Pharmacology

More than one-third of Americans and > 20% of veterans have obesity with a body mass index (BMI) ≥ 30 kg/m².^1,2 It is well documented that patients with obesity have altered lipid metabolism, drug distribution, and drug clearance.^3-5 As many as 8.2 million Americans may receive statin (3-hydroxymethylglutaryl coenzyme A reductase inhibitors) prescriptions if the American College of Cardiology/American Heart Association 2013 Cholesterol Guidelines are followed; therefore, it is important to examine how the efficacy of these drugs is altered in patients with obesity.⁶

Multiple studies have examined the benefits of statin therapy through lowering low-density lipoprotein cholesterol (LDL-C); however, few have examined the impact of obesity on statin efficacy. For example, only 18% of subjects in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial were classified as having obesity, and subjects in the Scandinavian Simvastatin Survival Study (4S) trial had a mean BMI of only 26 kg/m².^7,8 Though statins decreased mortality in both of these studies, it is unknown whether the lipid-lowering effects were the same for participants with and without obesity. The Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated a decrease in major cardiovascular events and all-cause mortality with atorvastatin 10 mg daily therapy in a sample where more than one-third of subjects had obesity.⁹ However, the mean baseline BMI of subjects in both study groups was only 28 kg/m², and outcomes for those with and without obesity were not compared.⁹

Studies that have examined statin efficacy in those with and without obesity include the Heart Protection Study (HPS), a post hoc analysis of the West of Scotland Coronary Prevention Study (WOSCOPS), and a meta-analysis by Blassetto and colleagues. The HPS examined the event rate of vascular events with simvastatin 40 mg daily in patients with diabetes mellitus (DM).¹⁰ Though these subgroups were compared in HPS, no statistical difference was demonstrated between these groups for the rate of vascular events among those with and without DM.¹⁰ However, the obesity subgroup’s event rate ratios were consistently higher than were those for the nonobese group.¹⁰

A post hoc analysis of WOSCOPS examined obesity as a factor for change in LDL-C with pravastatin 40 mg therapy.¹¹ Though the authors found that no significant difference was present between those with and those without obesity, the data supporting this claim were not disclosed, which makes drawing clinical conclusions from this analysis difficult.¹¹ A meta-analysis by Blassetto and colleagues examined the association between rosuvastatin’s efficacy in lowering LDL-C among the subgroups of hypertension, atherosclerosis, type 2 DM, and obesity.¹² Though these subgroups were not compared statistically, the obesity subgroup had the lowest mean percent change in lowering LDL-C. Moreover, patients without obesity were not examined as a subgroup.¹²

With the expected increase in statin therapy and a significant portion of the U.S. population having obesity, it is necessary to determine if obesity alters the efficacy of statins. This study was conducted to determine the effect of obesity on the percent change in LDL-C with statin therapy within a veteran population.

Methods

This study was a retrospective review examining follow-up data from January 1, 2009 to July 1, 2014 from the VA Midsouth Healthcare Network. This network services more than 350,000 patients each year in Tennessee, Kentucky, and West Virginia. Data were gathered and analyzed on the VA Informatics and Computing Infrastructure (VINCI) servers. Patients were included in this study if they were aged ≥ 18 years with a new filled prescription for simvastatin 20 mg or simvastatin 40 mg daily. Simvastatin was chosen because it was the formulary statin during the study period. This study was approved by the James H. Quillen VAMC/East Tennessee State University Institutional Review Board.

Patients were excluded if they had received treatment for hyperlipidemia (niacin, colestyramine, colestipol, colesevelam, other statins, gemfibrozil, fenofibrate, omega-3 ethyl esters, ezetimibe) during the 6 weeks prior to the initial fill date of the statin prescription. Patients whose simvastatin therapy did not span the follow-up period from the time of filling to the follow-up lipid panel were excluded, as were those who had not filled a simvastatin prescription within 30 days of their baseline lipid panel. Also excluded were patients who were newly established at the VA, pregnant, or receiving concomitant antihyperlipidemia agents, dialysis, or interacting medications (tacrolimus, cyclosporine, atazanavir, darunavir, nelfinavir, saquinavir, ritonavir, indinavir, lopinavir, tipranavir, fosamprenavir, fluconazole, voriconazole, itraconazole, voriconazole, posaconazole, amiodarone, or colchicine). Patients with a BMI < 18 kg/m², hepatic failure as measured by an aspartate transaminase/alanine transaminase (AST/ALT) ratio > 3 times the upper limit of normal, hepatitis, a history of alcoholism, any change in statin dose prior to follow-up cholesterol values, or no follow-up LDL-C values also were excluded.

The baseline data collected included age, sex, weight, height, BMI, hemoglobin A_1c, LDL-C, ALT/AST, and serum creatinine (SCr). All other laboratory results were required to be within 270 days of the time the lipid panel was obtained. The index date was set as the date the initial prescription was filled between February 1, 2009 and April 1, 2014. Follow-up levels for LDL-C were obtained 40 to 95 days after the index date. Direct LDL-C values were preferred unless only calculated values were available. Calculated LDL-C values were determined by using the Friedewald equation. An audit of 150 patient charts was conducted to ensure the integrity of data pulled from the database.

The percent changes in LDL-C were calculated for those with and without obesity for both simvastatin 20 mg daily and simvastatin 40 mg daily. The primary outcome was the percent change in LDL-C from baseline. All laboratory values were compared using independent 2-tailed t tests with α set to .05. To have an 80% chance of detecting a 5% difference in percent change in LDL-C between the experimental and control groups, 129 patients were required. To determine whether an association was present, a correlation between BMI and percent change in LDL-C was conducted. All statistics were conducted using SAS software (Cary, North Carolina).

Results

From January 2009 through July 2014, 35,216 patients were initially screened. The majority of patients did not have a baseline LDL-C value and were excluded. A total of 1,183 patients with simvastatin 20 mg daily (BMI < 30 = 661; BMI ≥ 30 = 1,122) and 478 patients with simvastatin 40 mg daily (BMI < 30 = 259; BMI ≥ 30 = 219) met the inclusion criteria.

Baseline characteristics were similar between groups except for a slightly higher age in both groups without obesity (Table). Hepatic and renal serum markers indicated a baseline of adequate organ function for drug clearance for all groups. The mean baseline BMI of those without obesity was about 26 kg/m², which is considered overweight. Baseline LDL-C values were clinically similar for those with and without obesity, though statistically different (145 mg/dL for the nonobese group and 141 mg/dL for the obese group, P < .05). The percent change in LDL-C was not statistically significant for those with and without obesity for simvastatin 20 mg daily (P = .293) or simvastatin 40 mg daily (P = .2773) (Figure). No correlation was found between the continuous percent change in LDL-C and continuous BMI for either simvastatin dosage (r² = 0.0016 and 0.0028, respectively).

Discussion

In this retrospective chart review, it was determined that obesity did not affect the percent change in LDL-C from baseline with statin therapy. The HPS found similar results as a secondary endpoint, although that study was underpowered.¹⁰ In this study, all groups met power, and there was still no difference between those with and without obesity.

Nicholls and colleagues examined REVERSAL study data to determine whether BMI greater than the median BMI impacted inflammatory markers or lipid levels with atorvastatin 80 mg daily or pravastatin 40 mg daily. The REVERSAL study authors found no difference in percent change LDL-C between those above the median BMI compared with those below the median BMI for patients on pravastatin therapy. However, the authors did find a difference in percent change LDL-C with atorvastatin therapy.¹³ No difference in percent change LDL-C was present with simvastatin therapy in this study. As simvastatin is more lipophilic than is atorvastatin, lipophilicity remains an area for further study for statin therapy in patients with obesity.

The surrogate marker of percent change in LDL-C was used for the primary outcome in this study. The ACC/AHA 2013 guidelines and the National Lipid Association 2014 guidelines recommend an alternative goal of 30% to 50% change in LDL-C from baseline.^14,15 Using this clinically relevant marker compensated for differences in baseline LDL-C and limited the effect of these differences on the primary outcome of this study.

Limitations

This study did not include patients who were underweight (BMI < 18 kg/m²), as these patients have previously demonstrated decreased outcomes with statin therapy.¹⁶ However, this limits these data to only those patients that have a BMI of at least 18 kg/m². Limitations of this study also included the inability to consider adherence and lifestyle changes. These limitations were unavoidable due to the nature of a retrospective chart review.

Conclusion

The prevalence of obesity is increasing, and it is a disease that alters pharmacokinetics and lipid metabolism. Though this study did not find a difference between the LDL-C-lowering efficacy of simvastatin in those with and without obesity, continued study of the effect of obesity on the efficacy of medications is vital.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the James H. Qullen VAMC in Mountain Home, Tennessee.

More than one-third of Americans and > 20% of veterans have obesity with a body mass index (BMI) ≥ 30 kg/m².^1,2 It is well documented that patients with obesity have altered lipid metabolism, drug distribution, and drug clearance.^3-5 As many as 8.2 million Americans may receive statin (3-hydroxymethylglutaryl coenzyme A reductase inhibitors) prescriptions if the American College of Cardiology/American Heart Association 2013 Cholesterol Guidelines are followed; therefore, it is important to examine how the efficacy of these drugs is altered in patients with obesity.⁶

Multiple studies have examined the benefits of statin therapy through lowering low-density lipoprotein cholesterol (LDL-C); however, few have examined the impact of obesity on statin efficacy. For example, only 18% of subjects in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial were classified as having obesity, and subjects in the Scandinavian Simvastatin Survival Study (4S) trial had a mean BMI of only 26 kg/m².^7,8 Though statins decreased mortality in both of these studies, it is unknown whether the lipid-lowering effects were the same for participants with and without obesity. The Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated a decrease in major cardiovascular events and all-cause mortality with atorvastatin 10 mg daily therapy in a sample where more than one-third of subjects had obesity.⁹ However, the mean baseline BMI of subjects in both study groups was only 28 kg/m², and outcomes for those with and without obesity were not compared.⁹

Studies that have examined statin efficacy in those with and without obesity include the Heart Protection Study (HPS), a post hoc analysis of the West of Scotland Coronary Prevention Study (WOSCOPS), and a meta-analysis by Blassetto and colleagues. The HPS examined the event rate of vascular events with simvastatin 40 mg daily in patients with diabetes mellitus (DM).¹⁰ Though these subgroups were compared in HPS, no statistical difference was demonstrated between these groups for the rate of vascular events among those with and without DM.¹⁰ However, the obesity subgroup’s event rate ratios were consistently higher than were those for the nonobese group.¹⁰

A post hoc analysis of WOSCOPS examined obesity as a factor for change in LDL-C with pravastatin 40 mg therapy.¹¹ Though the authors found that no significant difference was present between those with and those without obesity, the data supporting this claim were not disclosed, which makes drawing clinical conclusions from this analysis difficult.¹¹ A meta-analysis by Blassetto and colleagues examined the association between rosuvastatin’s efficacy in lowering LDL-C among the subgroups of hypertension, atherosclerosis, type 2 DM, and obesity.¹² Though these subgroups were not compared statistically, the obesity subgroup had the lowest mean percent change in lowering LDL-C. Moreover, patients without obesity were not examined as a subgroup.¹²

With the expected increase in statin therapy and a significant portion of the U.S. population having obesity, it is necessary to determine if obesity alters the efficacy of statins. This study was conducted to determine the effect of obesity on the percent change in LDL-C with statin therapy within a veteran population.

Methods

This study was a retrospective review examining follow-up data from January 1, 2009 to July 1, 2014 from the VA Midsouth Healthcare Network. This network services more than 350,000 patients each year in Tennessee, Kentucky, and West Virginia. Data were gathered and analyzed on the VA Informatics and Computing Infrastructure (VINCI) servers. Patients were included in this study if they were aged ≥ 18 years with a new filled prescription for simvastatin 20 mg or simvastatin 40 mg daily. Simvastatin was chosen because it was the formulary statin during the study period. This study was approved by the James H. Quillen VAMC/East Tennessee State University Institutional Review Board.

Patients were excluded if they had received treatment for hyperlipidemia (niacin, colestyramine, colestipol, colesevelam, other statins, gemfibrozil, fenofibrate, omega-3 ethyl esters, ezetimibe) during the 6 weeks prior to the initial fill date of the statin prescription. Patients whose simvastatin therapy did not span the follow-up period from the time of filling to the follow-up lipid panel were excluded, as were those who had not filled a simvastatin prescription within 30 days of their baseline lipid panel. Also excluded were patients who were newly established at the VA, pregnant, or receiving concomitant antihyperlipidemia agents, dialysis, or interacting medications (tacrolimus, cyclosporine, atazanavir, darunavir, nelfinavir, saquinavir, ritonavir, indinavir, lopinavir, tipranavir, fosamprenavir, fluconazole, voriconazole, itraconazole, voriconazole, posaconazole, amiodarone, or colchicine). Patients with a BMI < 18 kg/m², hepatic failure as measured by an aspartate transaminase/alanine transaminase (AST/ALT) ratio > 3 times the upper limit of normal, hepatitis, a history of alcoholism, any change in statin dose prior to follow-up cholesterol values, or no follow-up LDL-C values also were excluded.

The baseline data collected included age, sex, weight, height, BMI, hemoglobin A_1c, LDL-C, ALT/AST, and serum creatinine (SCr). All other laboratory results were required to be within 270 days of the time the lipid panel was obtained. The index date was set as the date the initial prescription was filled between February 1, 2009 and April 1, 2014. Follow-up levels for LDL-C were obtained 40 to 95 days after the index date. Direct LDL-C values were preferred unless only calculated values were available. Calculated LDL-C values were determined by using the Friedewald equation. An audit of 150 patient charts was conducted to ensure the integrity of data pulled from the database.

The percent changes in LDL-C were calculated for those with and without obesity for both simvastatin 20 mg daily and simvastatin 40 mg daily. The primary outcome was the percent change in LDL-C from baseline. All laboratory values were compared using independent 2-tailed t tests with α set to .05. To have an 80% chance of detecting a 5% difference in percent change in LDL-C between the experimental and control groups, 129 patients were required. To determine whether an association was present, a correlation between BMI and percent change in LDL-C was conducted. All statistics were conducted using SAS software (Cary, North Carolina).

Results

From January 2009 through July 2014, 35,216 patients were initially screened. The majority of patients did not have a baseline LDL-C value and were excluded. A total of 1,183 patients with simvastatin 20 mg daily (BMI < 30 = 661; BMI ≥ 30 = 1,122) and 478 patients with simvastatin 40 mg daily (BMI < 30 = 259; BMI ≥ 30 = 219) met the inclusion criteria.

Baseline characteristics were similar between groups except for a slightly higher age in both groups without obesity (Table). Hepatic and renal serum markers indicated a baseline of adequate organ function for drug clearance for all groups. The mean baseline BMI of those without obesity was about 26 kg/m², which is considered overweight. Baseline LDL-C values were clinically similar for those with and without obesity, though statistically different (145 mg/dL for the nonobese group and 141 mg/dL for the obese group, P < .05). The percent change in LDL-C was not statistically significant for those with and without obesity for simvastatin 20 mg daily (P = .293) or simvastatin 40 mg daily (P = .2773) (Figure). No correlation was found between the continuous percent change in LDL-C and continuous BMI for either simvastatin dosage (r² = 0.0016 and 0.0028, respectively).

Discussion

In this retrospective chart review, it was determined that obesity did not affect the percent change in LDL-C from baseline with statin therapy. The HPS found similar results as a secondary endpoint, although that study was underpowered.¹⁰ In this study, all groups met power, and there was still no difference between those with and without obesity.

