no disclosures.

[email protected]

SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.

Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.

No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.

Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.

Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m² on day 1 and oxaliplatin 85 mg/m² on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.

In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.

The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.

The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.

“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”

Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.

“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.

“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.

Dr. Edeline reported having no disclosures.

[email protected]

SAN FRANCISCO – Post-surgery adjuvant treatment with gemcitabine and oxaliplatin (GEMOX) was feasible, but failed to significantly improve relapse-free survival when compared with surveillance among patients with localized biliary tract cancer in the randomized phase III PRODIGE 12-ACCORD 18 (UNICANCER GI) trial.

Relapse-free survival at a median of 44.3 months in 196 patients who were randomized within 3 months of R0 or R1 resection of a localized biliary tract cancer to receive either GEMOX for 12 cycles or surveillance was 30.4 months vs. 22.0 months in the groups, respectively. At 4 years, relapse-free survival was 39.3% and 33.2%, respectively, Julien Edeline, MD, of Oncology Medical Eugene Marquis Comprehensive Cancer Center, Rennes, France, reported at the symposium, sponsored by ASCO, ASTRO, the American Gastroenterological Association, and Society of Surgical Oncology.

No difference was seen between the groups with respect to the co-primary endpoint of 12- and 24-month global health-related quality of life scores (70.8 vs. 83.3, and 75.0 vs. 83.3, respectively), he said.

Study subjects had localized intra-hepatic, perihilar, or extra-hepatic cholangiocarcinoma, or gallbladder cancer and were enrolled from 33 centers between July 2009 and February 2014. They had ECOG performance status of 0-2, and adequate liver function. The treatment and surveillance arms were well balanced, with similar primary disease sites, Dr. Edeline said.

Those in the GEMOX arm received 12 cycles (6 months) of gemcitabine 1,000 mg/m² on day 1 and oxaliplatin 85 mg/m² on day 2. Those in the surveillance arm underwent ACE, CA19.9 testing, and CT scans every 3 months for 2 years then every 6 months for 3 years.

In the treatment and surveillance arms, respectively, R0 resection rates were 86.2% and 87.9%, and lymph node invasion was present in 37.2% and 36.4%.

The maximal grade of adverse events was 3 in 57.5% vs. 22.2% of patients in the groups, respectively, and grade 4 in 17.0% vs. 9.1%. One patient in each arm died during treatment.

The main grade 3 or greater adverse events were peripheral neuropathy in 50.0% vs. 1.1% and neutropenia in 22.3% vs. 0% for GEMOX vs. surveillance group patients.

“As you know, there is a high risk of relapse following surgery for localized biliary tract cancer. There is currently no proven adjuvant or neoadjuvant treatment,” Dr. Edeline said. “In the palliative setting, we know that the combination of gemcitabine and cisplatin improves overall survival. GEMOX is considered an active regimen based on data from phase II trials. At the time of the design of our study, GEMOX was considered the standard first line treatment for biliary tract cancer.”

Based on this background, the aim of the current phase III trial was to assess whether GEMOX would increase relapse-free survival while maintaining health-related quality of life in patients with localized disease.

“We showed that adjuvant GEMOX was feasible. Toxicities were as expected and manageable, and we didn’t see detrimental effects on quality of life. However, adjuvant GEMOX was not associated in the PRODIGE 12 trial with an improvement in relapse-free survival,” he said, noting that this was also true in subgroup analyses, which showed no benefit of GEMOX with respect to relapse-free survival in any predefined subgroups.

“Clearly, further research through international collaboration is required to improve outcomes in these patients,” he concluded.

Dr. Edeline reported having no disclosures.

[email protected]

SAN FRANCISCO – It’s not uncommon for children to arrive at the Western Psychiatric Institute and Clinic in Pittsburgh with selective serotonin reuptake inhibitor activation that was misdiagnosed as bipolar disorder, according to Boris Birmaher, MD.

“We get many kids into our clinic with a diagnosis of bipolar because of this, and they are not bipolar. You have to be careful,” he said during a talk about pediatric depression at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

SSRIs activate about 5%-10% of children. There might be sleep problems, fast speech, hyperactivity, agitation, aggression, and even suicidality, he said.

[email protected]

SAN FRANCISCO – It’s not uncommon for children to arrive at the Western Psychiatric Institute and Clinic in Pittsburgh with selective serotonin reuptake inhibitor activation that was misdiagnosed as bipolar disorder, according to Boris Birmaher, MD.

“We get many kids into our clinic with a diagnosis of bipolar because of this, and they are not bipolar. You have to be careful,” he said during a talk about pediatric depression at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

SSRIs activate about 5%-10% of children. There might be sleep problems, fast speech, hyperactivity, agitation, aggression, and even suicidality, he said.

[email protected]

SAN FRANCISCO – It’s not uncommon for children to arrive at the Western Psychiatric Institute and Clinic in Pittsburgh with selective serotonin reuptake inhibitor activation that was misdiagnosed as bipolar disorder, according to Boris Birmaher, MD.

“We get many kids into our clinic with a diagnosis of bipolar because of this, and they are not bipolar. You have to be careful,” he said during a talk about pediatric depression at a psychopharmacology update held by the American Academy of Child and Adolescent Psychiatry.

SSRIs activate about 5%-10% of children. There might be sleep problems, fast speech, hyperactivity, agitation, aggression, and even suicidality, he said.

[email protected]

Organizations representing physicians and medical students have expressed their concern regarding President Trump’s executive order of Jan. 27 that curtails entry into the United States by travelers from seven Muslim-majority countries. The order also suspends for 120 days entry into the United States for all persons seeking refugee status, and it bars refugees from Syria indefinitely.

Following are direct excerpts from statements issued by medical organizations.
 

American Academy of Family Physicians

“We are deeply concerned that steps your Administration has taken will have a chilling effect on our nation’s physician workforce, biomedical research, and global health. It is often America’s physicians who answer the call to assist people around the world when a public health crisis occurs. Imagine a world where physicians fail to answer the call of the needy because they fear they may not be able to return to their home and families in the United States.

Many family physicians are international medical graduates (IMG), who have completed all or part of their education and training in the United States. They are professionals who dedicate their careers to the service of their patients in communities large and small, urban and rural. In fact, 20% of our membership and over 25% of family medicine residents [comprise] IMGs. The AAFP applauds and supports wholly the contributions of these individual family physicians to their patients and communities and we celebrate their diversity.

tupungato/Thinkstock

American Academy of Pediatrics

“The executive orders signed today are harmful to immigrant children and families throughout our country. Many of the children who will be most affected are the victims of unspeakable violence and have been exposed to trauma. Children do not immigrate, they flee. They are coming to the United States seeking safe haven in our country and they need our compassion and assistance. Broad scale expansion of family detention only exacerbates their suffering ... The AAP is non-partisan and pro-children. We urge President Trump and his administration to ensure that children and families who are fleeing violence and adversity can continue to seek refuge in our country. Immigrant children and families are an integral part of our communities and our nation, and they deserve to be cared for, treated with compassion, and celebrated. Most of all, they deserve to be healthy and safe. Pediatricians stand with the immigrant families we care for and will continue to advocate that their needs are met and prioritized.”

American Association of Medical Colleges

“The United States is facing a serious shortage of physicians. IMGs play an important role in U.S. health care, representing roughly 25% of the workforce. Current immigration pathways – including student, exchange-visitor, and employment visas – provide a balanced solution that improves health care access across the country through programs like the National Interest Waiver and the Conrad 30 J-1 Visa Waiver. In the last decade, Conrad 30 alone has directed nearly 10,000 physicians into rural and urban underserved communities. Impeding these U.S. immigration pathways jeopardizes critical access to high-quality physician care for our nation’s most vulnerable populations.

Our ability to attract top talent from around the world also enriches the research laboratories at medical schools and teaching hospitals that are working toward cures and has helped position the United States as a global leader in medical research, strengthening our economy and bolstering the public’s health. Because disease knows no geographic boundaries, it is essential to ensure that we continue to foster, rather than impede, scientific cooperation with physicians and researchers of all nationalities, as we strive to keep our country healthy.”
 

American College of Cardiology

“The ability to share ideas and knowledge necessary to address [the global epidemic of cardiovascular disease] is imperative. Policies that impede this free-flow of ideas will have a detrimental impact on scientific discovery, as well as the lives of patients around the world. If we are to realize a future where cardiovascular disease is no longer the number one killer of men and women worldwide we must ensure that our system of scientific exchange allows for health care professionals to learn from each other regardless of their nationality.

Additionally, IMGs, naturalized citizens, and legal residents make up a significant portion of the health care workforce in hospitals and practices across the country. More than 25% of current practicing physicians are IMGs, with cardiology ranking among the top when broken down by medical specialty. Policies that bring the immigration status of those already here into question, while also limiting the ability of others to legally train in the United States going forward, will only serve to exacerbate the already existing cardiovascular workforce shortage, especially in rural America. Such policies also threaten the care continuum of patients who rely on these providers for their medical care.”
 

American College of Physicians

“The executive order could deny entry or reentry to tens of thousands more persons, including medical students and physicians who are being trained in the United States and/or are delivering direct patient care. ... It also creates a precedent for barring entry of IMGs based on their religion and country of origin. ... Approximately 30% of ACP members are IMGs.”

American Gastroenterological Association

Science and illness ignore borders and political divides. That is why AGA is concerned that the recent U.S. executive order on immigration could limit scientific exchange, delay patient care and impair medical training.

AGA is committed to diversity, which we define as inclusive of race, ethnicity and national origin. Diversity within training programs and laboratories in the United States built today’s practice of gastroenterology. Scientists from around the world publish in our journals, work in our laboratories, train in our programs and present data at Digestive Disease Week. This exchange leads to better patient care, and very sick patients travel to the United States from around the world for the best digestive health care.

AGA adds our support to a growing number of medical institutions urging the administration to consider the devastating impact of the executive order on the health of the nation that will result from turning away patients, health professionals, and researchers. The recent immigration policy is clearly detrimental to America’s leadership role in advancing health care, and to the standing of the United States within the international community.
 

American Society of Clinical Oncology

ASCO is deeply concerned about the potential impact of the recent executive order on cancer research, patient care, and international scientific collaboration.

Our more than 40,000 members in 148 countries lead the charge to conquer cancer in all its forms and in every nation. Tens of thousands of people from more than 100 countries participate in our scientific meetings to exchange advances and ideas to improve patient care. Millions of cancer survivors are alive today because of the progress made possible by scientific collaboration. Progress against this disease will falter if the close-knit global community of cancer care providers is divided by policies that bar members of certain nationalities from entering the United States to conduct research, care for people with cancer, or participate in scientific and medical conferences.
 

American Society of Hematology

We express our deep concern about the Administration’s executive order that has denied U.S. entry to people who bring unique expertise to the practice of medicine and the conduct of cancer and biomedical research. Our nation depends on the contributions of the greatest minds from around the world to maintain the high quality of our biomedical research enterprise and health care services.

The benefits of scientific collaborations are amplified by our diversity. Limiting the exchange of ideas, practices, and data across cultures has the potential to significantly retard scientific progress and adversely affect public health. Any loss of researchers and physicians will render the United States less competitive over time, and our traditionally strong research institutions and the patients they serve will be negatively affected.

We remain deeply concerned that restricting travel will prohibit participation in scientific meetings, where cutting-edge science and treatment methods are often first introduced. These in-person meetings and other global exchanges are vitally important because they provide unparalleled opportunities for collaborations and information-sharing. Such scientific and medical meetings are absolutely essential to the conquest of cancer and blood diseases.

(Statement issued on behalf of ASH, American Association for Cancer Research, Association of American Cancer Institutes, American Society for Radiation Oncology, The American Society for Pediatric Hematology/Oncology, and LUNGevity Foundation.)

The text of the executive order can be found on the White House website.

Updated 2/2/17 to include the position of the American Gastroenterological Association.

[email protected]
On Twitter @denisefulton

Organizations representing physicians and medical students have expressed their concern regarding President Trump’s executive order of Jan. 27 that curtails entry into the United States by travelers from seven Muslim-majority countries. The order also suspends for 120 days entry into the United States for all persons seeking refugee status, and it bars refugees from Syria indefinitely.

Following are direct excerpts from statements issued by medical organizations.
 

American Academy of Family Physicians

“We are deeply concerned that steps your Administration has taken will have a chilling effect on our nation’s physician workforce, biomedical research, and global health. It is often America’s physicians who answer the call to assist people around the world when a public health crisis occurs. Imagine a world where physicians fail to answer the call of the needy because they fear they may not be able to return to their home and families in the United States.

Many family physicians are international medical graduates (IMG), who have completed all or part of their education and training in the United States. They are professionals who dedicate their careers to the service of their patients in communities large and small, urban and rural. In fact, 20% of our membership and over 25% of family medicine residents [comprise] IMGs. The AAFP applauds and supports wholly the contributions of these individual family physicians to their patients and communities and we celebrate their diversity.

tupungato/Thinkstock

American Academy of Pediatrics

“The executive orders signed today are harmful to immigrant children and families throughout our country. Many of the children who will be most affected are the victims of unspeakable violence and have been exposed to trauma. Children do not immigrate, they flee. They are coming to the United States seeking safe haven in our country and they need our compassion and assistance. Broad scale expansion of family detention only exacerbates their suffering ... The AAP is non-partisan and pro-children. We urge President Trump and his administration to ensure that children and families who are fleeing violence and adversity can continue to seek refuge in our country. Immigrant children and families are an integral part of our communities and our nation, and they deserve to be cared for, treated with compassion, and celebrated. Most of all, they deserve to be healthy and safe. Pediatricians stand with the immigrant families we care for and will continue to advocate that their needs are met and prioritized.”

American Association of Medical Colleges

“The United States is facing a serious shortage of physicians. IMGs play an important role in U.S. health care, representing roughly 25% of the workforce. Current immigration pathways – including student, exchange-visitor, and employment visas – provide a balanced solution that improves health care access across the country through programs like the National Interest Waiver and the Conrad 30 J-1 Visa Waiver. In the last decade, Conrad 30 alone has directed nearly 10,000 physicians into rural and urban underserved communities. Impeding these U.S. immigration pathways jeopardizes critical access to high-quality physician care for our nation’s most vulnerable populations.

Our ability to attract top talent from around the world also enriches the research laboratories at medical schools and teaching hospitals that are working toward cures and has helped position the United States as a global leader in medical research, strengthening our economy and bolstering the public’s health. Because disease knows no geographic boundaries, it is essential to ensure that we continue to foster, rather than impede, scientific cooperation with physicians and researchers of all nationalities, as we strive to keep our country healthy.”
 

American College of Cardiology

“The ability to share ideas and knowledge necessary to address [the global epidemic of cardiovascular disease] is imperative. Policies that impede this free-flow of ideas will have a detrimental impact on scientific discovery, as well as the lives of patients around the world. If we are to realize a future where cardiovascular disease is no longer the number one killer of men and women worldwide we must ensure that our system of scientific exchange allows for health care professionals to learn from each other regardless of their nationality.

Additionally, IMGs, naturalized citizens, and legal residents make up a significant portion of the health care workforce in hospitals and practices across the country. More than 25% of current practicing physicians are IMGs, with cardiology ranking among the top when broken down by medical specialty. Policies that bring the immigration status of those already here into question, while also limiting the ability of others to legally train in the United States going forward, will only serve to exacerbate the already existing cardiovascular workforce shortage, especially in rural America. Such policies also threaten the care continuum of patients who rely on these providers for their medical care.”
 

American College of Physicians

“The executive order could deny entry or reentry to tens of thousands more persons, including medical students and physicians who are being trained in the United States and/or are delivering direct patient care. ... It also creates a precedent for barring entry of IMGs based on their religion and country of origin. ... Approximately 30% of ACP members are IMGs.”

American Gastroenterological Association

Science and illness ignore borders and political divides. That is why AGA is concerned that the recent U.S. executive order on immigration could limit scientific exchange, delay patient care and impair medical training.

AGA is committed to diversity, which we define as inclusive of race, ethnicity and national origin. Diversity within training programs and laboratories in the United States built today’s practice of gastroenterology. Scientists from around the world publish in our journals, work in our laboratories, train in our programs and present data at Digestive Disease Week. This exchange leads to better patient care, and very sick patients travel to the United States from around the world for the best digestive health care.

AGA adds our support to a growing number of medical institutions urging the administration to consider the devastating impact of the executive order on the health of the nation that will result from turning away patients, health professionals, and researchers. The recent immigration policy is clearly detrimental to America’s leadership role in advancing health care, and to the standing of the United States within the international community.
 

American Society of Clinical Oncology

ASCO is deeply concerned about the potential impact of the recent executive order on cancer research, patient care, and international scientific collaboration.

Our more than 40,000 members in 148 countries lead the charge to conquer cancer in all its forms and in every nation. Tens of thousands of people from more than 100 countries participate in our scientific meetings to exchange advances and ideas to improve patient care. Millions of cancer survivors are alive today because of the progress made possible by scientific collaboration. Progress against this disease will falter if the close-knit global community of cancer care providers is divided by policies that bar members of certain nationalities from entering the United States to conduct research, care for people with cancer, or participate in scientific and medical conferences.
 

American Society of Hematology

We express our deep concern about the Administration’s executive order that has denied U.S. entry to people who bring unique expertise to the practice of medicine and the conduct of cancer and biomedical research. Our nation depends on the contributions of the greatest minds from around the world to maintain the high quality of our biomedical research enterprise and health care services.

The benefits of scientific collaborations are amplified by our diversity. Limiting the exchange of ideas, practices, and data across cultures has the potential to significantly retard scientific progress and adversely affect public health. Any loss of researchers and physicians will render the United States less competitive over time, and our traditionally strong research institutions and the patients they serve will be negatively affected.

We remain deeply concerned that restricting travel will prohibit participation in scientific meetings, where cutting-edge science and treatment methods are often first introduced. These in-person meetings and other global exchanges are vitally important because they provide unparalleled opportunities for collaborations and information-sharing. Such scientific and medical meetings are absolutely essential to the conquest of cancer and blood diseases.

(Statement issued on behalf of ASH, American Association for Cancer Research, Association of American Cancer Institutes, American Society for Radiation Oncology, The American Society for Pediatric Hematology/Oncology, and LUNGevity Foundation.)

The text of the executive order can be found on the White House website.

Updated 2/2/17 to include the position of the American Gastroenterological Association.

[email protected]
On Twitter @denisefulton

Organizations representing physicians and medical students have expressed their concern regarding President Trump’s executive order of Jan. 27 that curtails entry into the United States by travelers from seven Muslim-majority countries. The order also suspends for 120 days entry into the United States for all persons seeking refugee status, and it bars refugees from Syria indefinitely.

Following are direct excerpts from statements issued by medical organizations.
 