Nicholls and colleagues examined REVERSAL study data to determine whether BMI greater than the median BMI impacted inflammatory markers or lipid levels with atorvastatin 80 mg daily or pravastatin 40 mg daily. The REVERSAL study authors found no difference in percent change LDL-C between those above the median BMI compared with those below the median BMI for patients on pravastatin therapy. However, the authors did find a difference in percent change LDL-C with atorvastatin therapy.¹³ No difference in percent change LDL-C was present with simvastatin therapy in this study. As simvastatin is more lipophilic than is atorvastatin, lipophilicity remains an area for further study for statin therapy in patients with obesity.

The surrogate marker of percent change in LDL-C was used for the primary outcome in this study. The ACC/AHA 2013 guidelines and the National Lipid Association 2014 guidelines recommend an alternative goal of 30% to 50% change in LDL-C from baseline.^14,15 Using this clinically relevant marker compensated for differences in baseline LDL-C and limited the effect of these differences on the primary outcome of this study.

Limitations

This study did not include patients who were underweight (BMI < 18 kg/m²), as these patients have previously demonstrated decreased outcomes with statin therapy.¹⁶ However, this limits these data to only those patients that have a BMI of at least 18 kg/m². Limitations of this study also included the inability to consider adherence and lifestyle changes. These limitations were unavoidable due to the nature of a retrospective chart review.

Conclusion

The prevalence of obesity is increasing, and it is a disease that alters pharmacokinetics and lipid metabolism. Though this study did not find a difference between the LDL-C-lowering efficacy of simvastatin in those with and without obesity, continued study of the effect of obesity on the efficacy of medications is vital.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the James H. Qullen VAMC in Mountain Home, Tennessee.

More than one-third of Americans and > 20% of veterans have obesity with a body mass index (BMI) ≥ 30 kg/m².^1,2 It is well documented that patients with obesity have altered lipid metabolism, drug distribution, and drug clearance.^3-5 As many as 8.2 million Americans may receive statin (3-hydroxymethylglutaryl coenzyme A reductase inhibitors) prescriptions if the American College of Cardiology/American Heart Association 2013 Cholesterol Guidelines are followed; therefore, it is important to examine how the efficacy of these drugs is altered in patients with obesity.⁶

Multiple studies have examined the benefits of statin therapy through lowering low-density lipoprotein cholesterol (LDL-C); however, few have examined the impact of obesity on statin efficacy. For example, only 18% of subjects in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial were classified as having obesity, and subjects in the Scandinavian Simvastatin Survival Study (4S) trial had a mean BMI of only 26 kg/m².^7,8 Though statins decreased mortality in both of these studies, it is unknown whether the lipid-lowering effects were the same for participants with and without obesity. The Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated a decrease in major cardiovascular events and all-cause mortality with atorvastatin 10 mg daily therapy in a sample where more than one-third of subjects had obesity.⁹ However, the mean baseline BMI of subjects in both study groups was only 28 kg/m², and outcomes for those with and without obesity were not compared.⁹

Studies that have examined statin efficacy in those with and without obesity include the Heart Protection Study (HPS), a post hoc analysis of the West of Scotland Coronary Prevention Study (WOSCOPS), and a meta-analysis by Blassetto and colleagues. The HPS examined the event rate of vascular events with simvastatin 40 mg daily in patients with diabetes mellitus (DM).¹⁰ Though these subgroups were compared in HPS, no statistical difference was demonstrated between these groups for the rate of vascular events among those with and without DM.¹⁰ However, the obesity subgroup’s event rate ratios were consistently higher than were those for the nonobese group.¹⁰

A post hoc analysis of WOSCOPS examined obesity as a factor for change in LDL-C with pravastatin 40 mg therapy.¹¹ Though the authors found that no significant difference was present between those with and those without obesity, the data supporting this claim were not disclosed, which makes drawing clinical conclusions from this analysis difficult.¹¹ A meta-analysis by Blassetto and colleagues examined the association between rosuvastatin’s efficacy in lowering LDL-C among the subgroups of hypertension, atherosclerosis, type 2 DM, and obesity.¹² Though these subgroups were not compared statistically, the obesity subgroup had the lowest mean percent change in lowering LDL-C. Moreover, patients without obesity were not examined as a subgroup.¹²

With the expected increase in statin therapy and a significant portion of the U.S. population having obesity, it is necessary to determine if obesity alters the efficacy of statins. This study was conducted to determine the effect of obesity on the percent change in LDL-C with statin therapy within a veteran population.

Methods

This study was a retrospective review examining follow-up data from January 1, 2009 to July 1, 2014 from the VA Midsouth Healthcare Network. This network services more than 350,000 patients each year in Tennessee, Kentucky, and West Virginia. Data were gathered and analyzed on the VA Informatics and Computing Infrastructure (VINCI) servers. Patients were included in this study if they were aged ≥ 18 years with a new filled prescription for simvastatin 20 mg or simvastatin 40 mg daily. Simvastatin was chosen because it was the formulary statin during the study period. This study was approved by the James H. Quillen VAMC/East Tennessee State University Institutional Review Board.

Patients were excluded if they had received treatment for hyperlipidemia (niacin, colestyramine, colestipol, colesevelam, other statins, gemfibrozil, fenofibrate, omega-3 ethyl esters, ezetimibe) during the 6 weeks prior to the initial fill date of the statin prescription. Patients whose simvastatin therapy did not span the follow-up period from the time of filling to the follow-up lipid panel were excluded, as were those who had not filled a simvastatin prescription within 30 days of their baseline lipid panel. Also excluded were patients who were newly established at the VA, pregnant, or receiving concomitant antihyperlipidemia agents, dialysis, or interacting medications (tacrolimus, cyclosporine, atazanavir, darunavir, nelfinavir, saquinavir, ritonavir, indinavir, lopinavir, tipranavir, fosamprenavir, fluconazole, voriconazole, itraconazole, voriconazole, posaconazole, amiodarone, or colchicine). Patients with a BMI < 18 kg/m², hepatic failure as measured by an aspartate transaminase/alanine transaminase (AST/ALT) ratio > 3 times the upper limit of normal, hepatitis, a history of alcoholism, any change in statin dose prior to follow-up cholesterol values, or no follow-up LDL-C values also were excluded.

The baseline data collected included age, sex, weight, height, BMI, hemoglobin A_1c, LDL-C, ALT/AST, and serum creatinine (SCr). All other laboratory results were required to be within 270 days of the time the lipid panel was obtained. The index date was set as the date the initial prescription was filled between February 1, 2009 and April 1, 2014. Follow-up levels for LDL-C were obtained 40 to 95 days after the index date. Direct LDL-C values were preferred unless only calculated values were available. Calculated LDL-C values were determined by using the Friedewald equation. An audit of 150 patient charts was conducted to ensure the integrity of data pulled from the database.

The percent changes in LDL-C were calculated for those with and without obesity for both simvastatin 20 mg daily and simvastatin 40 mg daily. The primary outcome was the percent change in LDL-C from baseline. All laboratory values were compared using independent 2-tailed t tests with α set to .05. To have an 80% chance of detecting a 5% difference in percent change in LDL-C between the experimental and control groups, 129 patients were required. To determine whether an association was present, a correlation between BMI and percent change in LDL-C was conducted. All statistics were conducted using SAS software (Cary, North Carolina).

Results

From January 2009 through July 2014, 35,216 patients were initially screened. The majority of patients did not have a baseline LDL-C value and were excluded. A total of 1,183 patients with simvastatin 20 mg daily (BMI < 30 = 661; BMI ≥ 30 = 1,122) and 478 patients with simvastatin 40 mg daily (BMI < 30 = 259; BMI ≥ 30 = 219) met the inclusion criteria.

Baseline characteristics were similar between groups except for a slightly higher age in both groups without obesity (Table). Hepatic and renal serum markers indicated a baseline of adequate organ function for drug clearance for all groups. The mean baseline BMI of those without obesity was about 26 kg/m², which is considered overweight. Baseline LDL-C values were clinically similar for those with and without obesity, though statistically different (145 mg/dL for the nonobese group and 141 mg/dL for the obese group, P < .05). The percent change in LDL-C was not statistically significant for those with and without obesity for simvastatin 20 mg daily (P = .293) or simvastatin 40 mg daily (P = .2773) (Figure). No correlation was found between the continuous percent change in LDL-C and continuous BMI for either simvastatin dosage (r² = 0.0016 and 0.0028, respectively).

Discussion

In this retrospective chart review, it was determined that obesity did not affect the percent change in LDL-C from baseline with statin therapy. The HPS found similar results as a secondary endpoint, although that study was underpowered.¹⁰ In this study, all groups met power, and there was still no difference between those with and without obesity.

Nicholls and colleagues examined REVERSAL study data to determine whether BMI greater than the median BMI impacted inflammatory markers or lipid levels with atorvastatin 80 mg daily or pravastatin 40 mg daily. The REVERSAL study authors found no difference in percent change LDL-C between those above the median BMI compared with those below the median BMI for patients on pravastatin therapy. However, the authors did find a difference in percent change LDL-C with atorvastatin therapy.¹³ No difference in percent change LDL-C was present with simvastatin therapy in this study. As simvastatin is more lipophilic than is atorvastatin, lipophilicity remains an area for further study for statin therapy in patients with obesity.

The surrogate marker of percent change in LDL-C was used for the primary outcome in this study. The ACC/AHA 2013 guidelines and the National Lipid Association 2014 guidelines recommend an alternative goal of 30% to 50% change in LDL-C from baseline.^14,15 Using this clinically relevant marker compensated for differences in baseline LDL-C and limited the effect of these differences on the primary outcome of this study.

Limitations

This study did not include patients who were underweight (BMI < 18 kg/m²), as these patients have previously demonstrated decreased outcomes with statin therapy.¹⁶ However, this limits these data to only those patients that have a BMI of at least 18 kg/m². Limitations of this study also included the inability to consider adherence and lifestyle changes. These limitations were unavoidable due to the nature of a retrospective chart review.

Conclusion

The prevalence of obesity is increasing, and it is a disease that alters pharmacokinetics and lipid metabolism. Though this study did not find a difference between the LDL-C-lowering efficacy of simvastatin in those with and without obesity, continued study of the effect of obesity on the efficacy of medications is vital.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the James H. Qullen VAMC in Mountain Home, Tennessee.

Inefficiencies in the operating room (OR) can occur before, during, and between cases and lead to multiple problems, including delays in the delivery of patient care. They also have a negative financial impact for the institution and cause frustration for surgeons, anesthesiologists, and other OR staff. Ultimately, delays lead to dissatisfaction among patients and health care providers. Operating room efficiency increasingly is becoming a marker of the quality of surgical care.

The Institute of Medicine (IOM) identified timeliness and efficiency as 2 of 6 areas for improvement for U.S. hospitals.¹ Organizations such as the Centers for Medicare and Medicaid Services, Agency for Healthcare Research and Quality, IOM, Institute for Healthcare Improvement, The Joint Commission, Leapfrog Group, and National Quality Forum are beginning to monitor patient care workflow in order to improve quality while reducing costs.²

About 187 million Americans take at least 1 prescription drug.³ An estimated 20% to 50% of patients do not take their medications as prescribed and are said to be nonadherent with therapy.^4,5 Nonadherence to medication also has been shown to result in increased health risks and costs of up to $290 billion.⁶ Patients who receive pharmacist services achieve better clinical outcomes for chronic diseases than national standards.⁷

Among patients with a chronic disease, poor adherence tends to result in poor outcomes and increased medical costs. Yet these are the patients who face the most risks in surgery and require the most preoperative care. Several studies have evaluated the frequency of medication nonadherence prior to surgery and its effect on surgery cancellations. These studies have examined a variety of factors related to patient preoperative education, medications, food intake, bowel prep, etc.

In a VA Puget Sound Health Care System study, 23% of patients undergoing ambulatory surgery were nonadherent to preoperative medication instructions.⁸ Studies have found that up to 7% of cancellations were impacted by medication nonadherence and preoperative education.^9-13 Furthermore, studies using large-scale databases have found medically treatable conditions as a significant source of surgical delay.¹⁴ Had these conditions been treated a priori, delay in surgery would not have occurred. Unfortunately, it is not clear whether the delays were the result of missed preoperative checks or medication nonadherence.

Ensuring patient safety, including reducing medical errors and adverse events (AEs), is imperative in the surgical workflow. In 1999, the IOM estimated that medical error was a leading cause of death in the U.S. and resulted in up to 100,000 deaths annually.¹⁵

In a retrospective study of 15,000 cases, Gawande and colleagues found that 66% of all AEs were surgical and 54% of these were preventable.¹⁶ In addition to improving reporting systems, creating a culture of safety with all members of the health care team and building a partnership with patients during preoperative visits can ensure increased adherence and reduced medication AEs. In a neurosurgical cohort of patients, Bernstein and colleagues found that 85% of patients were subjected to at least 1 error; 10% of the errors were major, and 65% were deemed preventable.¹⁷

The purpose of this study is to evaluate whether redundancy built into the patient care protocols prior to surgery helps catch errors as demonstrated in time-out analyses.¹⁸ Decreasing these errors would lead to fewer surgical cancellations and medical workup delays. The authors hypothesize that a structured preoperative pharmacologic workup would result in decreased preoperative delay in the surgical workflow.

Methods

The study protocol was reviewed and determined to be a quality improvement/quality assurance initiative, which exempted it from institutional review board or other oversight committee review, at the Minneapolis VA Health Care System. The VA OR Efficiency Task Force identified medication adherence as a possible source of delay. A study therefore was undertaken to determine the adherence rate and how it impacted operative delays. Data were extracted from this study to test the stated hypothesis and compare with historic data.

Fifty consecutive patients undergoing neurosurgical procedures from May 2010 through July 2010 were retrospectively reviewed and evaluated. All patients had a preoperative consultation with a pharmacist and the neurosurgery coordinator who reviewed all medications with the patient and gave specific instructions on which medications should be continued or discontinued prior to the surgery date. This information was documented on the OR Medication Compliance Worksheet and included in the patient’s preoperative chart by the neurosurgery coordinator. On the day of surgery, all active medications on this chart were reviewed with the patient by the anesthesiologist and documented on the OR Medication Compliance Worksheet. The worksheet was then sent to the neurosurgery coordinator for secondary review and analysis.

To evaluate delays, the authors reviewed the patient anesthesiology records. Delays were defined as either cancellations of the case due to medication nonadherence, which would make it unsafe to proceed with surgery, or minor delays due to medication nonadherence, which required further preoperative assessment and workup before proceeding with surgery. Cancelled cases were defined as cases on the final copy of the published OR schedule that did not occur.

Medication Adherence Program

In order to ensure medication adherence prior to surgery there were 5 points of contact with a patient from the time the patient was scheduled for surgery and the date of the surgery (Figure 1):

1.  The coordinator reviewed medications with patient at time of scheduling
2. A letter was sent with specific instructions about medications
3. Preoperative medicine clearance
4. Preoperative neurosurgery appointment
5. Call from pharmacist 1 week before surgery
   

Results

The authors reviewed 10 months of the neurosurgical service prior to initiation of the protocol. Of 317 analyzed cases, 30 were delayed/cancelled. Among these, 5 cases with the possibility of a 6th were cancelled due to medication issues. Following the initialization of the study, 50 patients underwent preoperative counseling with the pharmacist and the neurosurgery coordinator and had an OR Medication Compliance Worksheet created.

Review of the OR Medication Compliance Worksheet demonstrated that 2 patients were nonadherent with their medications.

Discussion

The OR is one of the most expensive areas in an acute care hospital.² Cancellations or delays can have significant negative financial implications (about $1,500 per hour of lost revenue).¹⁹ In order to improve OR efficiency and reduce preoperative delays, the causes of preoperative delays must be determined.