American Academy of Family Physicians

“We are deeply concerned that steps your Administration has taken will have a chilling effect on our nation’s physician workforce, biomedical research, and global health. It is often America’s physicians who answer the call to assist people around the world when a public health crisis occurs. Imagine a world where physicians fail to answer the call of the needy because they fear they may not be able to return to their home and families in the United States.

Many family physicians are international medical graduates (IMG), who have completed all or part of their education and training in the United States. They are professionals who dedicate their careers to the service of their patients in communities large and small, urban and rural. In fact, 20% of our membership and over 25% of family medicine residents [comprise] IMGs. The AAFP applauds and supports wholly the contributions of these individual family physicians to their patients and communities and we celebrate their diversity.

tupungato/Thinkstock

American Academy of Pediatrics

“The executive orders signed today are harmful to immigrant children and families throughout our country. Many of the children who will be most affected are the victims of unspeakable violence and have been exposed to trauma. Children do not immigrate, they flee. They are coming to the United States seeking safe haven in our country and they need our compassion and assistance. Broad scale expansion of family detention only exacerbates their suffering ... The AAP is non-partisan and pro-children. We urge President Trump and his administration to ensure that children and families who are fleeing violence and adversity can continue to seek refuge in our country. Immigrant children and families are an integral part of our communities and our nation, and they deserve to be cared for, treated with compassion, and celebrated. Most of all, they deserve to be healthy and safe. Pediatricians stand with the immigrant families we care for and will continue to advocate that their needs are met and prioritized.”

American Association of Medical Colleges

“The United States is facing a serious shortage of physicians. IMGs play an important role in U.S. health care, representing roughly 25% of the workforce. Current immigration pathways – including student, exchange-visitor, and employment visas – provide a balanced solution that improves health care access across the country through programs like the National Interest Waiver and the Conrad 30 J-1 Visa Waiver. In the last decade, Conrad 30 alone has directed nearly 10,000 physicians into rural and urban underserved communities. Impeding these U.S. immigration pathways jeopardizes critical access to high-quality physician care for our nation’s most vulnerable populations.

Our ability to attract top talent from around the world also enriches the research laboratories at medical schools and teaching hospitals that are working toward cures and has helped position the United States as a global leader in medical research, strengthening our economy and bolstering the public’s health. Because disease knows no geographic boundaries, it is essential to ensure that we continue to foster, rather than impede, scientific cooperation with physicians and researchers of all nationalities, as we strive to keep our country healthy.”
 

American College of Cardiology

“The ability to share ideas and knowledge necessary to address [the global epidemic of cardiovascular disease] is imperative. Policies that impede this free-flow of ideas will have a detrimental impact on scientific discovery, as well as the lives of patients around the world. If we are to realize a future where cardiovascular disease is no longer the number one killer of men and women worldwide we must ensure that our system of scientific exchange allows for health care professionals to learn from each other regardless of their nationality.

Additionally, IMGs, naturalized citizens, and legal residents make up a significant portion of the health care workforce in hospitals and practices across the country. More than 25% of current practicing physicians are IMGs, with cardiology ranking among the top when broken down by medical specialty. Policies that bring the immigration status of those already here into question, while also limiting the ability of others to legally train in the United States going forward, will only serve to exacerbate the already existing cardiovascular workforce shortage, especially in rural America. Such policies also threaten the care continuum of patients who rely on these providers for their medical care.”
 

American College of Physicians

“The executive order could deny entry or reentry to tens of thousands more persons, including medical students and physicians who are being trained in the United States and/or are delivering direct patient care. ... It also creates a precedent for barring entry of IMGs based on their religion and country of origin. ... Approximately 30% of ACP members are IMGs.”

American Gastroenterological Association

Science and illness ignore borders and political divides. That is why AGA is concerned that the recent U.S. executive order on immigration could limit scientific exchange, delay patient care and impair medical training.

AGA is committed to diversity, which we define as inclusive of race, ethnicity and national origin. Diversity within training programs and laboratories in the United States built today’s practice of gastroenterology. Scientists from around the world publish in our journals, work in our laboratories, train in our programs and present data at Digestive Disease Week. This exchange leads to better patient care, and very sick patients travel to the United States from around the world for the best digestive health care.

AGA adds our support to a growing number of medical institutions urging the administration to consider the devastating impact of the executive order on the health of the nation that will result from turning away patients, health professionals, and researchers. The recent immigration policy is clearly detrimental to America’s leadership role in advancing health care, and to the standing of the United States within the international community.
 

American Society of Clinical Oncology

ASCO is deeply concerned about the potential impact of the recent executive order on cancer research, patient care, and international scientific collaboration.

Our more than 40,000 members in 148 countries lead the charge to conquer cancer in all its forms and in every nation. Tens of thousands of people from more than 100 countries participate in our scientific meetings to exchange advances and ideas to improve patient care. Millions of cancer survivors are alive today because of the progress made possible by scientific collaboration. Progress against this disease will falter if the close-knit global community of cancer care providers is divided by policies that bar members of certain nationalities from entering the United States to conduct research, care for people with cancer, or participate in scientific and medical conferences.
 

American Society of Hematology

We express our deep concern about the Administration’s executive order that has denied U.S. entry to people who bring unique expertise to the practice of medicine and the conduct of cancer and biomedical research. Our nation depends on the contributions of the greatest minds from around the world to maintain the high quality of our biomedical research enterprise and health care services.

The benefits of scientific collaborations are amplified by our diversity. Limiting the exchange of ideas, practices, and data across cultures has the potential to significantly retard scientific progress and adversely affect public health. Any loss of researchers and physicians will render the United States less competitive over time, and our traditionally strong research institutions and the patients they serve will be negatively affected.

We remain deeply concerned that restricting travel will prohibit participation in scientific meetings, where cutting-edge science and treatment methods are often first introduced. These in-person meetings and other global exchanges are vitally important because they provide unparalleled opportunities for collaborations and information-sharing. Such scientific and medical meetings are absolutely essential to the conquest of cancer and blood diseases.

(Statement issued on behalf of ASH, American Association for Cancer Research, Association of American Cancer Institutes, American Society for Radiation Oncology, The American Society for Pediatric Hematology/Oncology, and LUNGevity Foundation.)

The text of the executive order can be found on the White House website.

Updated 2/2/17 to include the position of the American Gastroenterological Association.

[email protected]
On Twitter @denisefulton

Q2: Answer: B

Objective: Recognize the features of CVID-associated noninfectious gastrointestinal manifestations.

Explanation: This patient has gastrointestinal manifestations of common variable immune deficiency (CVID), which can present similarly to celiac disease or inflammatory bowel disease. Histologically, intestinal biopsies will reveal villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis similar to celiac disease. However, while plasma cells are increased in celiac disease, they are absent in CVID.

The initial treatment strategy for CVID typically includes oral corticosteroids, either prednisone or budesonide, with other immunosuppressants such as the thiopurines or anti–tumor necrosis factor agents reserved for steroid-dependent or refractory disease.

Gluten-free diet is ineffective for the treatment of CVID-associated enteropathy. Intravenous immunoglobulin therapy reduces the frequency of infections associated with CVID, but does not affect the noninfectious GI symptoms. While bacterial overgrowth can occur in CVID, it is typically the consequence of the luminal changes, not the cause.

Reference

1. Agarwal S., Mayer L. Gastrointestinal manifestations in primary immune disorders. Inflamm Bowel Dis. 2010;16:703-11.

Q2: Answer: B

Objective: Recognize the features of CVID-associated noninfectious gastrointestinal manifestations.

Explanation: This patient has gastrointestinal manifestations of common variable immune deficiency (CVID), which can present similarly to celiac disease or inflammatory bowel disease. Histologically, intestinal biopsies will reveal villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis similar to celiac disease. However, while plasma cells are increased in celiac disease, they are absent in CVID.

The initial treatment strategy for CVID typically includes oral corticosteroids, either prednisone or budesonide, with other immunosuppressants such as the thiopurines or anti–tumor necrosis factor agents reserved for steroid-dependent or refractory disease.

Gluten-free diet is ineffective for the treatment of CVID-associated enteropathy. Intravenous immunoglobulin therapy reduces the frequency of infections associated with CVID, but does not affect the noninfectious GI symptoms. While bacterial overgrowth can occur in CVID, it is typically the consequence of the luminal changes, not the cause.

Reference

1. Agarwal S., Mayer L. Gastrointestinal manifestations in primary immune disorders. Inflamm Bowel Dis. 2010;16:703-11.

Q2: Answer: B

Objective: Recognize the features of CVID-associated noninfectious gastrointestinal manifestations.

Explanation: This patient has gastrointestinal manifestations of common variable immune deficiency (CVID), which can present similarly to celiac disease or inflammatory bowel disease. Histologically, intestinal biopsies will reveal villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis similar to celiac disease. However, while plasma cells are increased in celiac disease, they are absent in CVID.

The initial treatment strategy for CVID typically includes oral corticosteroids, either prednisone or budesonide, with other immunosuppressants such as the thiopurines or anti–tumor necrosis factor agents reserved for steroid-dependent or refractory disease.

Gluten-free diet is ineffective for the treatment of CVID-associated enteropathy. Intravenous immunoglobulin therapy reduces the frequency of infections associated with CVID, but does not affect the noninfectious GI symptoms. While bacterial overgrowth can occur in CVID, it is typically the consequence of the luminal changes, not the cause.

Reference

1. Agarwal S., Mayer L. Gastrointestinal manifestations in primary immune disorders. Inflamm Bowel Dis. 2010;16:703-11.

Q1: Answer: D

Current recommendations suggest H. pylori testing for patients with active or a documented history of peptic ulcer disease, gastric MALT lymphoma, or gastric carcinoma. The H. pylori test-and-treat strategy is also recommended for patients less than 55 years of age who present with dyspepsia symptoms without “alarm features.”

There is currently no recommendation for asymptomatic family members of patients diagnosed with H. pylori infection to be tested, unless there are known factors that may increase the patient’s risk for gastric malignancy (e.g., family history of gastric carcinoma, and ethnic background from areas with high prevalence of H. pylori and gastric cancer such as East Asia, Latin America, and Eastern Europe).

References

1. Chey W.D., Wong B.C. Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-25.

2. Talley N.J., Vakil N.B., Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756-80.

3. Suerbaum S., Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:1175-86.

4. Everhart J.E., Kruszon-Moran D., Perez-Perez G.I., et al. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. J Infect Dis. 2000;181:1359-63.

Q1: Answer: D

Current recommendations suggest H. pylori testing for patients with active or a documented history of peptic ulcer disease, gastric MALT lymphoma, or gastric carcinoma. The H. pylori test-and-treat strategy is also recommended for patients less than 55 years of age who present with dyspepsia symptoms without “alarm features.”

There is currently no recommendation for asymptomatic family members of patients diagnosed with H. pylori infection to be tested, unless there are known factors that may increase the patient’s risk for gastric malignancy (e.g., family history of gastric carcinoma, and ethnic background from areas with high prevalence of H. pylori and gastric cancer such as East Asia, Latin America, and Eastern Europe).

References

1. Chey W.D., Wong B.C. Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-25.

2. Talley N.J., Vakil N.B., Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756-80.

3. Suerbaum S., Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:1175-86.

4. Everhart J.E., Kruszon-Moran D., Perez-Perez G.I., et al. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. J Infect Dis. 2000;181:1359-63.

Q1: Answer: D

Current recommendations suggest H. pylori testing for patients with active or a documented history of peptic ulcer disease, gastric MALT lymphoma, or gastric carcinoma. The H. pylori test-and-treat strategy is also recommended for patients less than 55 years of age who present with dyspepsia symptoms without “alarm features.”

There is currently no recommendation for asymptomatic family members of patients diagnosed with H. pylori infection to be tested, unless there are known factors that may increase the patient’s risk for gastric malignancy (e.g., family history of gastric carcinoma, and ethnic background from areas with high prevalence of H. pylori and gastric cancer such as East Asia, Latin America, and Eastern Europe).

References

1. Chey W.D., Wong B.C. Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102:1808-25.

2. Talley N.J., Vakil N.B., Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756-80.

3. Suerbaum S., Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:1175-86.

4. Everhart J.E., Kruszon-Moran D., Perez-Perez G.I., et al. Seroprevalence and ethnic differences in Helicobacter pylori infection among adults in the United States. J Infect Dis. 2000;181:1359-63.

The safety and the efficacy of shorter durations of antibiotic therapy for uncomplicated pneumonia have been clearly established in the past decade.^1,2 Guidelines from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society have been available since 2007. These expert consensus statements recommend that uncomplicated community-acquired pneumonia (CAP) should be treated for 5 to 7 days, as long as the patient exhibits signs and symptoms of clinical stability.³ Similarly, recently updated guidelines for hospital-acquired and ventilator-associated pneumonias call for short-course therapy.⁴ Despite this guidance, pneumonia treatment duration is often discordant.⁵ Unnecessary antimicrobial use is associated with greater selection pressure on pathogens, increased risk of adverse events (AEs), and elevated treatment costs.⁶ The growing burden of antibiotic resistance coupled with limited availability of new antibiotics requires judicious use of these agents.

The IDSA guidelines for Clostridium difficile infection (CDI) note that exposure to antimicrobial agents is the most important modifiable risk factor for the development of CDI.⁷ Longer durations of antibiotics increase the risk of CDI compared with shorter durations.^8,9 Antibiotics are a frequent cause of drug-associated AEs and likely are underestimated.¹⁰ To decrease the unwanted effects of excessive therapy, IDSA and CDC suggest that antimicrobial stewardship interventions should be implemented.^11-13

Antimicrobial stewardship efforts in small community hospitals (also known as district, rural, general, and primary hospitals) are varied and can be challenging due to limited staff and resources.^14,15 The World Health Organization defines a primary care facility as having few specialties, mainly internal medicine and general surgery with limited laboratory services for general (but not specialized) pathologic analysis, and bed size ranging from 30 to 200 beds.¹⁶ Although guidance is available for effective intervention strategies in smaller hospitals, there are limited data in the literature regarding successful outcomes.^17-22

The purpose of this study was to establish the need and evaluate the impact of a pharmacy-initiated 3-part intervention targeting treatment duration in patients hospitalized with uncomplicated pneumonia in a primary hospital setting. The Veterans Health Care System of the Ozarks (VHSO) in Fayetteville, Arkansas, has 50 acute care beds, including 7 intensive care unit beds and excluding 15 mental health beds. The pharmacy is staffed 24 hours a day. Acute-care providers consist of 7 full-time hospitalists, not including nocturnists and contract physicians. The VHSO does not have an infectious disease physician on staff.

The antimicrobial stewardship committee consists of 3 clinical pharmacists, a pulmonologist, a pathologist, and 2 infection-control nurses. There is 1 full-time equivalent allotted for inpatient clinical pharmacy activities in the acute care areas, including enforcement of all antimicrobial stewardship policies, which are conducted by a single pharmacist.

Methods

This was a retrospective chart review of two 12-month periods using a before and after study design. Medical records were reviewed during October 2012 through September 2013 (before the stewardship implementation) and December 2014 through November 2015 (after implementation). Inclusion criteria consisted of a primary discharge diagnosis of pneumonia as documented by the provider (or secondary diagnosis if sepsis was primary), hospitalization for at least 48 hours, administration of antibiotics for a minimum of 24 hours, and survival to discharge.

Exclusion criteria consisted of direct transfer from another facility, inappropriate empiric therapy as evidenced by culture data (isolated pathogens not covered by prescribed antibiotics), pneumonia that developed 48 hours after admission, extrapulmonary sources of infection, hospitalization > 14 days, discharge without a known duration of outpatient antibiotics, discharge for pneumonia within 28 days prior to admission, documented infection caused by Pseudomonas aeruginosa or other nonlactose fermenting Gram-negative rod, and complicated pneumonias defined as lung abscess, empyema, or severe immunosuppression (eg, cancer with chemotherapy within the previous 30 days, transplant recipients, HIV infection, acquired or congenital immunodeficiency, or absolute neutrophil count 1,500 cell/mm³ within past 28 days).

Patients were designated with health care-associated pneumonia (HCAP) if they were hospitalized ≥ 2 days or resided in a skilled nursing or extended-care facility within the previous 90 days; on chronic dialysis; or had wound care, tracheostomy care, or ventilator care from a health care professional within the previous 28 days. Criteria for clinical stability were defined as ≤ 100.4º F temperature, ≤ 100 beats/min heart rate, ≤ 24 breaths/min respiratory rate, ≥ 90 mm Hg systolic blood pressure, ≥ 90% or PaO₂ ≥ 60 mm Hg oxygen saturation on room air (or baseline oxygen requirements), and return to baseline mental status. To compare groups, researchers tabulated the pneumonia severity index on hospital day 1.

The intervention consisted of a 3-part process. First, hospitalists were educated on VHSO’s baseline treatment duration data, and these were compared with current IDSA recommendations. The education was followed by an open-discussion component to solicit feedback from providers on perceived barriers to following guidelines. Provider feedback was used to tailor an antimicrobial stewardship intervention to address perceived barriers to optimal antibiotic treatment duration.

After the education component, prospective intervention and feedback were provided for hospitalized patients by a single clinical pharmacist. This pharmacist interacted verbally and in writing with the patients’ providers, discussing antimicrobial appropriateness, de-escalation, duration of therapy, and intravenous to oral switching. Finally, a stewardship note for the Computerized Patient Record System (CPRS) was generated and included a template with reminders of clinical stability, duration of current therapy, and a request to discontinue therapy if the patient met criteria. For patients who remained hospitalized, this note was entered into CPRS on or about day 7 of antibiotic therapy; this required an electronic signature from the provider.

The VHSO Pharmacy and Therapeutics Committee approved both the provider education and the stewardship note in November 2014, and implementation of the stewardship intervention occurred immediately afterward. The pharmacy staff also was educated on the VHSO baseline data and stewardship efforts.

The primary outcome of the study was the change in days of total antibiotic treatment. Secondary outcomes included days of intravenous antibiotic therapy, days of inpatient oral therapy, mean length of stay (LOS), and number of outpatient antibiotic days once discharged. Incidence of CDI and 28-day readmissions were also evaluated. The VHSO Institutional Review Board approved these methods and the procedures that followed were in accord with the ethical standards of the VHSO Committee on Human Experimentation.

Statistical Analysis

All continuous variables are reported as mean ± standard deviation. Data analysis for significance was performed using a Student t test for continuous variables and a χ² test (or Fisher exact test) for categorical variables in R Foundation for Statistical Computing version 3.1.0. All samples were 2-tailed. A P value < .05 was considered statistically significant. Using the smaller of the 2 study populations, the investigators calculated that the given sample size of 88 in each group would provide 99% power to detect a 2-day difference in the primary endpoint at a 2-sided significance level of 5%.