Some delays and cancellations result from either preoperative or perioperative issues. Prolonged wait time and postponement may cause preoperative delays. Perioperative delays include delays in getting into the OR once the patient has arrived in the hospital as well as delays during the operation. These delays can be due to both human error and system deficiencies.²⁰

One Toronto, Canada study looked at the different etiologies for delays in cranial and spinal procedures and found that equipment failure followed by physical transit into the OR were the top reasons for delays.²¹ These researchers also found that first cases each day sometimes had a higher incidence of delays than did subsequent cases because several ORs prepare to start simultaneously, which causes an increased demand on hospital support services (eg, registration desk, imaging department, nurses in the patient holding area, or transportation). The number of these support staff remains constant throughout the day, whereas the first-case patients all arrive at about the same time, causing a bottleneck in the early morning. The authors looked at 1 facet of the delay problem as an ongoing analysis for hospital efficiency improvement.

With the implementation of a simple 5-step process, medication adherence was > 90% and the impact of nonadherence on surgical procedure delays was eliminated during the trial period. In this sample, nonadherence did not impact surgery, which resulted in fewer delays and cancellations. The process emphasized repetition and communication, involving 5 reminders between the date of OR scheduling and the date of the actual surgery. The authors found that in this quality improvement study, redundancy in the workflow actually improved the efficiency of the patient’s hospital course.

Within the OR, there are many perspectives to consider for improving OR efficiency. For instance, Archer and colleagues present several distinct perspectives: that of the health care institution, the individual practitioner, the patient, and evidenced-based medicine.² According to Strum and colleagues, OR inefficiency is the sum of under- and overutilized time and efficiency is highest when OR inefficiency is minimized.²² An OR is considered underutilized when it is staffed at regular wages but not used for surgery, setup, or cleanup. An OR is considered overutilized when the OR staff receives overtime wages, multiplied by the relative cost of overtime compared with straight time. Delayed or cancelled surgeries can result in idle operating room staff, while repeat or correlative studies (ie, electrocardiogram, drug levels) may overutilize support services.

Limitations

This study has obvious limitations due to its small scale. Because the protocol implementation resulted in few delays, a very large cohort would have been necessary to attain statistical power.

Conclusion

By improving OR efficiency and reducing preoperative delays, surgical capacity can be increased.

In this study, the authors demonstrate that with little addition of cost, medication nonadherence can be reduced or eliminated as an issue for surgical delays. With the implementation of the 5-step reminder process as well as the addition of a pharmacist consultation/visit, medication adherence was > 90% among preoperative patients in this small study. With the number of patients with complex medication regimens, increasing medication adherence in the preoperative period is not only important in reducing operative delays, but also an opportunity to ensure the patient is safe and optimally treated. ˜

Inefficiencies in the operating room (OR) can occur before, during, and between cases and lead to multiple problems, including delays in the delivery of patient care. They also have a negative financial impact for the institution and cause frustration for surgeons, anesthesiologists, and other OR staff. Ultimately, delays lead to dissatisfaction among patients and health care providers. Operating room efficiency increasingly is becoming a marker of the quality of surgical care.

The Institute of Medicine (IOM) identified timeliness and efficiency as 2 of 6 areas for improvement for U.S. hospitals.¹ Organizations such as the Centers for Medicare and Medicaid Services, Agency for Healthcare Research and Quality, IOM, Institute for Healthcare Improvement, The Joint Commission, Leapfrog Group, and National Quality Forum are beginning to monitor patient care workflow in order to improve quality while reducing costs.²

About 187 million Americans take at least 1 prescription drug.³ An estimated 20% to 50% of patients do not take their medications as prescribed and are said to be nonadherent with therapy.^4,5 Nonadherence to medication also has been shown to result in increased health risks and costs of up to $290 billion.⁶ Patients who receive pharmacist services achieve better clinical outcomes for chronic diseases than national standards.⁷

Among patients with a chronic disease, poor adherence tends to result in poor outcomes and increased medical costs. Yet these are the patients who face the most risks in surgery and require the most preoperative care. Several studies have evaluated the frequency of medication nonadherence prior to surgery and its effect on surgery cancellations. These studies have examined a variety of factors related to patient preoperative education, medications, food intake, bowel prep, etc.

In a VA Puget Sound Health Care System study, 23% of patients undergoing ambulatory surgery were nonadherent to preoperative medication instructions.⁸ Studies have found that up to 7% of cancellations were impacted by medication nonadherence and preoperative education.^9-13 Furthermore, studies using large-scale databases have found medically treatable conditions as a significant source of surgical delay.¹⁴ Had these conditions been treated a priori, delay in surgery would not have occurred. Unfortunately, it is not clear whether the delays were the result of missed preoperative checks or medication nonadherence.

Ensuring patient safety, including reducing medical errors and adverse events (AEs), is imperative in the surgical workflow. In 1999, the IOM estimated that medical error was a leading cause of death in the U.S. and resulted in up to 100,000 deaths annually.¹⁵

In a retrospective study of 15,000 cases, Gawande and colleagues found that 66% of all AEs were surgical and 54% of these were preventable.¹⁶ In addition to improving reporting systems, creating a culture of safety with all members of the health care team and building a partnership with patients during preoperative visits can ensure increased adherence and reduced medication AEs. In a neurosurgical cohort of patients, Bernstein and colleagues found that 85% of patients were subjected to at least 1 error; 10% of the errors were major, and 65% were deemed preventable.¹⁷

The purpose of this study is to evaluate whether redundancy built into the patient care protocols prior to surgery helps catch errors as demonstrated in time-out analyses.¹⁸ Decreasing these errors would lead to fewer surgical cancellations and medical workup delays. The authors hypothesize that a structured preoperative pharmacologic workup would result in decreased preoperative delay in the surgical workflow.

Methods

The study protocol was reviewed and determined to be a quality improvement/quality assurance initiative, which exempted it from institutional review board or other oversight committee review, at the Minneapolis VA Health Care System. The VA OR Efficiency Task Force identified medication adherence as a possible source of delay. A study therefore was undertaken to determine the adherence rate and how it impacted operative delays. Data were extracted from this study to test the stated hypothesis and compare with historic data.

Fifty consecutive patients undergoing neurosurgical procedures from May 2010 through July 2010 were retrospectively reviewed and evaluated. All patients had a preoperative consultation with a pharmacist and the neurosurgery coordinator who reviewed all medications with the patient and gave specific instructions on which medications should be continued or discontinued prior to the surgery date. This information was documented on the OR Medication Compliance Worksheet and included in the patient’s preoperative chart by the neurosurgery coordinator. On the day of surgery, all active medications on this chart were reviewed with the patient by the anesthesiologist and documented on the OR Medication Compliance Worksheet. The worksheet was then sent to the neurosurgery coordinator for secondary review and analysis.

To evaluate delays, the authors reviewed the patient anesthesiology records. Delays were defined as either cancellations of the case due to medication nonadherence, which would make it unsafe to proceed with surgery, or minor delays due to medication nonadherence, which required further preoperative assessment and workup before proceeding with surgery. Cancelled cases were defined as cases on the final copy of the published OR schedule that did not occur.

Medication Adherence Program

In order to ensure medication adherence prior to surgery there were 5 points of contact with a patient from the time the patient was scheduled for surgery and the date of the surgery (Figure 1):

1.  The coordinator reviewed medications with patient at time of scheduling
2. A letter was sent with specific instructions about medications
3. Preoperative medicine clearance
4. Preoperative neurosurgery appointment
5. Call from pharmacist 1 week before surgery
   

Results

The authors reviewed 10 months of the neurosurgical service prior to initiation of the protocol. Of 317 analyzed cases, 30 were delayed/cancelled. Among these, 5 cases with the possibility of a 6th were cancelled due to medication issues. Following the initialization of the study, 50 patients underwent preoperative counseling with the pharmacist and the neurosurgery coordinator and had an OR Medication Compliance Worksheet created.

Review of the OR Medication Compliance Worksheet demonstrated that 2 patients were nonadherent with their medications.

Discussion

The OR is one of the most expensive areas in an acute care hospital.² Cancellations or delays can have significant negative financial implications (about $1,500 per hour of lost revenue).¹⁹ In order to improve OR efficiency and reduce preoperative delays, the causes of preoperative delays must be determined.

Some delays and cancellations result from either preoperative or perioperative issues. Prolonged wait time and postponement may cause preoperative delays. Perioperative delays include delays in getting into the OR once the patient has arrived in the hospital as well as delays during the operation. These delays can be due to both human error and system deficiencies.²⁰

One Toronto, Canada study looked at the different etiologies for delays in cranial and spinal procedures and found that equipment failure followed by physical transit into the OR were the top reasons for delays.²¹ These researchers also found that first cases each day sometimes had a higher incidence of delays than did subsequent cases because several ORs prepare to start simultaneously, which causes an increased demand on hospital support services (eg, registration desk, imaging department, nurses in the patient holding area, or transportation). The number of these support staff remains constant throughout the day, whereas the first-case patients all arrive at about the same time, causing a bottleneck in the early morning. The authors looked at 1 facet of the delay problem as an ongoing analysis for hospital efficiency improvement.

With the implementation of a simple 5-step process, medication adherence was > 90% and the impact of nonadherence on surgical procedure delays was eliminated during the trial period. In this sample, nonadherence did not impact surgery, which resulted in fewer delays and cancellations. The process emphasized repetition and communication, involving 5 reminders between the date of OR scheduling and the date of the actual surgery. The authors found that in this quality improvement study, redundancy in the workflow actually improved the efficiency of the patient’s hospital course.

Within the OR, there are many perspectives to consider for improving OR efficiency. For instance, Archer and colleagues present several distinct perspectives: that of the health care institution, the individual practitioner, the patient, and evidenced-based medicine.² According to Strum and colleagues, OR inefficiency is the sum of under- and overutilized time and efficiency is highest when OR inefficiency is minimized.²² An OR is considered underutilized when it is staffed at regular wages but not used for surgery, setup, or cleanup. An OR is considered overutilized when the OR staff receives overtime wages, multiplied by the relative cost of overtime compared with straight time. Delayed or cancelled surgeries can result in idle operating room staff, while repeat or correlative studies (ie, electrocardiogram, drug levels) may overutilize support services.

Limitations

This study has obvious limitations due to its small scale. Because the protocol implementation resulted in few delays, a very large cohort would have been necessary to attain statistical power.

Conclusion

By improving OR efficiency and reducing preoperative delays, surgical capacity can be increased.

In this study, the authors demonstrate that with little addition of cost, medication nonadherence can be reduced or eliminated as an issue for surgical delays. With the implementation of the 5-step reminder process as well as the addition of a pharmacist consultation/visit, medication adherence was > 90% among preoperative patients in this small study. With the number of patients with complex medication regimens, increasing medication adherence in the preoperative period is not only important in reducing operative delays, but also an opportunity to ensure the patient is safe and optimally treated. ˜

Inefficiencies in the operating room (OR) can occur before, during, and between cases and lead to multiple problems, including delays in the delivery of patient care. They also have a negative financial impact for the institution and cause frustration for surgeons, anesthesiologists, and other OR staff. Ultimately, delays lead to dissatisfaction among patients and health care providers. Operating room efficiency increasingly is becoming a marker of the quality of surgical care.

The Institute of Medicine (IOM) identified timeliness and efficiency as 2 of 6 areas for improvement for U.S. hospitals.¹ Organizations such as the Centers for Medicare and Medicaid Services, Agency for Healthcare Research and Quality, IOM, Institute for Healthcare Improvement, The Joint Commission, Leapfrog Group, and National Quality Forum are beginning to monitor patient care workflow in order to improve quality while reducing costs.²

About 187 million Americans take at least 1 prescription drug.³ An estimated 20% to 50% of patients do not take their medications as prescribed and are said to be nonadherent with therapy.^4,5 Nonadherence to medication also has been shown to result in increased health risks and costs of up to $290 billion.⁶ Patients who receive pharmacist services achieve better clinical outcomes for chronic diseases than national standards.⁷

Among patients with a chronic disease, poor adherence tends to result in poor outcomes and increased medical costs. Yet these are the patients who face the most risks in surgery and require the most preoperative care. Several studies have evaluated the frequency of medication nonadherence prior to surgery and its effect on surgery cancellations. These studies have examined a variety of factors related to patient preoperative education, medications, food intake, bowel prep, etc.

In a VA Puget Sound Health Care System study, 23% of patients undergoing ambulatory surgery were nonadherent to preoperative medication instructions.⁸ Studies have found that up to 7% of cancellations were impacted by medication nonadherence and preoperative education.^9-13 Furthermore, studies using large-scale databases have found medically treatable conditions as a significant source of surgical delay.¹⁴ Had these conditions been treated a priori, delay in surgery would not have occurred. Unfortunately, it is not clear whether the delays were the result of missed preoperative checks or medication nonadherence.

Ensuring patient safety, including reducing medical errors and adverse events (AEs), is imperative in the surgical workflow. In 1999, the IOM estimated that medical error was a leading cause of death in the U.S. and resulted in up to 100,000 deaths annually.¹⁵

In a retrospective study of 15,000 cases, Gawande and colleagues found that 66% of all AEs were surgical and 54% of these were preventable.¹⁶ In addition to improving reporting systems, creating a culture of safety with all members of the health care team and building a partnership with patients during preoperative visits can ensure increased adherence and reduced medication AEs. In a neurosurgical cohort of patients, Bernstein and colleagues found that 85% of patients were subjected to at least 1 error; 10% of the errors were major, and 65% were deemed preventable.¹⁷

The purpose of this study is to evaluate whether redundancy built into the patient care protocols prior to surgery helps catch errors as demonstrated in time-out analyses.¹⁸ Decreasing these errors would lead to fewer surgical cancellations and medical workup delays. The authors hypothesize that a structured preoperative pharmacologic workup would result in decreased preoperative delay in the surgical workflow.

Methods

The study protocol was reviewed and determined to be a quality improvement/quality assurance initiative, which exempted it from institutional review board or other oversight committee review, at the Minneapolis VA Health Care System. The VA OR Efficiency Task Force identified medication adherence as a possible source of delay. A study therefore was undertaken to determine the adherence rate and how it impacted operative delays. Data were extracted from this study to test the stated hypothesis and compare with historic data.

Fifty consecutive patients undergoing neurosurgical procedures from May 2010 through July 2010 were retrospectively reviewed and evaluated. All patients had a preoperative consultation with a pharmacist and the neurosurgery coordinator who reviewed all medications with the patient and gave specific instructions on which medications should be continued or discontinued prior to the surgery date. This information was documented on the OR Medication Compliance Worksheet and included in the patient’s preoperative chart by the neurosurgery coordinator. On the day of surgery, all active medications on this chart were reviewed with the patient by the anesthesiologist and documented on the OR Medication Compliance Worksheet. The worksheet was then sent to the neurosurgery coordinator for secondary review and analysis.

To evaluate delays, the authors reviewed the patient anesthesiology records. Delays were defined as either cancellations of the case due to medication nonadherence, which would make it unsafe to proceed with surgery, or minor delays due to medication nonadherence, which required further preoperative assessment and workup before proceeding with surgery. Cancelled cases were defined as cases on the final copy of the published OR schedule that did not occur.