Results

During the baseline assessment (group 1), 192 cases were reviewed with 103 meeting the inclusion criteria. Group 1 consisted of 85 cases of CAP and 18 cases of HCAP (mean age, 70.7 years). During the follow-up assessment (group 2), 168 cases were reviewed with 88 meeting the inclusion criteria. Group 2 consisted of 68 cases of CAP and 20 cases of HCAP (mean age, 70.8 years).

There was no difference in inpatient mortality rates between groups (3.1% vs 3.0%, P = .99). This mortality rate is consistent with published reports.²³ Empiric antibiotic selection was appropriate because there were no exclusions for drug/pathogen mismatch. Pneumonia severity was similar in both groups (Table).

The total duration of antibiotic treatment decreased significantly for CAP and HCAP (Figure). The observed median treatment days for groups 1 and 2 were 11 days and 8 days, respectively. Outpatient antibiotic days also decreased. Mean LOS was shorter in the follow-up group (4.9 ± 2.6 days vs 4.0 ± 2.6 days, P = .02). Length of IV antibiotic duration decreased. Oral antibiotic days while inpatient were not statistically different (1.5 ± 1.8 days vs 1.1 ± 1.5 days, P = .15). During the follow-up period, 26 stewardship notes were entered into CPRS; antibiotics were stopped in 65% of cases.

There were no recorded cases of CDI in either group. There were eleven 28-day readmissions in group 1, only 3 of which were due to infectious causes. One patient had a primary diagnosis of necrotizing pneumonia, 1 had Pseudomonas pneumonia, and 1 patient had a new lung mass and was diagnosed with postobstructive pneumonia. Of eight 28-day readmissions in group 2, only 2 resulted from infectious causes. One readmission primary diagnosis was sinusitis and 1 was recurrent pneumonia (of note, this patient received a 10-day treatment course for pneumonia on initial admission). Two patients died within 28 days of discharge in each group.

Discussion

Other multifaceted single-center interventions have been shown to be effective in large, teaching hospitals,^24,25 and it has been suggested that smaller, rural hospitals may be underserved in antimicrobial stewardship activities.^26,27 In the global struggle with antimicrobial resistance, McGregor and colleagues highlighted the importance of evaluating successful stewardship methods in an array of clinical settings to help tailor an approach for a specific type of facility.²⁸ To the authors knowledge, this is the first publication showing efficacy of such antimicrobial stewardship interventions specific to pneumonia therapy in a small, primary facility.

The intervention methods used at VHSO are supported by recent IDSA and Society for Healthcare Epidemiology of America guidelines for effective stewardship implementation.²⁹ Prospective audit and feedback is considered a core recommendation, whereas didactic education is recommended only in conjunction with other stewardship activities. Additionally, the guidelines recommend evaluating specific infectious disease syndromes, in this case uncomplicated pneumonia, to focus on specific treatment guidelines. Last, the results of the 3-part intervention can be used to aid in demonstrating facility improvement and encourage continued success.

Of note, VHSO has had established inpatient and outpatient clinical pharmacy roles for several years. Stewardship interventions already in place included an intravenous-to-oral antibiotic switch policy, automatic antibiotic stop dates, as well as pharmacist-driven vancomycin and aminoglycoside dosing. Prior to this multifaceted intervention specific to pneumonia duration, prospective audit and feedback interventions (verbal and written) also were common. The number of interventions specific to this study outside of the stewardship note was not recorded. Using rapid diagnostic testing and biomarkers to aid in stewardship activities at VHSO have been considered, but these tools are not available due to a lab personnel shortage.

Soliciting feedback from providers on their preferred stewardship strategy and perceived barriers was a key component of the educational intervention. Of equal importance was presenting providers with their baseline prescribing data to provide objective evidence of a problem. While all were familiar with existing treatment guidelines, some feedback indicated that it can be difficult to determine accurate antibiotic duration in CPRS. Prescribers reported that identifying antibiotic duration was especially challenging when antibiotics as well as providers change during an admission. Also frequently overlooked were antibiotics given in the emergency department. This could be a key area for clinical pharmacists’ intervention given their familiarity with the CPRS medication sections.

Charani and colleagues suggest that recognizing barriers to implementing best practices and adapting to the local facility culture is paramount for changing prescribing behaviors and developing a successful stewardship intervention.³⁰ At VHSO, the providers were presented with multiple stewardship options but agreed to the new note and template. This process gave providers a voice in selecting their own stewardship intervention. In a culture with no infectious disease physician to champion initiatives, the investigators felt that provider involvement in the intervention selection was unique and may have encouraged provider concurrence.

Although not directly targeted by the intervention strategies, average LOS was shorter in the follow-up group. According to investigators, frequent reminders of clinical stability in the stewardship notes may have influenced this. Even though the note was used only in patients who remained hospitalized for their entire treatment course, investigators felt that it still served as a reminder for prescribing habits as they were also able to show a decrease in outpatient prescription duration.

Limitations

Potential weaknesses of the study include changes in providers. During the transition between group 1 and group 2, 2 hospitalists left and 2 new hospitalists arrived. Given the small size of the staff, this could significantly impact prescribing trends. Another potential weakness is the high exclusion rate, although these rates were similar in both groups (46% group 1, 47% group 2). Furthermore, similar exclusion rates have been reported elsewhere.^24,25,31 The most common reasons for exclusion were complicated pneumonias (36%) and immunocompromised patients (18%). These patient populations were not evaluated in the current study, and optimal treatment durations are unknown. Hospital-acquired and ventilator-associated pneumonias also were excluded. Therefore, limitations in applicability of the results should be noted.

The authors acknowledge that, prior to this publication, the IDSA guidelines have removed the designation of HCAP as a separate clinical entity.⁴ However, this should not affect the significance of the intervention for treatment duration.

The study facility experienced a hiring freeze resulting in a 9.3% decrease in overall admissions from fiscal year 2013 to fiscal year 2015. This is likely why there were fewer admissions for pneumonia in group 2. Regardless, power analysis revealed the study was of adequate sample size to detect its primary outcome. It is possible that patients in either group could have sought health care at other facilities, making the CDI and readmission endpoints less inclusive.

The study was not of a scale to detect changes in antimicrobial resistance pressure or clinical outcomes. Cost savings were not analyzed. However, this study adds to the growing body of evidence that a structured intervention can result in positive outcomes at the facility level. This study shows that interventions targeting pneumonia treatment duration could feasibly be added to the menu of stewardship options available to smaller facilities.

Like other stewardship studies in the literature, the follow-up treatment duration, while improved, still exceeded those recommended in the IDSA guidelines. The investigators noted that not all providers were equal regarding change in prescribing habits, perhaps making the average duration longer. Additionally, the request to discontinue antibiotic therapy through the stewardship note could have been entered earlier (eg, as early as day 5 of therapy) to target the shortest effective date as recommended in the recent stewardship guidelines.²⁹ Future steps include continued feedback to providers on their progress in this area and encouragement to document day of antibiotic treatment in their daily progress notes.

Conclusion

This study showed a significant decrease in antibiotic duration for the treatment of uncomplicated pneumonia using a 3-part pharmacy intervention in a primary hospital setting. The investigators feel that each arm of the strategy was equally important and fewer interventions were not likely to be as effective.³² Although data collection for baseline prescribing and follow-up on outcomes may be a time-consuming task, it can be a valuable component of successful stewardship interventions.

The safety and the efficacy of shorter durations of antibiotic therapy for uncomplicated pneumonia have been clearly established in the past decade.^1,2 Guidelines from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society have been available since 2007. These expert consensus statements recommend that uncomplicated community-acquired pneumonia (CAP) should be treated for 5 to 7 days, as long as the patient exhibits signs and symptoms of clinical stability.³ Similarly, recently updated guidelines for hospital-acquired and ventilator-associated pneumonias call for short-course therapy.⁴ Despite this guidance, pneumonia treatment duration is often discordant.⁵ Unnecessary antimicrobial use is associated with greater selection pressure on pathogens, increased risk of adverse events (AEs), and elevated treatment costs.⁶ The growing burden of antibiotic resistance coupled with limited availability of new antibiotics requires judicious use of these agents.

The IDSA guidelines for Clostridium difficile infection (CDI) note that exposure to antimicrobial agents is the most important modifiable risk factor for the development of CDI.⁷ Longer durations of antibiotics increase the risk of CDI compared with shorter durations.^8,9 Antibiotics are a frequent cause of drug-associated AEs and likely are underestimated.¹⁰ To decrease the unwanted effects of excessive therapy, IDSA and CDC suggest that antimicrobial stewardship interventions should be implemented.^11-13

Antimicrobial stewardship efforts in small community hospitals (also known as district, rural, general, and primary hospitals) are varied and can be challenging due to limited staff and resources.^14,15 The World Health Organization defines a primary care facility as having few specialties, mainly internal medicine and general surgery with limited laboratory services for general (but not specialized) pathologic analysis, and bed size ranging from 30 to 200 beds.¹⁶ Although guidance is available for effective intervention strategies in smaller hospitals, there are limited data in the literature regarding successful outcomes.^17-22

The purpose of this study was to establish the need and evaluate the impact of a pharmacy-initiated 3-part intervention targeting treatment duration in patients hospitalized with uncomplicated pneumonia in a primary hospital setting. The Veterans Health Care System of the Ozarks (VHSO) in Fayetteville, Arkansas, has 50 acute care beds, including 7 intensive care unit beds and excluding 15 mental health beds. The pharmacy is staffed 24 hours a day. Acute-care providers consist of 7 full-time hospitalists, not including nocturnists and contract physicians. The VHSO does not have an infectious disease physician on staff.