Medication Adherence Program

In order to ensure medication adherence prior to surgery there were 5 points of contact with a patient from the time the patient was scheduled for surgery and the date of the surgery (Figure 1):

1.  The coordinator reviewed medications with patient at time of scheduling
2. A letter was sent with specific instructions about medications
3. Preoperative medicine clearance
4. Preoperative neurosurgery appointment
5. Call from pharmacist 1 week before surgery
   

Results

The authors reviewed 10 months of the neurosurgical service prior to initiation of the protocol. Of 317 analyzed cases, 30 were delayed/cancelled. Among these, 5 cases with the possibility of a 6th were cancelled due to medication issues. Following the initialization of the study, 50 patients underwent preoperative counseling with the pharmacist and the neurosurgery coordinator and had an OR Medication Compliance Worksheet created.

Review of the OR Medication Compliance Worksheet demonstrated that 2 patients were nonadherent with their medications.

Discussion

The OR is one of the most expensive areas in an acute care hospital.² Cancellations or delays can have significant negative financial implications (about $1,500 per hour of lost revenue).¹⁹ In order to improve OR efficiency and reduce preoperative delays, the causes of preoperative delays must be determined.

Some delays and cancellations result from either preoperative or perioperative issues. Prolonged wait time and postponement may cause preoperative delays. Perioperative delays include delays in getting into the OR once the patient has arrived in the hospital as well as delays during the operation. These delays can be due to both human error and system deficiencies.²⁰

One Toronto, Canada study looked at the different etiologies for delays in cranial and spinal procedures and found that equipment failure followed by physical transit into the OR were the top reasons for delays.²¹ These researchers also found that first cases each day sometimes had a higher incidence of delays than did subsequent cases because several ORs prepare to start simultaneously, which causes an increased demand on hospital support services (eg, registration desk, imaging department, nurses in the patient holding area, or transportation). The number of these support staff remains constant throughout the day, whereas the first-case patients all arrive at about the same time, causing a bottleneck in the early morning. The authors looked at 1 facet of the delay problem as an ongoing analysis for hospital efficiency improvement.

With the implementation of a simple 5-step process, medication adherence was > 90% and the impact of nonadherence on surgical procedure delays was eliminated during the trial period. In this sample, nonadherence did not impact surgery, which resulted in fewer delays and cancellations. The process emphasized repetition and communication, involving 5 reminders between the date of OR scheduling and the date of the actual surgery. The authors found that in this quality improvement study, redundancy in the workflow actually improved the efficiency of the patient’s hospital course.

Within the OR, there are many perspectives to consider for improving OR efficiency. For instance, Archer and colleagues present several distinct perspectives: that of the health care institution, the individual practitioner, the patient, and evidenced-based medicine.² According to Strum and colleagues, OR inefficiency is the sum of under- and overutilized time and efficiency is highest when OR inefficiency is minimized.²² An OR is considered underutilized when it is staffed at regular wages but not used for surgery, setup, or cleanup. An OR is considered overutilized when the OR staff receives overtime wages, multiplied by the relative cost of overtime compared with straight time. Delayed or cancelled surgeries can result in idle operating room staff, while repeat or correlative studies (ie, electrocardiogram, drug levels) may overutilize support services.

Limitations

This study has obvious limitations due to its small scale. Because the protocol implementation resulted in few delays, a very large cohort would have been necessary to attain statistical power.

Conclusion

By improving OR efficiency and reducing preoperative delays, surgical capacity can be increased.

In this study, the authors demonstrate that with little addition of cost, medication nonadherence can be reduced or eliminated as an issue for surgical delays. With the implementation of the 5-step reminder process as well as the addition of a pharmacist consultation/visit, medication adherence was > 90% among preoperative patients in this small study. With the number of patients with complex medication regimens, increasing medication adherence in the preoperative period is not only important in reducing operative delays, but also an opportunity to ensure the patient is safe and optimally treated. ˜

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

IMODIUM (LOPERAMIDE HYDROCHLORIDE):

• New warning December 2016

WARNING: TORSADES DE POINTES AND SUDDEN DEATH

Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of a higher than recommended dosages of Imodium (see WARNINGS and OVERDOSAGE).

Imodium is contraindicated in pediatric patients less than 2 years of age (see CONTRANIDICATIONS).

Avoid Imodium dosages higher than recommended in adults and pediatric patients 2 years of age and older due to the risk of serious cardiac adverse reactions (see DOSAGE AND ADMINISTRATION).

AUBAGIO (TERIFLUNOMIDE) TABLETS:

• Edited and updated warning December 2016

Risk of Teratogenicity
Aubagio is contraindicated for use in pregnant women and in women of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with Aubagio in females of reproductive potential. Advise females of reproductive potential to use effective contraception during Aubagio treatment and during an accelerated drug elimination procedure after Aubagio treatment. Stop Aubagio and use an accelerated drug elimination procedure if the patient becomes pregnant.

PROMACTA (ELTROMBOPAG) TABLETS, FOR ORAL USE AND ORAL SUSPENSION:

• Edited and updated warning December 2016

Chronic Hepatitis C
Promacta may increase the risk of severe and potentially lifethreatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

ICLUSIG (PONATINIB HYDROCHLORIDE):

• Edited and updated warning December 2016

WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

Arterial Occlusion
Arterial occlusions have occurred in at least 35% of Iclusig-treated patients. Some patients experienced more than 1 type of event. Events observed included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop Iclusig immediately for arterial occlusion.

Venous Thromboembolism
Venous occlusive events have occurred in 6% of Iclusig-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure
Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

IMODIUM (LOPERAMIDE HYDROCHLORIDE):

• New warning December 2016

WARNING: TORSADES DE POINTES AND SUDDEN DEATH

Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of a higher than recommended dosages of Imodium (see WARNINGS and OVERDOSAGE).

Imodium is contraindicated in pediatric patients less than 2 years of age (see CONTRANIDICATIONS).

Avoid Imodium dosages higher than recommended in adults and pediatric patients 2 years of age and older due to the risk of serious cardiac adverse reactions (see DOSAGE AND ADMINISTRATION).

AUBAGIO (TERIFLUNOMIDE) TABLETS:

• Edited and updated warning December 2016

Risk of Teratogenicity
Aubagio is contraindicated for use in pregnant women and in women of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with Aubagio in females of reproductive potential. Advise females of reproductive potential to use effective contraception during Aubagio treatment and during an accelerated drug elimination procedure after Aubagio treatment. Stop Aubagio and use an accelerated drug elimination procedure if the patient becomes pregnant.

PROMACTA (ELTROMBOPAG) TABLETS, FOR ORAL USE AND ORAL SUSPENSION:

• Edited and updated warning December 2016

Chronic Hepatitis C
Promacta may increase the risk of severe and potentially lifethreatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

ICLUSIG (PONATINIB HYDROCHLORIDE):

• Edited and updated warning December 2016

WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

Arterial Occlusion
Arterial occlusions have occurred in at least 35% of Iclusig-treated patients. Some patients experienced more than 1 type of event. Events observed included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop Iclusig immediately for arterial occlusion.

Venous Thromboembolism
Venous occlusive events have occurred in 6% of Iclusig-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure
Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

IMODIUM (LOPERAMIDE HYDROCHLORIDE):

• New warning December 2016

WARNING: TORSADES DE POINTES AND SUDDEN DEATH

Cases of Torsades de Pointes, cardiac arrest, and death have been reported with the use of a higher than recommended dosages of Imodium (see WARNINGS and OVERDOSAGE).

Imodium is contraindicated in pediatric patients less than 2 years of age (see CONTRANIDICATIONS).

Avoid Imodium dosages higher than recommended in adults and pediatric patients 2 years of age and older due to the risk of serious cardiac adverse reactions (see DOSAGE AND ADMINISTRATION).

AUBAGIO (TERIFLUNOMIDE) TABLETS:

• Edited and updated warning December 2016

Risk of Teratogenicity
Aubagio is contraindicated for use in pregnant women and in women of reproductive potential who are not using effective contraception because of the potential for fetal harm. Teratogenicity and embryolethality occurred in animals at plasma teriflunomide exposures lower than that in humans. Exclude pregnancy before the start of treatment with Aubagio in females of reproductive potential. Advise females of reproductive potential to use effective contraception during Aubagio treatment and during an accelerated drug elimination procedure after Aubagio treatment. Stop Aubagio and use an accelerated drug elimination procedure if the patient becomes pregnant.

PROMACTA (ELTROMBOPAG) TABLETS, FOR ORAL USE AND ORAL SUSPENSION:

• Edited and updated warning December 2016

Chronic Hepatitis C
Promacta may increase the risk of severe and potentially lifethreatening hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended.

ICLUSIG (PONATINIB HYDROCHLORIDE):

• Edited and updated warning December 2016

WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

Arterial Occlusion
Arterial occlusions have occurred in at least 35% of Iclusig-treated patients. Some patients experienced more than 1 type of event. Events observed included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop Iclusig immediately for arterial occlusion.

Venous Thromboembolism
Venous occlusive events have occurred in 6% of Iclusig-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure
Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients.

The IHS has partnered with 3 top American universities to give pharmacy students an opportunity to get real-life work experience and potentially careers at IHS facilities.

Related: Dangerous Staff Shortages in the IHS

In the IHS Advanced Pharmacy Practice Experience Program, PharmD candidates at Howard University, Purdue University, and the University of Southern California will join students from more than 80 universities in 39 states to complete rotations at IHS direct service facilities. “Many return to start their career in providing quality health care to the American Indian and Alaska Native community,” said Mary Smith, IHS principal deputy director.

“My experience with IHS as a student inspired me to apply to work here when I graduated,” said Fengyee Zhou, now a pharmacist at the IHS Whiteriver Indian Hospital in Arizona. “The level of teamwork among all health care disciplines and the extent to which pharmacists engage in patient care activities brought me back to Whiteriver.”

Related: What s the VA? The Largest Educator of Health Care Professionals in the U.S.

The IHS also offers internships, externships, rotations, and residencies to pharmacy, behavioral health, dentistry, optometry, nursing, and medical students.

The IHS has partnered with 3 top American universities to give pharmacy students an opportunity to get real-life work experience and potentially careers at IHS facilities.

Related: Dangerous Staff Shortages in the IHS

In the IHS Advanced Pharmacy Practice Experience Program, PharmD candidates at Howard University, Purdue University, and the University of Southern California will join students from more than 80 universities in 39 states to complete rotations at IHS direct service facilities. “Many return to start their career in providing quality health care to the American Indian and Alaska Native community,” said Mary Smith, IHS principal deputy director.

“My experience with IHS as a student inspired me to apply to work here when I graduated,” said Fengyee Zhou, now a pharmacist at the IHS Whiteriver Indian Hospital in Arizona. “The level of teamwork among all health care disciplines and the extent to which pharmacists engage in patient care activities brought me back to Whiteriver.”

Related: What s the VA? The Largest Educator of Health Care Professionals in the U.S.

The IHS also offers internships, externships, rotations, and residencies to pharmacy, behavioral health, dentistry, optometry, nursing, and medical students.

The IHS has partnered with 3 top American universities to give pharmacy students an opportunity to get real-life work experience and potentially careers at IHS facilities.

Related: Dangerous Staff Shortages in the IHS

In the IHS Advanced Pharmacy Practice Experience Program, PharmD candidates at Howard University, Purdue University, and the University of Southern California will join students from more than 80 universities in 39 states to complete rotations at IHS direct service facilities. “Many return to start their career in providing quality health care to the American Indian and Alaska Native community,” said Mary Smith, IHS principal deputy director.

“My experience with IHS as a student inspired me to apply to work here when I graduated,” said Fengyee Zhou, now a pharmacist at the IHS Whiteriver Indian Hospital in Arizona. “The level of teamwork among all health care disciplines and the extent to which pharmacists engage in patient care activities brought me back to Whiteriver.”

Related: What s the VA? The Largest Educator of Health Care Professionals in the U.S.

The IHS also offers internships, externships, rotations, and residencies to pharmacy, behavioral health, dentistry, optometry, nursing, and medical students.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. You can search these and other label changes in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

QUINOLONE:

• Edited and updated warning September 2016

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together including:

• Tendinitis and tendon rupture
• Peripheral neuropathy
• Central nervous system effects

Discontinue immediately and avoid the use of fluoroquinolones in patients who experience any of these serious adverse reactions. Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis. Avoid quinolones in patients with known history of myasthenia gravis. Because fluoroquinolones
have been associated with serious adverse reactions, reserve quinolones for use in patients who have no alternative treatment options for the following
indications:

Avelox (moxifloxacin hydrochloride): Avelox in sodium chloride 0.8% in plastic container; moxifloxacin hydrochloride; Cipro in dextrose 5% in plastic container):
Acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis.

Cipro (ciprofloxacin; ciprofloxacin hydrochloride): Acute exacerbation of chronic bronchitis, acute uncomplicated cystitis, and acute sinusitis.

Cipro XR; Noroxin (norfloxacin): Uncomplicated urinary tract infections.

Factive (gemifloxacin mesylate): Acute bacterial exacerbation of chronic bronchitis.

Levaquin (levofloxacin): Uncomplicated urinary tract infection, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis.
 

KRYSTEXXA (PEGLOTICASE):

• Added section to warning September 2016

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS; G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA (Title Updated)

Addition of: Screen patients at risk for G6PD deficiency prior to starting Krystexxa. Hemolysis and methemoglobinemia have been reported with Krystexxa in patients with G6PD deficiency. Do not administer Krystexxa to patients with G6PD deficiency.
 

PLAVIX (CLOPIDOGREL BISULFATE):

• Edited and updated warning September 2016

WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE

The effectiveness of Plavix results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
 

SYNJARDY (EMPAGLIFLOZIN; METFORMIN HYDROCHLORIDE):

• Edited and updated warning September 2016

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metforminassociated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.

If metformin-associated lactic acidosis is suspected, immediately discontinue Synjardy and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
 

ZYDELIG (IDELALISIB)

• Edited and updated warning September 2016

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, AND INTESTINAL PERFORATION

• Fatal and/or serious hepatotoxicity occurred in 11 % to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 19% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.
• Fatal and/or serious infections occurred in 21% to 36% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
• Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig for intestinal perforation.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. You can search these and other label changes in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

QUINOLONE:

• Edited and updated warning September 2016

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together including:

• Tendinitis and tendon rupture
• Peripheral neuropathy
• Central nervous system effects

Discontinue immediately and avoid the use of fluoroquinolones in patients who experience any of these serious adverse reactions. Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis. Avoid quinolones in patients with known history of myasthenia gravis. Because fluoroquinolones
have been associated with serious adverse reactions, reserve quinolones for use in patients who have no alternative treatment options for the following
indications:

Avelox (moxifloxacin hydrochloride): Avelox in sodium chloride 0.8% in plastic container; moxifloxacin hydrochloride; Cipro in dextrose 5% in plastic container):
Acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis.

Cipro (ciprofloxacin; ciprofloxacin hydrochloride): Acute exacerbation of chronic bronchitis, acute uncomplicated cystitis, and acute sinusitis.

Cipro XR; Noroxin (norfloxacin): Uncomplicated urinary tract infections.

Factive (gemifloxacin mesylate): Acute bacterial exacerbation of chronic bronchitis.

Levaquin (levofloxacin): Uncomplicated urinary tract infection, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis.
 

KRYSTEXXA (PEGLOTICASE):

• Added section to warning September 2016

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS; G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA (Title Updated)

Addition of: Screen patients at risk for G6PD deficiency prior to starting Krystexxa. Hemolysis and methemoglobinemia have been reported with Krystexxa in patients with G6PD deficiency. Do not administer Krystexxa to patients with G6PD deficiency.
 

PLAVIX (CLOPIDOGREL BISULFATE):

• Edited and updated warning September 2016

WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE

The effectiveness of Plavix results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
 

SYNJARDY (EMPAGLIFLOZIN; METFORMIN HYDROCHLORIDE):

• Edited and updated warning September 2016

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metforminassociated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.

If metformin-associated lactic acidosis is suspected, immediately discontinue Synjardy and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
 

ZYDELIG (IDELALISIB)

• Edited and updated warning September 2016

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, AND INTESTINAL PERFORATION

• Fatal and/or serious hepatotoxicity occurred in 11 % to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 19% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.
• Fatal and/or serious infections occurred in 21% to 36% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
• Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig for intestinal perforation.

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. You can search these and other label changes in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted.

QUINOLONE:

• Edited and updated warning September 2016

WARNING: SERIOUS ADVERSE REACTIONS INCLUDING TENDINITIS, TENDON RUPTURE, PERIPHERAL NEUROPATHY, CENTRAL NERVOUS SYSTEM EFFECTS AND EXACERBATION OF MYASTHENIA GRAVIS

Fluoroquinolones have been associated with disabling and potentially irreversible serious adverse reactions that have occurred together including:

• Tendinitis and tendon rupture
• Peripheral neuropathy
• Central nervous system effects

Discontinue immediately and avoid the use of fluoroquinolones in patients who experience any of these serious adverse reactions. Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis. Avoid quinolones in patients with known history of myasthenia gravis. Because fluoroquinolones
have been associated with serious adverse reactions, reserve quinolones for use in patients who have no alternative treatment options for the following
indications:

Avelox (moxifloxacin hydrochloride): Avelox in sodium chloride 0.8% in plastic container; moxifloxacin hydrochloride; Cipro in dextrose 5% in plastic container):
Acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis.

Cipro (ciprofloxacin; ciprofloxacin hydrochloride): Acute exacerbation of chronic bronchitis, acute uncomplicated cystitis, and acute sinusitis.

Cipro XR; Noroxin (norfloxacin): Uncomplicated urinary tract infections.

Factive (gemifloxacin mesylate): Acute bacterial exacerbation of chronic bronchitis.

Levaquin (levofloxacin): Uncomplicated urinary tract infection, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis.
 

KRYSTEXXA (PEGLOTICASE):

• Added section to warning September 2016

WARNING: ANAPHYLAXIS AND INFUSION REACTIONS; G6PD DEFICIENCY ASSOCIATED HEMOLYSIS AND METHEMOGLOBINEMIA (Title Updated)

Addition of: Screen patients at risk for G6PD deficiency prior to starting Krystexxa. Hemolysis and methemoglobinemia have been reported with Krystexxa in patients with G6PD deficiency. Do not administer Krystexxa to patients with G6PD deficiency.
 

PLAVIX (CLOPIDOGREL BISULFATE):

• Edited and updated warning September 2016

WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE

The effectiveness of Plavix results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
 

SYNJARDY (EMPAGLIFLOZIN; METFORMIN HYDROCHLORIDE):

• Edited and updated warning September 2016

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metforminassociated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information.

If metformin-associated lactic acidosis is suspected, immediately discontinue Synjardy and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
 

ZYDELIG (IDELALISIB)

• Edited and updated warning September 2016

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, AND INTESTINAL PERFORATION

• Fatal and/or serious hepatotoxicity occurred in 11 % to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 19% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig as recommended.
• Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig as recommended.
• Fatal and/or serious infections occurred in 21% to 36% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
• Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig for intestinal perforation.

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.

In the U.S. about 2.7 to 6.1 million people have atrial fibrillation (AF).¹ This condition affects the rhythm of the heart, causes blood in the heart to become stagnant, and puts patients at high risk for developing a systemic embolism, particularly a stroke.1 Recent studies have shown that AF accounts for at least 15% of all strokes in the U.S. and 36% of strokes in people aged > 80 years.²

For patients aged > 60 years, the gold standard of long-term anticoagulation for reducing the risk of stroke has been oral vitamin K antagonist (warfarin) therapy.² Although overwhelming evidence exists that supports the use of warfarin in these patients, warfarin is a narrow therapeutic index medication that requires frequent laboratory monitoring of international normalized ratio (INR) for dose titration guidance. There is also strong evidence that pharmacist-run anticoagulation clinics have improved patient-centered outcomes in patients prescribed warfarin.^3-5

Direct oral anticoagulants (DOACs) are recently approved oral medications used as alternatives to warfarin for anticoagulation in AF. Direct oral anticoagulants do not require INR monitoring or any laboratory test for efficacy. In 2010, the FDA approved the first DOAC, dabigatran, for use in patients with AF. In 2011, rivaroxaban received approval for the same indication. One potential drawback of these new agents relative to warfarin is the lack of availability of a reversal agent that can be used in the event of a life-threatening bleeding event. Dabigatran is the only DOAC with an FDA-approved available reversal agent. In both 2011 and 2012, dabigatran, warfarin, and other anticoagulants topped the Institute for Safe Medicine Practice list of suspect drugs related to adverse events (AEs). These data prompted the Joint Commission to incorporate anticoagulation into the 2017 National Hospital Patient Safety Goals to improve patient outcomes and reduce harm from use of anticoagulants.⁶  

In early 2011, the VHA produced national guidance on the treatment of patients who receive DOACs; this guidance was updated most recently in September 2016.⁷ Patients who were receiving DOACs at the Ralph H. Johnson VAMC (RHJVAMC) were initially monitored by 12 primary care pharmacists at the main hospital or at community-based outpatient clinics (CBOCs). Ambulatory care pharmacists at RHJVAMC work under a scope of practice to prescribe and adjust certain classes of medications to provide the highest level of care to more than 65,000 veterans in South Carolina and Georgia. Historically at RHJVAMC, warfarin has been the anticoagulant most commonly used for AF, though dabigatran and rivaroxaban have gained in popularity after being added to the national VA formulary.  

In November 2012, for better monitoring of patient outcomes, improved efficiency of the primary care pharmacist clinics, and increased access to care in these clinics, treatment of patients prescribed DOACs was shifted to a centralized model that involved 3 anticoagulation clinical pharmacy specialists.  

Centralized pharmacy services have a small number of core team members in a specific service for a particular disease, which reduces the number of different pharmacists a patient could talk to for management of a particular condition. Centralized pharmacy services allow for streamlining anticoagulation management to a small group of individual pharmacists considered specialists in anticoagulation. This shift in management to centralized anticoagulation services was supported at RHJVAMC by findings from a study of a pharmacist-run centralized anticoagulation clinic: Patients treated by the centralized clinic were 39% less likely to experience an anticoagulation therapy complication.⁸  

Protocol for dabigatran follow-up and monitoring at RHJVAMC was developed by clinical and supervisory pharmacy staff, to align with national VA guidance. When a provider determines a patient is a candidate for dabigatran, an outpatient consultation is entered for the clinical pharmacy specialist to review the appropriateness of the patient selection for therapy. If the patient is eligible for therapy, the pharmacist contacts the patient to set up an initial visit to confirm selection and to provide the first dabigatran prescription and counseling. For assessments, with specific emphasis on adherence and AE monitoring, the patient is contacted 2 weeks, 1 month, 3 months, and every 6 months after the initial appointment.

Although most of the literature supports pharmacist-managed anticoagulation for patients who receive warfarin, DOACs have become more integrated into practice and more evaluated. Evidence supports pharmacists' interventions on evaluation of patient education and dosing, but there is conflicting evidence regarding pharmacists' impact on adherence after 3 months of therapy.^9,10 In a larger VA study of the impact of dabigatran adherence on patient-centered outcomes, patients were mostly nonadherent to prescribed dosing.¹¹ These studies support the need for improved adherence in patients prescribed DOACs and the need for further investigation of pharmacists' roles in improving patient outcomes.

Methods

This single-center, retrospective anticoagulant-use evaluation covered 2 study periods between November 1, 2011 and October 31, 2013. Study approval was obtained from the institutional review board of the Medical University of South Carolina and the research and development committee of RHJVAMC. The study population consisted of veterans who had a diagnosis of AF and received at least 3 outpatient prescription fills of a 30-day supply of dabigatran at RHJVAMC during either or both of the study periods. Patients were excluded if they were pregnant or planning to become pregnant or were incarcerated at any time during the study period. Dabigatran was selected because it was the first DOAC added to the local VA formulary before the start of this study.

Patients who met the inclusion criteria were separated into 2 groups based on the dates of their prescription fills. The precentralization group included patients treated by primary care pharmacists from November 1, 2011 to October 31, 2012; the postcentralization group included patients treated by anticoagulation clinical pharmacy specialists from November 1, 2012 to October 31, 2013. In each group, patients were followed for 1 year during their respective study period. For analysis, patients were included in both study periods if they received at least 3 fills of dabigatran during each period.

Medication possession ratio (MPR), which was used to measure the primary endpoint of adherence, is defined as the proportion of days a patient had dabigatran. The MPR denominator is the total number of days between the first and last prescription refill dates within the 52-week study period; the numerator is calculated by summing the days' supply for all but the last filling of the medication during each respective period. Nonadherence was defined as an MPR < 0.8 (or 80%), which has been used to define poor adherence in the literature.¹² The authors calculated all patients' mean MPRs and compared them to determine statistical significance by repeated-measures linear regression. Descriptive statistics on proportion of patients in each study group with MPR < 0.8 were examined. Last, the authors performed a comparative subanalysis of median MPRs to determine whether there was an adherence difference between patients initially started on dabigatran at RHJVAMC and patients who were started on dabigatran before receiving it at RHJVAMC.

The secondary focus of this study was safety outcomes, including any bleeding event or thromboembolism within either study period. A bleeding event was defined as any major or minor bleeding event recognized through ICD-9 codes or any bleeding recorded in the patient's chart and noted during chart review, as well as any serum hemoglobin (Hgb) level decrease of ≥ to 2 g/dL during the study period. Thromboembolism was defined as a thromboembolism recognized through ICD-9 codes or any thromboembolism noted during chart review. Descriptive statistics were reported for this outcome, and a chi-square test was used to compare bleeding events between groups to determine significance.

The tertiary focus of this study was clinical efficiency as determined by number of primary care pharmacist visits during each study period. Primary care pharmacist visits were included for all primary care pharmacists in primary care clinics at the main hospital and in all 6 CBOCs.
For statistical analysis α was set at 0.05, and P < .05 was considered statistically significant. SAS Enterprise Guide software (Cary, North Carolina) was used for all statistical analyses.

Results

An initial data pull was completed from the RHJVAMC prescription records database for patients who had ≥ 3 prescriptions of dabigatran filled for treatment of AF during the study period, which yielded 65 unique patients. There were 34 patients in the precentralization group and 55 patients in the postcentralization group. Twenty-four unique patients were included in both study groups.

Mean MPR was 1.01 (range, 0.59-1.41) for the precentralization study period and 0.96 (range, 0.33-1.36) for the postcentralization period (Table 1). The difference was not statistically significant (P = .91). Number of patients considered nonadherent (MPR < 0.8) was 3 (8.82%) in the precentralization group and 8 (14.6%) in the postcentralization group.

The primary endpoint subanalysis compared the median MPRs for the patients initially started on dabigatran at RHJVAMC (de novo starts) and the patients who were started on dabigatran before receiving it at RHJVAMC (prior starts). In each group, number and percentage of patients determined to be nonadherent by MPR were evaluated as well. De novo patients received initial assessment, counseling, and a dabigatran prescription from RHJVAMC pharmacists before or during the study period, and prior patients were initially prescribed dabigatran at another VA facility or at a non-VA facility (Table 2).

Regarding safety outcomes (secondary endpoint), a bleeding event was identified in 6 (17.7%) of the precentralization patients and 7 (12.7%) of the postcentralization patients. Of the 6 precentralization events, 1 was a case of hemoptysis, 1 was a hematoma on the forehead, 1 was a lower gastrointestinal bleed (unconfirmed), 1 was retinal hemorrhaging (noted by ophthalmologist), and 2 were serum Hgb level decreases of more than 2 g/dL (neither patient required transfusion of packed red blood cells). Of the 7 postcentralization events, 1 was persistent hematochezia caused by hemorrhoids, 1 was hematuria, 1 was a hematoma, 1 was an upper gastrointestinal bleed (required blood transfusion), and 4 were serum Hgb level decreases of more than 2 g/dL (1 of the 4 required transfusion). No precentralization patient had any evidence of thromboembolism during the study period; 1 postcentralization patient had a superficial venous thromboembolism near a hematoma on the elbow.

Discussion

In this single-center, retrospective medication-use evaluation, the authors found a high rate of adherence to dabigatran before and after centralization of outpatient DOAC management by pharmacists. There was no statistically significant difference in bleeding events between the study periods, but primary care pharmacist visits increased by 108% from precentralization to postcentralization. Although the primary outcome findings did not refute the study's null hypothesis, results support implementing centralized pharmacist DOAC management to maintain a high rate of adherence and a low incidence of adverse outcomes and providing more primary care pharmacist services to increase access to care for other chronic diseases.  

Although there was no statistically significant difference in adherence rates between study periods, the 2 groups' rates were higher than the national average of 72%, as calculated by the proportion-of-days-covered (PDC) equation (median, 74%) in a 2015 large-scale study of site-level adherence in more than 5,000 VA patients.¹³ The authors' findings support that study's significant finding of a high rate of adherence to pharmacist-provided dabigatran treatment. This study's adherence rate also was higher than the median PDC rate reported in a 2014 study that focused on dabigatran adherence: 94% (mean, 84%; SD, 22%).¹¹  

The RHJVAMC follows national VA guidance on pharmacist follow-up for patients who receive DOACs. This follow-up focuses on frequent counseling over the first 6 months of de novo DOAC treatment and on monitoring and assessing adherence and AEs. Although there is less laboratory monitoring for DOAC treatment than for treatment with vitamin K antagonists (eg, warfarin), telephone monitoring as described in this study has been associated with a high adherence rate and minimization of AEs. The 2014 study with the 94% median PDC rate also showed an association of decreased adherence and increased harm, including combined all-cause mortality and stroke (hazard ratio, 1.13; 95% confidence interval [CI], 1.07-1.19 per 10% decrease in PDC rate).¹¹  

This study's subanalysis revealed no difference in adherence between patients initially started on dabigatran at RHJVAMC and patients who were started on dabigatran before receiving it at RHJVAMC. Each group had a high rate of adherence. Shore and colleagues found that most of the VA sites they surveyed (22/41) had anticoagulation clinics monitoring patients who were prescribed dabigatran.¹³ Pharmacist-led monitoring of adherence and AEs led to increased adherence to dabigatran treatment (relative risk, 1.25; 95% CI, 1.11-1.41), which was the standard of care at RHJVAMC throughout their entire study. Many of these factors may explain the very high rate of adherence found in the present study, specifically in comparison to previously reported national averages.  

In addition, the authors found no statistically significant difference in bleeding outcomes between the precentralization and postcentralization groups. Their incidence of bleeding was similar to the 16.6% rate reported in the package insert for dabigatran.¹⁴ Furthermore, the safety outcomes were similar for both groups in this study, which may be attributable to the quality of patient care provided by all RHJVAMC pharmacists, particularly in the setting of dabigatran management.  

Many studies have found an association between dabigatran use and an increased rate of bleeding, particularly gastrointestinal, as demonstrated in several patients in this study. Evidence of these clinically significant AEs further supports pharmacists' close monitoring to detect these AEs and working with patients' providers to determine whether an alternative anticoagulant should be used.

A significant finding of this study regarding centralization of DOAC management by pharmacists was the increased number of primary care pharmacist visits. By streamlining all anticoagulant services to anticoagulation clinical pharmacy specialists, primary care pharmacists were able to care for more veterans and increase access to care without adding staff. The centralized anticoagulation pharmacists were volunteers who held other positions within the department; they did not have to be replaced when they became anticoagulation providers. This workload reallocation helped the RHJVAMC pharmacy department increase access to care.  