The antimicrobial stewardship committee consists of 3 clinical pharmacists, a pulmonologist, a pathologist, and 2 infection-control nurses. There is 1 full-time equivalent allotted for inpatient clinical pharmacy activities in the acute care areas, including enforcement of all antimicrobial stewardship policies, which are conducted by a single pharmacist.

Methods

This was a retrospective chart review of two 12-month periods using a before and after study design. Medical records were reviewed during October 2012 through September 2013 (before the stewardship implementation) and December 2014 through November 2015 (after implementation). Inclusion criteria consisted of a primary discharge diagnosis of pneumonia as documented by the provider (or secondary diagnosis if sepsis was primary), hospitalization for at least 48 hours, administration of antibiotics for a minimum of 24 hours, and survival to discharge.

Exclusion criteria consisted of direct transfer from another facility, inappropriate empiric therapy as evidenced by culture data (isolated pathogens not covered by prescribed antibiotics), pneumonia that developed 48 hours after admission, extrapulmonary sources of infection, hospitalization > 14 days, discharge without a known duration of outpatient antibiotics, discharge for pneumonia within 28 days prior to admission, documented infection caused by Pseudomonas aeruginosa or other nonlactose fermenting Gram-negative rod, and complicated pneumonias defined as lung abscess, empyema, or severe immunosuppression (eg, cancer with chemotherapy within the previous 30 days, transplant recipients, HIV infection, acquired or congenital immunodeficiency, or absolute neutrophil count 1,500 cell/mm³ within past 28 days).

Patients were designated with health care-associated pneumonia (HCAP) if they were hospitalized ≥ 2 days or resided in a skilled nursing or extended-care facility within the previous 90 days; on chronic dialysis; or had wound care, tracheostomy care, or ventilator care from a health care professional within the previous 28 days. Criteria for clinical stability were defined as ≤ 100.4º F temperature, ≤ 100 beats/min heart rate, ≤ 24 breaths/min respiratory rate, ≥ 90 mm Hg systolic blood pressure, ≥ 90% or PaO₂ ≥ 60 mm Hg oxygen saturation on room air (or baseline oxygen requirements), and return to baseline mental status. To compare groups, researchers tabulated the pneumonia severity index on hospital day 1.

The intervention consisted of a 3-part process. First, hospitalists were educated on VHSO’s baseline treatment duration data, and these were compared with current IDSA recommendations. The education was followed by an open-discussion component to solicit feedback from providers on perceived barriers to following guidelines. Provider feedback was used to tailor an antimicrobial stewardship intervention to address perceived barriers to optimal antibiotic treatment duration.

After the education component, prospective intervention and feedback were provided for hospitalized patients by a single clinical pharmacist. This pharmacist interacted verbally and in writing with the patients’ providers, discussing antimicrobial appropriateness, de-escalation, duration of therapy, and intravenous to oral switching. Finally, a stewardship note for the Computerized Patient Record System (CPRS) was generated and included a template with reminders of clinical stability, duration of current therapy, and a request to discontinue therapy if the patient met criteria. For patients who remained hospitalized, this note was entered into CPRS on or about day 7 of antibiotic therapy; this required an electronic signature from the provider.

The VHSO Pharmacy and Therapeutics Committee approved both the provider education and the stewardship note in November 2014, and implementation of the stewardship intervention occurred immediately afterward. The pharmacy staff also was educated on the VHSO baseline data and stewardship efforts.

The primary outcome of the study was the change in days of total antibiotic treatment. Secondary outcomes included days of intravenous antibiotic therapy, days of inpatient oral therapy, mean length of stay (LOS), and number of outpatient antibiotic days once discharged. Incidence of CDI and 28-day readmissions were also evaluated. The VHSO Institutional Review Board approved these methods and the procedures that followed were in accord with the ethical standards of the VHSO Committee on Human Experimentation.

Statistical Analysis

All continuous variables are reported as mean ± standard deviation. Data analysis for significance was performed using a Student t test for continuous variables and a χ² test (or Fisher exact test) for categorical variables in R Foundation for Statistical Computing version 3.1.0. All samples were 2-tailed. A P value < .05 was considered statistically significant. Using the smaller of the 2 study populations, the investigators calculated that the given sample size of 88 in each group would provide 99% power to detect a 2-day difference in the primary endpoint at a 2-sided significance level of 5%.

Results

During the baseline assessment (group 1), 192 cases were reviewed with 103 meeting the inclusion criteria. Group 1 consisted of 85 cases of CAP and 18 cases of HCAP (mean age, 70.7 years). During the follow-up assessment (group 2), 168 cases were reviewed with 88 meeting the inclusion criteria. Group 2 consisted of 68 cases of CAP and 20 cases of HCAP (mean age, 70.8 years).

There was no difference in inpatient mortality rates between groups (3.1% vs 3.0%, P = .99). This mortality rate is consistent with published reports.²³ Empiric antibiotic selection was appropriate because there were no exclusions for drug/pathogen mismatch. Pneumonia severity was similar in both groups (Table).

The total duration of antibiotic treatment decreased significantly for CAP and HCAP (Figure). The observed median treatment days for groups 1 and 2 were 11 days and 8 days, respectively. Outpatient antibiotic days also decreased. Mean LOS was shorter in the follow-up group (4.9 ± 2.6 days vs 4.0 ± 2.6 days, P = .02). Length of IV antibiotic duration decreased. Oral antibiotic days while inpatient were not statistically different (1.5 ± 1.8 days vs 1.1 ± 1.5 days, P = .15). During the follow-up period, 26 stewardship notes were entered into CPRS; antibiotics were stopped in 65% of cases.

There were no recorded cases of CDI in either group. There were eleven 28-day readmissions in group 1, only 3 of which were due to infectious causes. One patient had a primary diagnosis of necrotizing pneumonia, 1 had Pseudomonas pneumonia, and 1 patient had a new lung mass and was diagnosed with postobstructive pneumonia. Of eight 28-day readmissions in group 2, only 2 resulted from infectious causes. One readmission primary diagnosis was sinusitis and 1 was recurrent pneumonia (of note, this patient received a 10-day treatment course for pneumonia on initial admission). Two patients died within 28 days of discharge in each group.

Discussion

Other multifaceted single-center interventions have been shown to be effective in large, teaching hospitals,^24,25 and it has been suggested that smaller, rural hospitals may be underserved in antimicrobial stewardship activities.^26,27 In the global struggle with antimicrobial resistance, McGregor and colleagues highlighted the importance of evaluating successful stewardship methods in an array of clinical settings to help tailor an approach for a specific type of facility.²⁸ To the authors knowledge, this is the first publication showing efficacy of such antimicrobial stewardship interventions specific to pneumonia therapy in a small, primary facility.

The intervention methods used at VHSO are supported by recent IDSA and Society for Healthcare Epidemiology of America guidelines for effective stewardship implementation.²⁹ Prospective audit and feedback is considered a core recommendation, whereas didactic education is recommended only in conjunction with other stewardship activities. Additionally, the guidelines recommend evaluating specific infectious disease syndromes, in this case uncomplicated pneumonia, to focus on specific treatment guidelines. Last, the results of the 3-part intervention can be used to aid in demonstrating facility improvement and encourage continued success.

Of note, VHSO has had established inpatient and outpatient clinical pharmacy roles for several years. Stewardship interventions already in place included an intravenous-to-oral antibiotic switch policy, automatic antibiotic stop dates, as well as pharmacist-driven vancomycin and aminoglycoside dosing. Prior to this multifaceted intervention specific to pneumonia duration, prospective audit and feedback interventions (verbal and written) also were common. The number of interventions specific to this study outside of the stewardship note was not recorded. Using rapid diagnostic testing and biomarkers to aid in stewardship activities at VHSO have been considered, but these tools are not available due to a lab personnel shortage.

Soliciting feedback from providers on their preferred stewardship strategy and perceived barriers was a key component of the educational intervention. Of equal importance was presenting providers with their baseline prescribing data to provide objective evidence of a problem. While all were familiar with existing treatment guidelines, some feedback indicated that it can be difficult to determine accurate antibiotic duration in CPRS. Prescribers reported that identifying antibiotic duration was especially challenging when antibiotics as well as providers change during an admission. Also frequently overlooked were antibiotics given in the emergency department. This could be a key area for clinical pharmacists’ intervention given their familiarity with the CPRS medication sections.

Charani and colleagues suggest that recognizing barriers to implementing best practices and adapting to the local facility culture is paramount for changing prescribing behaviors and developing a successful stewardship intervention.³⁰ At VHSO, the providers were presented with multiple stewardship options but agreed to the new note and template. This process gave providers a voice in selecting their own stewardship intervention. In a culture with no infectious disease physician to champion initiatives, the investigators felt that provider involvement in the intervention selection was unique and may have encouraged provider concurrence.

Although not directly targeted by the intervention strategies, average LOS was shorter in the follow-up group. According to investigators, frequent reminders of clinical stability in the stewardship notes may have influenced this. Even though the note was used only in patients who remained hospitalized for their entire treatment course, investigators felt that it still served as a reminder for prescribing habits as they were also able to show a decrease in outpatient prescription duration.