Limitations

This study had several potential limitations. First, MPR, a widely studied common tool for assessing adherence, has been criticized for often being imprecise when used with short study periods.¹² Another commonly used adherence measure is PDC rate, which has been reported in several large-scale studies of dabigatran therapy. The authors selected MPR for the present study because MPR calculation is more practical in the patient population and because MPR and PDC rate are predicted to yield similar results in assessments of adherence to a single medication.¹² It also should be noted that both MPR and PDC rate are surrogate markers for adherence and assume adherence based on the availability of medication to the patient. Assessing adherence in a retrospective study is a challenge, as more reliable adherence assessment--for example, with use of pill counts or blister packs--is not possible. This study's retrospective design was another potential limitation, as an active intervention was not used.

In addition, this study had a small sample, likely attributable to the addition of dabigatran to the VA national formulary just months before the start of the study period. Furthermore, this study was not powered to detect significant differences in safety or efficacy outcomes. Other potential study limitations included having national VA guidance regarding follow-up periods and dabigatran prescription quantity limits during both study periods. Also, there was some potential for pharmacist-initiated refills at follow-up visits, which could falsely increase MPR. Last, the study analyzed only 1 DOAC and not the entire class of medications.  

Conclusion

Centralizing DOAC management by clinical pharmacy specialists at a single VA facility helped maintain high rates of dabigatran adherence, above the national average, and low rates of adverse outcomes were maintained in both study groups. In addition, centralization of anticoagulation services improved access to care through an increase in primary care pharmacist visits without the addition of staff. Centralization of DOAC management by pharmacists is a viable option for maintaining high rates of adherence and low rates of adverse outcomes in facilities where the goal is to achieve clinical efficiency.

In the U.S. about 2.7 to 6.1 million people have atrial fibrillation (AF).¹ This condition affects the rhythm of the heart, causes blood in the heart to become stagnant, and puts patients at high risk for developing a systemic embolism, particularly a stroke.1 Recent studies have shown that AF accounts for at least 15% of all strokes in the U.S. and 36% of strokes in people aged > 80 years.²

For patients aged > 60 years, the gold standard of long-term anticoagulation for reducing the risk of stroke has been oral vitamin K antagonist (warfarin) therapy.² Although overwhelming evidence exists that supports the use of warfarin in these patients, warfarin is a narrow therapeutic index medication that requires frequent laboratory monitoring of international normalized ratio (INR) for dose titration guidance. There is also strong evidence that pharmacist-run anticoagulation clinics have improved patient-centered outcomes in patients prescribed warfarin.^3-5

Direct oral anticoagulants (DOACs) are recently approved oral medications used as alternatives to warfarin for anticoagulation in AF. Direct oral anticoagulants do not require INR monitoring or any laboratory test for efficacy. In 2010, the FDA approved the first DOAC, dabigatran, for use in patients with AF. In 2011, rivaroxaban received approval for the same indication. One potential drawback of these new agents relative to warfarin is the lack of availability of a reversal agent that can be used in the event of a life-threatening bleeding event. Dabigatran is the only DOAC with an FDA-approved available reversal agent. In both 2011 and 2012, dabigatran, warfarin, and other anticoagulants topped the Institute for Safe Medicine Practice list of suspect drugs related to adverse events (AEs). These data prompted the Joint Commission to incorporate anticoagulation into the 2017 National Hospital Patient Safety Goals to improve patient outcomes and reduce harm from use of anticoagulants.⁶  

In early 2011, the VHA produced national guidance on the treatment of patients who receive DOACs; this guidance was updated most recently in September 2016.⁷ Patients who were receiving DOACs at the Ralph H. Johnson VAMC (RHJVAMC) were initially monitored by 12 primary care pharmacists at the main hospital or at community-based outpatient clinics (CBOCs). Ambulatory care pharmacists at RHJVAMC work under a scope of practice to prescribe and adjust certain classes of medications to provide the highest level of care to more than 65,000 veterans in South Carolina and Georgia. Historically at RHJVAMC, warfarin has been the anticoagulant most commonly used for AF, though dabigatran and rivaroxaban have gained in popularity after being added to the national VA formulary.  

In November 2012, for better monitoring of patient outcomes, improved efficiency of the primary care pharmacist clinics, and increased access to care in these clinics, treatment of patients prescribed DOACs was shifted to a centralized model that involved 3 anticoagulation clinical pharmacy specialists.  

Centralized pharmacy services have a small number of core team members in a specific service for a particular disease, which reduces the number of different pharmacists a patient could talk to for management of a particular condition. Centralized pharmacy services allow for streamlining anticoagulation management to a small group of individual pharmacists considered specialists in anticoagulation. This shift in management to centralized anticoagulation services was supported at RHJVAMC by findings from a study of a pharmacist-run centralized anticoagulation clinic: Patients treated by the centralized clinic were 39% less likely to experience an anticoagulation therapy complication.⁸  

Protocol for dabigatran follow-up and monitoring at RHJVAMC was developed by clinical and supervisory pharmacy staff, to align with national VA guidance. When a provider determines a patient is a candidate for dabigatran, an outpatient consultation is entered for the clinical pharmacy specialist to review the appropriateness of the patient selection for therapy. If the patient is eligible for therapy, the pharmacist contacts the patient to set up an initial visit to confirm selection and to provide the first dabigatran prescription and counseling. For assessments, with specific emphasis on adherence and AE monitoring, the patient is contacted 2 weeks, 1 month, 3 months, and every 6 months after the initial appointment.

Although most of the literature supports pharmacist-managed anticoagulation for patients who receive warfarin, DOACs have become more integrated into practice and more evaluated. Evidence supports pharmacists' interventions on evaluation of patient education and dosing, but there is conflicting evidence regarding pharmacists' impact on adherence after 3 months of therapy.^9,10 In a larger VA study of the impact of dabigatran adherence on patient-centered outcomes, patients were mostly nonadherent to prescribed dosing.¹¹ These studies support the need for improved adherence in patients prescribed DOACs and the need for further investigation of pharmacists' roles in improving patient outcomes.

Methods

This single-center, retrospective anticoagulant-use evaluation covered 2 study periods between November 1, 2011 and October 31, 2013. Study approval was obtained from the institutional review board of the Medical University of South Carolina and the research and development committee of RHJVAMC. The study population consisted of veterans who had a diagnosis of AF and received at least 3 outpatient prescription fills of a 30-day supply of dabigatran at RHJVAMC during either or both of the study periods. Patients were excluded if they were pregnant or planning to become pregnant or were incarcerated at any time during the study period. Dabigatran was selected because it was the first DOAC added to the local VA formulary before the start of this study.

Patients who met the inclusion criteria were separated into 2 groups based on the dates of their prescription fills. The precentralization group included patients treated by primary care pharmacists from November 1, 2011 to October 31, 2012; the postcentralization group included patients treated by anticoagulation clinical pharmacy specialists from November 1, 2012 to October 31, 2013. In each group, patients were followed for 1 year during their respective study period. For analysis, patients were included in both study periods if they received at least 3 fills of dabigatran during each period.

Medication possession ratio (MPR), which was used to measure the primary endpoint of adherence, is defined as the proportion of days a patient had dabigatran. The MPR denominator is the total number of days between the first and last prescription refill dates within the 52-week study period; the numerator is calculated by summing the days' supply for all but the last filling of the medication during each respective period. Nonadherence was defined as an MPR < 0.8 (or 80%), which has been used to define poor adherence in the literature.¹² The authors calculated all patients' mean MPRs and compared them to determine statistical significance by repeated-measures linear regression. Descriptive statistics on proportion of patients in each study group with MPR < 0.8 were examined. Last, the authors performed a comparative subanalysis of median MPRs to determine whether there was an adherence difference between patients initially started on dabigatran at RHJVAMC and patients who were started on dabigatran before receiving it at RHJVAMC.

The secondary focus of this study was safety outcomes, including any bleeding event or thromboembolism within either study period. A bleeding event was defined as any major or minor bleeding event recognized through ICD-9 codes or any bleeding recorded in the patient's chart and noted during chart review, as well as any serum hemoglobin (Hgb) level decrease of ≥ to 2 g/dL during the study period. Thromboembolism was defined as a thromboembolism recognized through ICD-9 codes or any thromboembolism noted during chart review. Descriptive statistics were reported for this outcome, and a chi-square test was used to compare bleeding events between groups to determine significance.

The tertiary focus of this study was clinical efficiency as determined by number of primary care pharmacist visits during each study period. Primary care pharmacist visits were included for all primary care pharmacists in primary care clinics at the main hospital and in all 6 CBOCs.
For statistical analysis α was set at 0.05, and P < .05 was considered statistically significant. SAS Enterprise Guide software (Cary, North Carolina) was used for all statistical analyses.

Results

An initial data pull was completed from the RHJVAMC prescription records database for patients who had ≥ 3 prescriptions of dabigatran filled for treatment of AF during the study period, which yielded 65 unique patients. There were 34 patients in the precentralization group and 55 patients in the postcentralization group. Twenty-four unique patients were included in both study groups.

Mean MPR was 1.01 (range, 0.59-1.41) for the precentralization study period and 0.96 (range, 0.33-1.36) for the postcentralization period (Table 1). The difference was not statistically significant (P = .91). Number of patients considered nonadherent (MPR < 0.8) was 3 (8.82%) in the precentralization group and 8 (14.6%) in the postcentralization group.

The primary endpoint subanalysis compared the median MPRs for the patients initially started on dabigatran at RHJVAMC (de novo starts) and the patients who were started on dabigatran before receiving it at RHJVAMC (prior starts). In each group, number and percentage of patients determined to be nonadherent by MPR were evaluated as well. De novo patients received initial assessment, counseling, and a dabigatran prescription from RHJVAMC pharmacists before or during the study period, and prior patients were initially prescribed dabigatran at another VA facility or at a non-VA facility (Table 2).

Regarding safety outcomes (secondary endpoint), a bleeding event was identified in 6 (17.7%) of the precentralization patients and 7 (12.7%) of the postcentralization patients. Of the 6 precentralization events, 1 was a case of hemoptysis, 1 was a hematoma on the forehead, 1 was a lower gastrointestinal bleed (unconfirmed), 1 was retinal hemorrhaging (noted by ophthalmologist), and 2 were serum Hgb level decreases of more than 2 g/dL (neither patient required transfusion of packed red blood cells). Of the 7 postcentralization events, 1 was persistent hematochezia caused by hemorrhoids, 1 was hematuria, 1 was a hematoma, 1 was an upper gastrointestinal bleed (required blood transfusion), and 4 were serum Hgb level decreases of more than 2 g/dL (1 of the 4 required transfusion). No precentralization patient had any evidence of thromboembolism during the study period; 1 postcentralization patient had a superficial venous thromboembolism near a hematoma on the elbow.

Discussion

In this single-center, retrospective medication-use evaluation, the authors found a high rate of adherence to dabigatran before and after centralization of outpatient DOAC management by pharmacists. There was no statistically significant difference in bleeding events between the study periods, but primary care pharmacist visits increased by 108% from precentralization to postcentralization. Although the primary outcome findings did not refute the study's null hypothesis, results support implementing centralized pharmacist DOAC management to maintain a high rate of adherence and a low incidence of adverse outcomes and providing more primary care pharmacist services to increase access to care for other chronic diseases.  

Although there was no statistically significant difference in adherence rates between study periods, the 2 groups' rates were higher than the national average of 72%, as calculated by the proportion-of-days-covered (PDC) equation (median, 74%) in a 2015 large-scale study of site-level adherence in more than 5,000 VA patients.¹³ The authors' findings support that study's significant finding of a high rate of adherence to pharmacist-provided dabigatran treatment. This study's adherence rate also was higher than the median PDC rate reported in a 2014 study that focused on dabigatran adherence: 94% (mean, 84%; SD, 22%).¹¹  

The RHJVAMC follows national VA guidance on pharmacist follow-up for patients who receive DOACs. This follow-up focuses on frequent counseling over the first 6 months of de novo DOAC treatment and on monitoring and assessing adherence and AEs. Although there is less laboratory monitoring for DOAC treatment than for treatment with vitamin K antagonists (eg, warfarin), telephone monitoring as described in this study has been associated with a high adherence rate and minimization of AEs. The 2014 study with the 94% median PDC rate also showed an association of decreased adherence and increased harm, including combined all-cause mortality and stroke (hazard ratio, 1.13; 95% confidence interval [CI], 1.07-1.19 per 10% decrease in PDC rate).¹¹  

This study's subanalysis revealed no difference in adherence between patients initially started on dabigatran at RHJVAMC and patients who were started on dabigatran before receiving it at RHJVAMC. Each group had a high rate of adherence. Shore and colleagues found that most of the VA sites they surveyed (22/41) had anticoagulation clinics monitoring patients who were prescribed dabigatran.¹³ Pharmacist-led monitoring of adherence and AEs led to increased adherence to dabigatran treatment (relative risk, 1.25; 95% CI, 1.11-1.41), which was the standard of care at RHJVAMC throughout their entire study. Many of these factors may explain the very high rate of adherence found in the present study, specifically in comparison to previously reported national averages.  

In addition, the authors found no statistically significant difference in bleeding outcomes between the precentralization and postcentralization groups. Their incidence of bleeding was similar to the 16.6% rate reported in the package insert for dabigatran.¹⁴ Furthermore, the safety outcomes were similar for both groups in this study, which may be attributable to the quality of patient care provided by all RHJVAMC pharmacists, particularly in the setting of dabigatran management.  

Many studies have found an association between dabigatran use and an increased rate of bleeding, particularly gastrointestinal, as demonstrated in several patients in this study. Evidence of these clinically significant AEs further supports pharmacists' close monitoring to detect these AEs and working with patients' providers to determine whether an alternative anticoagulant should be used.

A significant finding of this study regarding centralization of DOAC management by pharmacists was the increased number of primary care pharmacist visits. By streamlining all anticoagulant services to anticoagulation clinical pharmacy specialists, primary care pharmacists were able to care for more veterans and increase access to care without adding staff. The centralized anticoagulation pharmacists were volunteers who held other positions within the department; they did not have to be replaced when they became anticoagulation providers. This workload reallocation helped the RHJVAMC pharmacy department increase access to care.  

Limitations

This study had several potential limitations. First, MPR, a widely studied common tool for assessing adherence, has been criticized for often being imprecise when used with short study periods.¹² Another commonly used adherence measure is PDC rate, which has been reported in several large-scale studies of dabigatran therapy. The authors selected MPR for the present study because MPR calculation is more practical in the patient population and because MPR and PDC rate are predicted to yield similar results in assessments of adherence to a single medication.¹² It also should be noted that both MPR and PDC rate are surrogate markers for adherence and assume adherence based on the availability of medication to the patient. Assessing adherence in a retrospective study is a challenge, as more reliable adherence assessment--for example, with use of pill counts or blister packs--is not possible. This study's retrospective design was another potential limitation, as an active intervention was not used.

In addition, this study had a small sample, likely attributable to the addition of dabigatran to the VA national formulary just months before the start of the study period. Furthermore, this study was not powered to detect significant differences in safety or efficacy outcomes. Other potential study limitations included having national VA guidance regarding follow-up periods and dabigatran prescription quantity limits during both study periods. Also, there was some potential for pharmacist-initiated refills at follow-up visits, which could falsely increase MPR. Last, the study analyzed only 1 DOAC and not the entire class of medications.  

Conclusion

Centralizing DOAC management by clinical pharmacy specialists at a single VA facility helped maintain high rates of dabigatran adherence, above the national average, and low rates of adverse outcomes were maintained in both study groups. In addition, centralization of anticoagulation services improved access to care through an increase in primary care pharmacist visits without the addition of staff. Centralization of DOAC management by pharmacists is a viable option for maintaining high rates of adherence and low rates of adverse outcomes in facilities where the goal is to achieve clinical efficiency.

In the U.S. about 2.7 to 6.1 million people have atrial fibrillation (AF).¹ This condition affects the rhythm of the heart, causes blood in the heart to become stagnant, and puts patients at high risk for developing a systemic embolism, particularly a stroke.1 Recent studies have shown that AF accounts for at least 15% of all strokes in the U.S. and 36% of strokes in people aged > 80 years.²

For patients aged > 60 years, the gold standard of long-term anticoagulation for reducing the risk of stroke has been oral vitamin K antagonist (warfarin) therapy.² Although overwhelming evidence exists that supports the use of warfarin in these patients, warfarin is a narrow therapeutic index medication that requires frequent laboratory monitoring of international normalized ratio (INR) for dose titration guidance. There is also strong evidence that pharmacist-run anticoagulation clinics have improved patient-centered outcomes in patients prescribed warfarin.^3-5

Direct oral anticoagulants (DOACs) are recently approved oral medications used as alternatives to warfarin for anticoagulation in AF. Direct oral anticoagulants do not require INR monitoring or any laboratory test for efficacy. In 2010, the FDA approved the first DOAC, dabigatran, for use in patients with AF. In 2011, rivaroxaban received approval for the same indication. One potential drawback of these new agents relative to warfarin is the lack of availability of a reversal agent that can be used in the event of a life-threatening bleeding event. Dabigatran is the only DOAC with an FDA-approved available reversal agent. In both 2011 and 2012, dabigatran, warfarin, and other anticoagulants topped the Institute for Safe Medicine Practice list of suspect drugs related to adverse events (AEs). These data prompted the Joint Commission to incorporate anticoagulation into the 2017 National Hospital Patient Safety Goals to improve patient outcomes and reduce harm from use of anticoagulants.⁶  

In early 2011, the VHA produced national guidance on the treatment of patients who receive DOACs; this guidance was updated most recently in September 2016.⁷ Patients who were receiving DOACs at the Ralph H. Johnson VAMC (RHJVAMC) were initially monitored by 12 primary care pharmacists at the main hospital or at community-based outpatient clinics (CBOCs). Ambulatory care pharmacists at RHJVAMC work under a scope of practice to prescribe and adjust certain classes of medications to provide the highest level of care to more than 65,000 veterans in South Carolina and Georgia. Historically at RHJVAMC, warfarin has been the anticoagulant most commonly used for AF, though dabigatran and rivaroxaban have gained in popularity after being added to the national VA formulary.  

In November 2012, for better monitoring of patient outcomes, improved efficiency of the primary care pharmacist clinics, and increased access to care in these clinics, treatment of patients prescribed DOACs was shifted to a centralized model that involved 3 anticoagulation clinical pharmacy specialists.  

Centralized pharmacy services have a small number of core team members in a specific service for a particular disease, which reduces the number of different pharmacists a patient could talk to for management of a particular condition. Centralized pharmacy services allow for streamlining anticoagulation management to a small group of individual pharmacists considered specialists in anticoagulation. This shift in management to centralized anticoagulation services was supported at RHJVAMC by findings from a study of a pharmacist-run centralized anticoagulation clinic: Patients treated by the centralized clinic were 39% less likely to experience an anticoagulation therapy complication.⁸  

Protocol for dabigatran follow-up and monitoring at RHJVAMC was developed by clinical and supervisory pharmacy staff, to align with national VA guidance. When a provider determines a patient is a candidate for dabigatran, an outpatient consultation is entered for the clinical pharmacy specialist to review the appropriateness of the patient selection for therapy. If the patient is eligible for therapy, the pharmacist contacts the patient to set up an initial visit to confirm selection and to provide the first dabigatran prescription and counseling. For assessments, with specific emphasis on adherence and AE monitoring, the patient is contacted 2 weeks, 1 month, 3 months, and every 6 months after the initial appointment.

Although most of the literature supports pharmacist-managed anticoagulation for patients who receive warfarin, DOACs have become more integrated into practice and more evaluated. Evidence supports pharmacists' interventions on evaluation of patient education and dosing, but there is conflicting evidence regarding pharmacists' impact on adherence after 3 months of therapy.^9,10 In a larger VA study of the impact of dabigatran adherence on patient-centered outcomes, patients were mostly nonadherent to prescribed dosing.¹¹ These studies support the need for improved adherence in patients prescribed DOACs and the need for further investigation of pharmacists' roles in improving patient outcomes.

Methods

This single-center, retrospective anticoagulant-use evaluation covered 2 study periods between November 1, 2011 and October 31, 2013. Study approval was obtained from the institutional review board of the Medical University of South Carolina and the research and development committee of RHJVAMC. The study population consisted of veterans who had a diagnosis of AF and received at least 3 outpatient prescription fills of a 30-day supply of dabigatran at RHJVAMC during either or both of the study periods. Patients were excluded if they were pregnant or planning to become pregnant or were incarcerated at any time during the study period. Dabigatran was selected because it was the first DOAC added to the local VA formulary before the start of this study.

Patients who met the inclusion criteria were separated into 2 groups based on the dates of their prescription fills. The precentralization group included patients treated by primary care pharmacists from November 1, 2011 to October 31, 2012; the postcentralization group included patients treated by anticoagulation clinical pharmacy specialists from November 1, 2012 to October 31, 2013. In each group, patients were followed for 1 year during their respective study period. For analysis, patients were included in both study periods if they received at least 3 fills of dabigatran during each period.

Medication possession ratio (MPR), which was used to measure the primary endpoint of adherence, is defined as the proportion of days a patient had dabigatran. The MPR denominator is the total number of days between the first and last prescription refill dates within the 52-week study period; the numerator is calculated by summing the days' supply for all but the last filling of the medication during each respective period. Nonadherence was defined as an MPR < 0.8 (or 80%), which has been used to define poor adherence in the literature.¹² The authors calculated all patients' mean MPRs and compared them to determine statistical significance by repeated-measures linear regression. Descriptive statistics on proportion of patients in each study group with MPR < 0.8 were examined. Last, the authors performed a comparative subanalysis of median MPRs to determine whether there was an adherence difference between patients initially started on dabigatran at RHJVAMC and patients who were started on dabigatran before receiving it at RHJVAMC.

The secondary focus of this study was safety outcomes, including any bleeding event or thromboembolism within either study period. A bleeding event was defined as any major or minor bleeding event recognized through ICD-9 codes or any bleeding recorded in the patient's chart and noted during chart review, as well as any serum hemoglobin (Hgb) level decrease of ≥ to 2 g/dL during the study period. Thromboembolism was defined as a thromboembolism recognized through ICD-9 codes or any thromboembolism noted during chart review. Descriptive statistics were reported for this outcome, and a chi-square test was used to compare bleeding events between groups to determine significance.

The tertiary focus of this study was clinical efficiency as determined by number of primary care pharmacist visits during each study period. Primary care pharmacist visits were included for all primary care pharmacists in primary care clinics at the main hospital and in all 6 CBOCs.
For statistical analysis α was set at 0.05, and P < .05 was considered statistically significant. SAS Enterprise Guide software (Cary, North Carolina) was used for all statistical analyses.

Results

An initial data pull was completed from the RHJVAMC prescription records database for patients who had ≥ 3 prescriptions of dabigatran filled for treatment of AF during the study period, which yielded 65 unique patients. There were 34 patients in the precentralization group and 55 patients in the postcentralization group. Twenty-four unique patients were included in both study groups.

Mean MPR was 1.01 (range, 0.59-1.41) for the precentralization study period and 0.96 (range, 0.33-1.36) for the postcentralization period (Table 1). The difference was not statistically significant (P = .91). Number of patients considered nonadherent (MPR < 0.8) was 3 (8.82%) in the precentralization group and 8 (14.6%) in the postcentralization group.

The primary endpoint subanalysis compared the median MPRs for the patients initially started on dabigatran at RHJVAMC (de novo starts) and the patients who were started on dabigatran before receiving it at RHJVAMC (prior starts). In each group, number and percentage of patients determined to be nonadherent by MPR were evaluated as well. De novo patients received initial assessment, counseling, and a dabigatran prescription from RHJVAMC pharmacists before or during the study period, and prior patients were initially prescribed dabigatran at another VA facility or at a non-VA facility (Table 2).

Regarding safety outcomes (secondary endpoint), a bleeding event was identified in 6 (17.7%) of the precentralization patients and 7 (12.7%) of the postcentralization patients. Of the 6 precentralization events, 1 was a case of hemoptysis, 1 was a hematoma on the forehead, 1 was a lower gastrointestinal bleed (unconfirmed), 1 was retinal hemorrhaging (noted by ophthalmologist), and 2 were serum Hgb level decreases of more than 2 g/dL (neither patient required transfusion of packed red blood cells). Of the 7 postcentralization events, 1 was persistent hematochezia caused by hemorrhoids, 1 was hematuria, 1 was a hematoma, 1 was an upper gastrointestinal bleed (required blood transfusion), and 4 were serum Hgb level decreases of more than 2 g/dL (1 of the 4 required transfusion). No precentralization patient had any evidence of thromboembolism during the study period; 1 postcentralization patient had a superficial venous thromboembolism near a hematoma on the elbow.

Discussion

In this single-center, retrospective medication-use evaluation, the authors found a high rate of adherence to dabigatran before and after centralization of outpatient DOAC management by pharmacists. There was no statistically significant difference in bleeding events between the study periods, but primary care pharmacist visits increased by 108% from precentralization to postcentralization. Although the primary outcome findings did not refute the study's null hypothesis, results support implementing centralized pharmacist DOAC management to maintain a high rate of adherence and a low incidence of adverse outcomes and providing more primary care pharmacist services to increase access to care for other chronic diseases.  

Although there was no statistically significant difference in adherence rates between study periods, the 2 groups' rates were higher than the national average of 72%, as calculated by the proportion-of-days-covered (PDC) equation (median, 74%) in a 2015 large-scale study of site-level adherence in more than 5,000 VA patients.¹³ The authors' findings support that study's significant finding of a high rate of adherence to pharmacist-provided dabigatran treatment. This study's adherence rate also was higher than the median PDC rate reported in a 2014 study that focused on dabigatran adherence: 94% (mean, 84%; SD, 22%).¹¹  

The RHJVAMC follows national VA guidance on pharmacist follow-up for patients who receive DOACs. This follow-up focuses on frequent counseling over the first 6 months of de novo DOAC treatment and on monitoring and assessing adherence and AEs. Although there is less laboratory monitoring for DOAC treatment than for treatment with vitamin K antagonists (eg, warfarin), telephone monitoring as described in this study has been associated with a high adherence rate and minimization of AEs. The 2014 study with the 94% median PDC rate also showed an association of decreased adherence and increased harm, including combined all-cause mortality and stroke (hazard ratio, 1.13; 95% confidence interval [CI], 1.07-1.19 per 10% decrease in PDC rate).¹¹  

This study's subanalysis revealed no difference in adherence between patients initially started on dabigatran at RHJVAMC and patients who were started on dabigatran before receiving it at RHJVAMC. Each group had a high rate of adherence. Shore and colleagues found that most of the VA sites they surveyed (22/41) had anticoagulation clinics monitoring patients who were prescribed dabigatran.¹³ Pharmacist-led monitoring of adherence and AEs led to increased adherence to dabigatran treatment (relative risk, 1.25; 95% CI, 1.11-1.41), which was the standard of care at RHJVAMC throughout their entire study. Many of these factors may explain the very high rate of adherence found in the present study, specifically in comparison to previously reported national averages.  

In addition, the authors found no statistically significant difference in bleeding outcomes between the precentralization and postcentralization groups. Their incidence of bleeding was similar to the 16.6% rate reported in the package insert for dabigatran.¹⁴ Furthermore, the safety outcomes were similar for both groups in this study, which may be attributable to the quality of patient care provided by all RHJVAMC pharmacists, particularly in the setting of dabigatran management.  

Many studies have found an association between dabigatran use and an increased rate of bleeding, particularly gastrointestinal, as demonstrated in several patients in this study. Evidence of these clinically significant AEs further supports pharmacists' close monitoring to detect these AEs and working with patients' providers to determine whether an alternative anticoagulant should be used.

A significant finding of this study regarding centralization of DOAC management by pharmacists was the increased number of primary care pharmacist visits. By streamlining all anticoagulant services to anticoagulation clinical pharmacy specialists, primary care pharmacists were able to care for more veterans and increase access to care without adding staff. The centralized anticoagulation pharmacists were volunteers who held other positions within the department; they did not have to be replaced when they became anticoagulation providers. This workload reallocation helped the RHJVAMC pharmacy department increase access to care.  

Limitations

This study had several potential limitations. First, MPR, a widely studied common tool for assessing adherence, has been criticized for often being imprecise when used with short study periods.¹² Another commonly used adherence measure is PDC rate, which has been reported in several large-scale studies of dabigatran therapy. The authors selected MPR for the present study because MPR calculation is more practical in the patient population and because MPR and PDC rate are predicted to yield similar results in assessments of adherence to a single medication.¹² It also should be noted that both MPR and PDC rate are surrogate markers for adherence and assume adherence based on the availability of medication to the patient. Assessing adherence in a retrospective study is a challenge, as more reliable adherence assessment--for example, with use of pill counts or blister packs--is not possible. This study's retrospective design was another potential limitation, as an active intervention was not used.

In addition, this study had a small sample, likely attributable to the addition of dabigatran to the VA national formulary just months before the start of the study period. Furthermore, this study was not powered to detect significant differences in safety or efficacy outcomes. Other potential study limitations included having national VA guidance regarding follow-up periods and dabigatran prescription quantity limits during both study periods. Also, there was some potential for pharmacist-initiated refills at follow-up visits, which could falsely increase MPR. Last, the study analyzed only 1 DOAC and not the entire class of medications.  

Conclusion

Centralizing DOAC management by clinical pharmacy specialists at a single VA facility helped maintain high rates of dabigatran adherence, above the national average, and low rates of adverse outcomes were maintained in both study groups. In addition, centralization of anticoagulation services improved access to care through an increase in primary care pharmacist visits without the addition of staff. Centralization of DOAC management by pharmacists is a viable option for maintaining high rates of adherence and low rates of adverse outcomes in facilities where the goal is to achieve clinical efficiency.

Opioid Abuse-Deterrent Formulations

The meaning of the term abuse-deterrent is often misunderstood to mean abuse-proof. The FDA defines abuse-deterrent properties as those properties expected to meaningfully deter abuse even if they do not fully prevent abuse. Abuse-deterrent properties make certain types of abuse, such as crushing in order to snort or dissolving in order to inject, more difficult or less rewarding. However, this does not mean that the product is impossible to abuse or that these properties will necessarily prevent addiction, overdose, or death.

Of note, currently marketed abuse-deterrent formulation technologies do not effectively deter one of the most common forms of opioid abuse—simply swallowing a number of intact tablets or capsules. Abuse-deterrent opioids do not reduce the risk for opioid addiction, and they carry the same warnings about the risk for addiction as do conventional opioids.

Abuse and Misuse Data

The FDA is encouraging pharmaceutical industry efforts to develop pain medicines that are more difficult to abuse and to prioritize the need for data and study methods that will help evaluate the impact of abuse-deterrent opioids on misuse and abuse in the community. To collect this important information, the FDA requires that all companies that have brand-name opioids with labeling describing abuse-deterrent properties conduct postmarketing studies to determine the impact of abuse-deterrent formulation technologies in the real world. Each company is given a time line to which they must adhere. These types of studies take several years to conduct and analyze. Data collected will include the amount prescribed for each product; adverse events related to the use, abuse, and misuse of the products; and epidemiologic data on the rates of abuse and misuse and their consequences (addiction, overdose, and death). These studies should allow the FDA to assess the impact in the community, if any, attributable to the abuse-deterrent properties.