Limitations

Potential weaknesses of the study include changes in providers. During the transition between group 1 and group 2, 2 hospitalists left and 2 new hospitalists arrived. Given the small size of the staff, this could significantly impact prescribing trends. Another potential weakness is the high exclusion rate, although these rates were similar in both groups (46% group 1, 47% group 2). Furthermore, similar exclusion rates have been reported elsewhere.^24,25,31 The most common reasons for exclusion were complicated pneumonias (36%) and immunocompromised patients (18%). These patient populations were not evaluated in the current study, and optimal treatment durations are unknown. Hospital-acquired and ventilator-associated pneumonias also were excluded. Therefore, limitations in applicability of the results should be noted.

The authors acknowledge that, prior to this publication, the IDSA guidelines have removed the designation of HCAP as a separate clinical entity.⁴ However, this should not affect the significance of the intervention for treatment duration.

The study facility experienced a hiring freeze resulting in a 9.3% decrease in overall admissions from fiscal year 2013 to fiscal year 2015. This is likely why there were fewer admissions for pneumonia in group 2. Regardless, power analysis revealed the study was of adequate sample size to detect its primary outcome. It is possible that patients in either group could have sought health care at other facilities, making the CDI and readmission endpoints less inclusive.

The study was not of a scale to detect changes in antimicrobial resistance pressure or clinical outcomes. Cost savings were not analyzed. However, this study adds to the growing body of evidence that a structured intervention can result in positive outcomes at the facility level. This study shows that interventions targeting pneumonia treatment duration could feasibly be added to the menu of stewardship options available to smaller facilities.

Like other stewardship studies in the literature, the follow-up treatment duration, while improved, still exceeded those recommended in the IDSA guidelines. The investigators noted that not all providers were equal regarding change in prescribing habits, perhaps making the average duration longer. Additionally, the request to discontinue antibiotic therapy through the stewardship note could have been entered earlier (eg, as early as day 5 of therapy) to target the shortest effective date as recommended in the recent stewardship guidelines.²⁹ Future steps include continued feedback to providers on their progress in this area and encouragement to document day of antibiotic treatment in their daily progress notes.

Conclusion

This study showed a significant decrease in antibiotic duration for the treatment of uncomplicated pneumonia using a 3-part pharmacy intervention in a primary hospital setting. The investigators feel that each arm of the strategy was equally important and fewer interventions were not likely to be as effective.³² Although data collection for baseline prescribing and follow-up on outcomes may be a time-consuming task, it can be a valuable component of successful stewardship interventions.

The safety and the efficacy of shorter durations of antibiotic therapy for uncomplicated pneumonia have been clearly established in the past decade.^1,2 Guidelines from the Infectious Diseases Society of America (IDSA) and the American Thoracic Society have been available since 2007. These expert consensus statements recommend that uncomplicated community-acquired pneumonia (CAP) should be treated for 5 to 7 days, as long as the patient exhibits signs and symptoms of clinical stability.³ Similarly, recently updated guidelines for hospital-acquired and ventilator-associated pneumonias call for short-course therapy.⁴ Despite this guidance, pneumonia treatment duration is often discordant.⁵ Unnecessary antimicrobial use is associated with greater selection pressure on pathogens, increased risk of adverse events (AEs), and elevated treatment costs.⁶ The growing burden of antibiotic resistance coupled with limited availability of new antibiotics requires judicious use of these agents.

The IDSA guidelines for Clostridium difficile infection (CDI) note that exposure to antimicrobial agents is the most important modifiable risk factor for the development of CDI.⁷ Longer durations of antibiotics increase the risk of CDI compared with shorter durations.^8,9 Antibiotics are a frequent cause of drug-associated AEs and likely are underestimated.¹⁰ To decrease the unwanted effects of excessive therapy, IDSA and CDC suggest that antimicrobial stewardship interventions should be implemented.^11-13

Antimicrobial stewardship efforts in small community hospitals (also known as district, rural, general, and primary hospitals) are varied and can be challenging due to limited staff and resources.^14,15 The World Health Organization defines a primary care facility as having few specialties, mainly internal medicine and general surgery with limited laboratory services for general (but not specialized) pathologic analysis, and bed size ranging from 30 to 200 beds.¹⁶ Although guidance is available for effective intervention strategies in smaller hospitals, there are limited data in the literature regarding successful outcomes.^17-22

The purpose of this study was to establish the need and evaluate the impact of a pharmacy-initiated 3-part intervention targeting treatment duration in patients hospitalized with uncomplicated pneumonia in a primary hospital setting. The Veterans Health Care System of the Ozarks (VHSO) in Fayetteville, Arkansas, has 50 acute care beds, including 7 intensive care unit beds and excluding 15 mental health beds. The pharmacy is staffed 24 hours a day. Acute-care providers consist of 7 full-time hospitalists, not including nocturnists and contract physicians. The VHSO does not have an infectious disease physician on staff.

The antimicrobial stewardship committee consists of 3 clinical pharmacists, a pulmonologist, a pathologist, and 2 infection-control nurses. There is 1 full-time equivalent allotted for inpatient clinical pharmacy activities in the acute care areas, including enforcement of all antimicrobial stewardship policies, which are conducted by a single pharmacist.

Methods

This was a retrospective chart review of two 12-month periods using a before and after study design. Medical records were reviewed during October 2012 through September 2013 (before the stewardship implementation) and December 2014 through November 2015 (after implementation). Inclusion criteria consisted of a primary discharge diagnosis of pneumonia as documented by the provider (or secondary diagnosis if sepsis was primary), hospitalization for at least 48 hours, administration of antibiotics for a minimum of 24 hours, and survival to discharge.

Exclusion criteria consisted of direct transfer from another facility, inappropriate empiric therapy as evidenced by culture data (isolated pathogens not covered by prescribed antibiotics), pneumonia that developed 48 hours after admission, extrapulmonary sources of infection, hospitalization > 14 days, discharge without a known duration of outpatient antibiotics, discharge for pneumonia within 28 days prior to admission, documented infection caused by Pseudomonas aeruginosa or other nonlactose fermenting Gram-negative rod, and complicated pneumonias defined as lung abscess, empyema, or severe immunosuppression (eg, cancer with chemotherapy within the previous 30 days, transplant recipients, HIV infection, acquired or congenital immunodeficiency, or absolute neutrophil count 1,500 cell/mm³ within past 28 days).

Patients were designated with health care-associated pneumonia (HCAP) if they were hospitalized ≥ 2 days or resided in a skilled nursing or extended-care facility within the previous 90 days; on chronic dialysis; or had wound care, tracheostomy care, or ventilator care from a health care professional within the previous 28 days. Criteria for clinical stability were defined as ≤ 100.4º F temperature, ≤ 100 beats/min heart rate, ≤ 24 breaths/min respiratory rate, ≥ 90 mm Hg systolic blood pressure, ≥ 90% or PaO₂ ≥ 60 mm Hg oxygen saturation on room air (or baseline oxygen requirements), and return to baseline mental status. To compare groups, researchers tabulated the pneumonia severity index on hospital day 1.

The intervention consisted of a 3-part process. First, hospitalists were educated on VHSO’s baseline treatment duration data, and these were compared with current IDSA recommendations. The education was followed by an open-discussion component to solicit feedback from providers on perceived barriers to following guidelines. Provider feedback was used to tailor an antimicrobial stewardship intervention to address perceived barriers to optimal antibiotic treatment duration.

After the education component, prospective intervention and feedback were provided for hospitalized patients by a single clinical pharmacist. This pharmacist interacted verbally and in writing with the patients’ providers, discussing antimicrobial appropriateness, de-escalation, duration of therapy, and intravenous to oral switching. Finally, a stewardship note for the Computerized Patient Record System (CPRS) was generated and included a template with reminders of clinical stability, duration of current therapy, and a request to discontinue therapy if the patient met criteria. For patients who remained hospitalized, this note was entered into CPRS on or about day 7 of antibiotic therapy; this required an electronic signature from the provider.

The VHSO Pharmacy and Therapeutics Committee approved both the provider education and the stewardship note in November 2014, and implementation of the stewardship intervention occurred immediately afterward. The pharmacy staff also was educated on the VHSO baseline data and stewardship efforts.

The primary outcome of the study was the change in days of total antibiotic treatment. Secondary outcomes included days of intravenous antibiotic therapy, days of inpatient oral therapy, mean length of stay (LOS), and number of outpatient antibiotic days once discharged. Incidence of CDI and 28-day readmissions were also evaluated. The VHSO Institutional Review Board approved these methods and the procedures that followed were in accord with the ethical standards of the VHSO Committee on Human Experimentation.

Statistical Analysis

All continuous variables are reported as mean ± standard deviation. Data analysis for significance was performed using a Student t test for continuous variables and a χ² test (or Fisher exact test) for categorical variables in R Foundation for Statistical Computing version 3.1.0. All samples were 2-tailed. A P value < .05 was considered statistically significant. Using the smaller of the 2 study populations, the investigators calculated that the given sample size of 88 in each group would provide 99% power to detect a 2-day difference in the primary endpoint at a 2-sided significance level of 5%.

Results

During the baseline assessment (group 1), 192 cases were reviewed with 103 meeting the inclusion criteria. Group 1 consisted of 85 cases of CAP and 18 cases of HCAP (mean age, 70.7 years). During the follow-up assessment (group 2), 168 cases were reviewed with 88 meeting the inclusion criteria. Group 2 consisted of 68 cases of CAP and 20 cases of HCAP (mean age, 70.8 years).

There was no difference in inpatient mortality rates between groups (3.1% vs 3.0%, P = .99). This mortality rate is consistent with published reports.²³ Empiric antibiotic selection was appropriate because there were no exclusions for drug/pathogen mismatch. Pneumonia severity was similar in both groups (Table).