The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies ar

Key Points for Practitioners

The FDA’s work to facilitate the safe use of opioids is taking place within a larger policy framework aimed at addressing opioid abuse while ensuring appropriate access to pain treatment. The FDA has undertaken several efforts helpful to clinicians. The FDA’s Extended-Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (ER/LA REMS) Program is required for all companies who make these products. The program’s goal is to reduce serious adverse outcomes of inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics while maintaining patient access to pain medications. Adverse outcomes of concern include addiction, unintentional overdose, and death.

As part of the REMS, all ER/LA opioid analgesic pharmaceutical companies must provide education for prescribers of their medications through accredited continuing education activities that are supported by independent educational grants. Companies must also provide information that prescribers can use when counseling patients about the risks and benefits associated with ER/LA opioid analgesic use.

The FDA has developed core messages that are communicated to prescribers in the Blueprint for Prescriber Education. The Blueprint is directed to prescribers of ER/LA opioid analgesics but also may be relevant for other health care professionals (eg, pharmacists). Companies involved in the ER/LA Opioid Analgesics REMS Program have collaborated to implement a single shared REMS. This group provides a list of REMS-compliant continuing education activities, which can be found at http://www.er-la-opioidrems.com.

It is important for practitioners to understand that all currently approved abuse-deterrent opioid products still can be abused, and as scheduled controlled substances, they are addictive. The abuse-deterrent properties are expected to deter but do not wholly prevent abuse. Because in the end opioid medications must be able to deliver the opioid to the patient, there probably always will be potential for abuse of these products. Consequently, practitioners should counsel their patients on the following:

• Keep medicines in a secure location out of the reach and out of sight of children and pets. Put away medicines after every use. Accidental exposure to medicine in the home is a major source of unintentional poisonings in the U.S.
• If medicines are no longer needed, dispose of them properly. Disposing of all unused opioid analgesics reduces access to these medications by family members and household guests seeking opioids for abuse.
• The FDA recommends returning most prescription medications through a local or U.S. Drug Enforcement Administration (DEA)-sponsored take-back program or DEA-authorized collector. For opioid analgesics, the FDA recommends immediate removal from the home by flushing them down the toilet or sink.

Opioids Action Plan

In February 2016, FDA Commissioner Robert Califf (then the deputy commissioner for medical products and tobacco) announced the FDA Opioids Action Plan. The plan focuses on policies aimed at reversing the opioid epidemic while still providing patients in pain access to effective pain relief. The FDA actions include:

• Convening an expert advisory committee before approving any new drug application for an opioid that does not have abuse-deterrent properties;
• Consulting with the Pediatric Advisory Committee about a framework for pediatric opioid labeling before any new labeling is approved;
• Updating the REMS requirements for ER/LA opioid analgesics after considering the advisory committee’s recommendations from a meeting held in May 2016 and reviewing existing requirements;
• Improving access to naloxone (by facilitating the development of an over-the-counter version of naloxone, which is currently available only by prescription, thereby making it more accessible to treat opioid overdose), and medication-assisted treatment options for patients with opioid use disorders; and
• Supporting better pain management options, including alternative, nonaddictive treatments for pain.

The FDA is conducting research on pain measurements for conditions such as chronic low back pain, osteoarthritis, diabetic neuropathy, postherpetic neuralgia, and fibromyalgia. The FDA is also working to support the development of nonopioid options for these patients.

Consistent with the plan, in March 2016, the FDA announced that it was requiring changes to the labeling on immediate-release opioids, including additional warnings and safety information that incorporate elements similar to the ER/LA opioid analgesics labeling. Furthermore, among other steps, the FDA has contracted with the National Academy of Medicine to provide advice on how to incorporate current evidence about the public health impact of opioid use (for patients who are prescribed opioids as well as for nonpatients) into regulatory activities concerning opioids.

The FDA shares the responsibility of keeping patients safe. Working with the health care community and federal and state partners to help reduce opioid misuse and abuse and improve appropriate opioid prescribing while ensuring that patients in pain continue to have appropriate access to opioid analgesics is a top priority for the FDA and part of the targeted approach of the HHS focused on prevention, treatment, and intervention.

Opioid Abuse-Deterrent Formulations

The meaning of the term abuse-deterrent is often misunderstood to mean abuse-proof. The FDA defines abuse-deterrent properties as those properties expected to meaningfully deter abuse even if they do not fully prevent abuse. Abuse-deterrent properties make certain types of abuse, such as crushing in order to snort or dissolving in order to inject, more difficult or less rewarding. However, this does not mean that the product is impossible to abuse or that these properties will necessarily prevent addiction, overdose, or death.

Of note, currently marketed abuse-deterrent formulation technologies do not effectively deter one of the most common forms of opioid abuse—simply swallowing a number of intact tablets or capsules. Abuse-deterrent opioids do not reduce the risk for opioid addiction, and they carry the same warnings about the risk for addiction as do conventional opioids.

Abuse and Misuse Data

The FDA is encouraging pharmaceutical industry efforts to develop pain medicines that are more difficult to abuse and to prioritize the need for data and study methods that will help evaluate the impact of abuse-deterrent opioids on misuse and abuse in the community. To collect this important information, the FDA requires that all companies that have brand-name opioids with labeling describing abuse-deterrent properties conduct postmarketing studies to determine the impact of abuse-deterrent formulation technologies in the real world. Each company is given a time line to which they must adhere. These types of studies take several years to conduct and analyze. Data collected will include the amount prescribed for each product; adverse events related to the use, abuse, and misuse of the products; and epidemiologic data on the rates of abuse and misuse and their consequences (addiction, overdose, and death). These studies should allow the FDA to assess the impact in the community, if any, attributable to the abuse-deterrent properties.

The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies ar

Key Points for Practitioners

The FDA’s work to facilitate the safe use of opioids is taking place within a larger policy framework aimed at addressing opioid abuse while ensuring appropriate access to pain treatment. The FDA has undertaken several efforts helpful to clinicians. The FDA’s Extended-Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (ER/LA REMS) Program is required for all companies who make these products. The program’s goal is to reduce serious adverse outcomes of inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics while maintaining patient access to pain medications. Adverse outcomes of concern include addiction, unintentional overdose, and death.

As part of the REMS, all ER/LA opioid analgesic pharmaceutical companies must provide education for prescribers of their medications through accredited continuing education activities that are supported by independent educational grants. Companies must also provide information that prescribers can use when counseling patients about the risks and benefits associated with ER/LA opioid analgesic use.

The FDA has developed core messages that are communicated to prescribers in the Blueprint for Prescriber Education. The Blueprint is directed to prescribers of ER/LA opioid analgesics but also may be relevant for other health care professionals (eg, pharmacists). Companies involved in the ER/LA Opioid Analgesics REMS Program have collaborated to implement a single shared REMS. This group provides a list of REMS-compliant continuing education activities, which can be found at http://www.er-la-opioidrems.com.

It is important for practitioners to understand that all currently approved abuse-deterrent opioid products still can be abused, and as scheduled controlled substances, they are addictive. The abuse-deterrent properties are expected to deter but do not wholly prevent abuse. Because in the end opioid medications must be able to deliver the opioid to the patient, there probably always will be potential for abuse of these products. Consequently, practitioners should counsel their patients on the following:

• Keep medicines in a secure location out of the reach and out of sight of children and pets. Put away medicines after every use. Accidental exposure to medicine in the home is a major source of unintentional poisonings in the U.S.
• If medicines are no longer needed, dispose of them properly. Disposing of all unused opioid analgesics reduces access to these medications by family members and household guests seeking opioids for abuse.
• The FDA recommends returning most prescription medications through a local or U.S. Drug Enforcement Administration (DEA)-sponsored take-back program or DEA-authorized collector. For opioid analgesics, the FDA recommends immediate removal from the home by flushing them down the toilet or sink.

Opioids Action Plan

In February 2016, FDA Commissioner Robert Califf (then the deputy commissioner for medical products and tobacco) announced the FDA Opioids Action Plan. The plan focuses on policies aimed at reversing the opioid epidemic while still providing patients in pain access to effective pain relief. The FDA actions include:

• Convening an expert advisory committee before approving any new drug application for an opioid that does not have abuse-deterrent properties;
• Consulting with the Pediatric Advisory Committee about a framework for pediatric opioid labeling before any new labeling is approved;
• Updating the REMS requirements for ER/LA opioid analgesics after considering the advisory committee’s recommendations from a meeting held in May 2016 and reviewing existing requirements;
• Improving access to naloxone (by facilitating the development of an over-the-counter version of naloxone, which is currently available only by prescription, thereby making it more accessible to treat opioid overdose), and medication-assisted treatment options for patients with opioid use disorders; and
• Supporting better pain management options, including alternative, nonaddictive treatments for pain.

The FDA is conducting research on pain measurements for conditions such as chronic low back pain, osteoarthritis, diabetic neuropathy, postherpetic neuralgia, and fibromyalgia. The FDA is also working to support the development of nonopioid options for these patients.

Consistent with the plan, in March 2016, the FDA announced that it was requiring changes to the labeling on immediate-release opioids, including additional warnings and safety information that incorporate elements similar to the ER/LA opioid analgesics labeling. Furthermore, among other steps, the FDA has contracted with the National Academy of Medicine to provide advice on how to incorporate current evidence about the public health impact of opioid use (for patients who are prescribed opioids as well as for nonpatients) into regulatory activities concerning opioids.

The FDA shares the responsibility of keeping patients safe. Working with the health care community and federal and state partners to help reduce opioid misuse and abuse and improve appropriate opioid prescribing while ensuring that patients in pain continue to have appropriate access to opioid analgesics is a top priority for the FDA and part of the targeted approach of the HHS focused on prevention, treatment, and intervention.

Opioid Abuse-Deterrent Formulations

The meaning of the term abuse-deterrent is often misunderstood to mean abuse-proof. The FDA defines abuse-deterrent properties as those properties expected to meaningfully deter abuse even if they do not fully prevent abuse. Abuse-deterrent properties make certain types of abuse, such as crushing in order to snort or dissolving in order to inject, more difficult or less rewarding. However, this does not mean that the product is impossible to abuse or that these properties will necessarily prevent addiction, overdose, or death.

Of note, currently marketed abuse-deterrent formulation technologies do not effectively deter one of the most common forms of opioid abuse—simply swallowing a number of intact tablets or capsules. Abuse-deterrent opioids do not reduce the risk for opioid addiction, and they carry the same warnings about the risk for addiction as do conventional opioids.

Abuse and Misuse Data

The FDA is encouraging pharmaceutical industry efforts to develop pain medicines that are more difficult to abuse and to prioritize the need for data and study methods that will help evaluate the impact of abuse-deterrent opioids on misuse and abuse in the community. To collect this important information, the FDA requires that all companies that have brand-name opioids with labeling describing abuse-deterrent properties conduct postmarketing studies to determine the impact of abuse-deterrent formulation technologies in the real world. Each company is given a time line to which they must adhere. These types of studies take several years to conduct and analyze. Data collected will include the amount prescribed for each product; adverse events related to the use, abuse, and misuse of the products; and epidemiologic data on the rates of abuse and misuse and their consequences (addiction, overdose, and death). These studies should allow the FDA to assess the impact in the community, if any, attributable to the abuse-deterrent properties.

The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies ar

Key Points for Practitioners

The FDA’s work to facilitate the safe use of opioids is taking place within a larger policy framework aimed at addressing opioid abuse while ensuring appropriate access to pain treatment. The FDA has undertaken several efforts helpful to clinicians. The FDA’s Extended-Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (ER/LA REMS) Program is required for all companies who make these products. The program’s goal is to reduce serious adverse outcomes of inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics while maintaining patient access to pain medications. Adverse outcomes of concern include addiction, unintentional overdose, and death.

As part of the REMS, all ER/LA opioid analgesic pharmaceutical companies must provide education for prescribers of their medications through accredited continuing education activities that are supported by independent educational grants. Companies must also provide information that prescribers can use when counseling patients about the risks and benefits associated with ER/LA opioid analgesic use.

The FDA has developed core messages that are communicated to prescribers in the Blueprint for Prescriber Education. The Blueprint is directed to prescribers of ER/LA opioid analgesics but also may be relevant for other health care professionals (eg, pharmacists). Companies involved in the ER/LA Opioid Analgesics REMS Program have collaborated to implement a single shared REMS. This group provides a list of REMS-compliant continuing education activities, which can be found at http://www.er-la-opioidrems.com.

It is important for practitioners to understand that all currently approved abuse-deterrent opioid products still can be abused, and as scheduled controlled substances, they are addictive. The abuse-deterrent properties are expected to deter but do not wholly prevent abuse. Because in the end opioid medications must be able to deliver the opioid to the patient, there probably always will be potential for abuse of these products. Consequently, practitioners should counsel their patients on the following:

• Keep medicines in a secure location out of the reach and out of sight of children and pets. Put away medicines after every use. Accidental exposure to medicine in the home is a major source of unintentional poisonings in the U.S.
• If medicines are no longer needed, dispose of them properly. Disposing of all unused opioid analgesics reduces access to these medications by family members and household guests seeking opioids for abuse.
• The FDA recommends returning most prescription medications through a local or U.S. Drug Enforcement Administration (DEA)-sponsored take-back program or DEA-authorized collector. For opioid analgesics, the FDA recommends immediate removal from the home by flushing them down the toilet or sink.

Opioids Action Plan

In February 2016, FDA Commissioner Robert Califf (then the deputy commissioner for medical products and tobacco) announced the FDA Opioids Action Plan. The plan focuses on policies aimed at reversing the opioid epidemic while still providing patients in pain access to effective pain relief. The FDA actions include:

• Convening an expert advisory committee before approving any new drug application for an opioid that does not have abuse-deterrent properties;
• Consulting with the Pediatric Advisory Committee about a framework for pediatric opioid labeling before any new labeling is approved;
• Updating the REMS requirements for ER/LA opioid analgesics after considering the advisory committee’s recommendations from a meeting held in May 2016 and reviewing existing requirements;
• Improving access to naloxone (by facilitating the development of an over-the-counter version of naloxone, which is currently available only by prescription, thereby making it more accessible to treat opioid overdose), and medication-assisted treatment options for patients with opioid use disorders; and
• Supporting better pain management options, including alternative, nonaddictive treatments for pain.

The FDA is conducting research on pain measurements for conditions such as chronic low back pain, osteoarthritis, diabetic neuropathy, postherpetic neuralgia, and fibromyalgia. The FDA is also working to support the development of nonopioid options for these patients.

Consistent with the plan, in March 2016, the FDA announced that it was requiring changes to the labeling on immediate-release opioids, including additional warnings and safety information that incorporate elements similar to the ER/LA opioid analgesics labeling. Furthermore, among other steps, the FDA has contracted with the National Academy of Medicine to provide advice on how to incorporate current evidence about the public health impact of opioid use (for patients who are prescribed opioids as well as for nonpatients) into regulatory activities concerning opioids.

The FDA shares the responsibility of keeping patients safe. Working with the health care community and federal and state partners to help reduce opioid misuse and abuse and improve appropriate opioid prescribing while ensuring that patients in pain continue to have appropriate access to opioid analgesics is a top priority for the FDA and part of the targeted approach of the HHS focused on prevention, treatment, and intervention.