The total duration of antibiotic treatment decreased significantly for CAP and HCAP (Figure). The observed median treatment days for groups 1 and 2 were 11 days and 8 days, respectively. Outpatient antibiotic days also decreased. Mean LOS was shorter in the follow-up group (4.9 ± 2.6 days vs 4.0 ± 2.6 days, P = .02). Length of IV antibiotic duration decreased. Oral antibiotic days while inpatient were not statistically different (1.5 ± 1.8 days vs 1.1 ± 1.5 days, P = .15). During the follow-up period, 26 stewardship notes were entered into CPRS; antibiotics were stopped in 65% of cases.

There were no recorded cases of CDI in either group. There were eleven 28-day readmissions in group 1, only 3 of which were due to infectious causes. One patient had a primary diagnosis of necrotizing pneumonia, 1 had Pseudomonas pneumonia, and 1 patient had a new lung mass and was diagnosed with postobstructive pneumonia. Of eight 28-day readmissions in group 2, only 2 resulted from infectious causes. One readmission primary diagnosis was sinusitis and 1 was recurrent pneumonia (of note, this patient received a 10-day treatment course for pneumonia on initial admission). Two patients died within 28 days of discharge in each group.

Discussion

Other multifaceted single-center interventions have been shown to be effective in large, teaching hospitals,^24,25 and it has been suggested that smaller, rural hospitals may be underserved in antimicrobial stewardship activities.^26,27 In the global struggle with antimicrobial resistance, McGregor and colleagues highlighted the importance of evaluating successful stewardship methods in an array of clinical settings to help tailor an approach for a specific type of facility.²⁸ To the authors knowledge, this is the first publication showing efficacy of such antimicrobial stewardship interventions specific to pneumonia therapy in a small, primary facility.

The intervention methods used at VHSO are supported by recent IDSA and Society for Healthcare Epidemiology of America guidelines for effective stewardship implementation.²⁹ Prospective audit and feedback is considered a core recommendation, whereas didactic education is recommended only in conjunction with other stewardship activities. Additionally, the guidelines recommend evaluating specific infectious disease syndromes, in this case uncomplicated pneumonia, to focus on specific treatment guidelines. Last, the results of the 3-part intervention can be used to aid in demonstrating facility improvement and encourage continued success.

Of note, VHSO has had established inpatient and outpatient clinical pharmacy roles for several years. Stewardship interventions already in place included an intravenous-to-oral antibiotic switch policy, automatic antibiotic stop dates, as well as pharmacist-driven vancomycin and aminoglycoside dosing. Prior to this multifaceted intervention specific to pneumonia duration, prospective audit and feedback interventions (verbal and written) also were common. The number of interventions specific to this study outside of the stewardship note was not recorded. Using rapid diagnostic testing and biomarkers to aid in stewardship activities at VHSO have been considered, but these tools are not available due to a lab personnel shortage.

Soliciting feedback from providers on their preferred stewardship strategy and perceived barriers was a key component of the educational intervention. Of equal importance was presenting providers with their baseline prescribing data to provide objective evidence of a problem. While all were familiar with existing treatment guidelines, some feedback indicated that it can be difficult to determine accurate antibiotic duration in CPRS. Prescribers reported that identifying antibiotic duration was especially challenging when antibiotics as well as providers change during an admission. Also frequently overlooked were antibiotics given in the emergency department. This could be a key area for clinical pharmacists’ intervention given their familiarity with the CPRS medication sections.

Charani and colleagues suggest that recognizing barriers to implementing best practices and adapting to the local facility culture is paramount for changing prescribing behaviors and developing a successful stewardship intervention.³⁰ At VHSO, the providers were presented with multiple stewardship options but agreed to the new note and template. This process gave providers a voice in selecting their own stewardship intervention. In a culture with no infectious disease physician to champion initiatives, the investigators felt that provider involvement in the intervention selection was unique and may have encouraged provider concurrence.

Although not directly targeted by the intervention strategies, average LOS was shorter in the follow-up group. According to investigators, frequent reminders of clinical stability in the stewardship notes may have influenced this. Even though the note was used only in patients who remained hospitalized for their entire treatment course, investigators felt that it still served as a reminder for prescribing habits as they were also able to show a decrease in outpatient prescription duration.

Limitations

Potential weaknesses of the study include changes in providers. During the transition between group 1 and group 2, 2 hospitalists left and 2 new hospitalists arrived. Given the small size of the staff, this could significantly impact prescribing trends. Another potential weakness is the high exclusion rate, although these rates were similar in both groups (46% group 1, 47% group 2). Furthermore, similar exclusion rates have been reported elsewhere.^24,25,31 The most common reasons for exclusion were complicated pneumonias (36%) and immunocompromised patients (18%). These patient populations were not evaluated in the current study, and optimal treatment durations are unknown. Hospital-acquired and ventilator-associated pneumonias also were excluded. Therefore, limitations in applicability of the results should be noted.

The authors acknowledge that, prior to this publication, the IDSA guidelines have removed the designation of HCAP as a separate clinical entity.⁴ However, this should not affect the significance of the intervention for treatment duration.

The study facility experienced a hiring freeze resulting in a 9.3% decrease in overall admissions from fiscal year 2013 to fiscal year 2015. This is likely why there were fewer admissions for pneumonia in group 2. Regardless, power analysis revealed the study was of adequate sample size to detect its primary outcome. It is possible that patients in either group could have sought health care at other facilities, making the CDI and readmission endpoints less inclusive.

The study was not of a scale to detect changes in antimicrobial resistance pressure or clinical outcomes. Cost savings were not analyzed. However, this study adds to the growing body of evidence that a structured intervention can result in positive outcomes at the facility level. This study shows that interventions targeting pneumonia treatment duration could feasibly be added to the menu of stewardship options available to smaller facilities.

Like other stewardship studies in the literature, the follow-up treatment duration, while improved, still exceeded those recommended in the IDSA guidelines. The investigators noted that not all providers were equal regarding change in prescribing habits, perhaps making the average duration longer. Additionally, the request to discontinue antibiotic therapy through the stewardship note could have been entered earlier (eg, as early as day 5 of therapy) to target the shortest effective date as recommended in the recent stewardship guidelines.²⁹ Future steps include continued feedback to providers on their progress in this area and encouragement to document day of antibiotic treatment in their daily progress notes.

Conclusion

This study showed a significant decrease in antibiotic duration for the treatment of uncomplicated pneumonia using a 3-part pharmacy intervention in a primary hospital setting. The investigators feel that each arm of the strategy was equally important and fewer interventions were not likely to be as effective.³² Although data collection for baseline prescribing and follow-up on outcomes may be a time-consuming task, it can be a valuable component of successful stewardship interventions.

ORLANDO – A uniquely designed multielectrode radiofrequency ablation (RFA) balloon catheter system for the treatment of atrial fibrillation (AF) performed well in a first-in-man study.

The new ablation system is designed to provide the flexibility of conventional RFA devices in treating a broad array of AF triggers with the type of predictable energy delivery more closely associated with cryoballoon ablation, according to the principal investigator, Matthew G. Daly, MB, ChB, a cardiologist at Christchurch (New Zealand) Hospital.

The inflatable experimental device features 18 electrodes, a built-in camera, integrated mapping and pacing, and irrigation designed to reduce the risk of clot formation. On contact, the 12 electrodes situated on the equator of the spherical device, along with the six electrodes situated on the polar ends, are initially employed to select the ablation pattern. RFA can be delivered immediately through the same electrodes once proper contact is established using the built-in cameras for real-time visualization.

Dr. Daly reported no industry relationships relevant to this study.

ORLANDO – A uniquely designed multielectrode radiofrequency ablation (RFA) balloon catheter system for the treatment of atrial fibrillation (AF) performed well in a first-in-man study.

The new ablation system is designed to provide the flexibility of conventional RFA devices in treating a broad array of AF triggers with the type of predictable energy delivery more closely associated with cryoballoon ablation, according to the principal investigator, Matthew G. Daly, MB, ChB, a cardiologist at Christchurch (New Zealand) Hospital.

The inflatable experimental device features 18 electrodes, a built-in camera, integrated mapping and pacing, and irrigation designed to reduce the risk of clot formation. On contact, the 12 electrodes situated on the equator of the spherical device, along with the six electrodes situated on the polar ends, are initially employed to select the ablation pattern. RFA can be delivered immediately through the same electrodes once proper contact is established using the built-in cameras for real-time visualization.

Dr. Daly reported no industry relationships relevant to this study.

ORLANDO – A uniquely designed multielectrode radiofrequency ablation (RFA) balloon catheter system for the treatment of atrial fibrillation (AF) performed well in a first-in-man study.

The new ablation system is designed to provide the flexibility of conventional RFA devices in treating a broad array of AF triggers with the type of predictable energy delivery more closely associated with cryoballoon ablation, according to the principal investigator, Matthew G. Daly, MB, ChB, a cardiologist at Christchurch (New Zealand) Hospital.

The inflatable experimental device features 18 electrodes, a built-in camera, integrated mapping and pacing, and irrigation designed to reduce the risk of clot formation. On contact, the 12 electrodes situated on the equator of the spherical device, along with the six electrodes situated on the polar ends, are initially employed to select the ablation pattern. RFA can be delivered immediately through the same electrodes once proper contact is established using the built-in cameras for real-time visualization.

Dr. Daly reported no industry relationships relevant to this study.