PharmD

Febrile neutropenia (FN) is a life-threatening oncologic emergency requiring timely evaluation and treatment. Chemotherapy-induced neutropenia is a major risk for life-threatening infection, and fever may be the only sign.^1,2 Unrecognized fever can progress to sepsis and may result in increased morbidity and mortality. FN is defined as the presence of fever with a single temperature of  ≥ 38.3 °C or a sustained temperature > 38 °C sustained over 1 hour with an absolute neutrophil count (ANC) of < 500 cells/mm³ or < 1000 cells/mm³ and expected to decrease to < 500 within 48 hours.^2,3 It is critical to quickly identify these patients on presentation to the emergency department (ED) and take appropriate steps to initiate treatment as soon as possible. To streamline care, the American Society of Clinical Oncology (ASCO) recommends that laboratory assessments be initiated within 15 minutes of triage and empiric antibiotic therapy be administered within 1 hour.²

In alignment with the Infectious Disease Society of America (IDSA) guidelines, the National Comprehensive Cancer Network (NCCN) highlights the importance of the initial assessment of fever and neutropenia and presents available treatment options for both inpatient and outpatient management of FN.¹ Once patients are identified, the appropriate laboratory tests and physical assessments should be initiated immediately. These tests include a complete blood count with differential, complete metabolic panel (CMP), and blood cultures from 2 separate IV sites.^1-3 The guidelines offer additional suggestions for cultures and radiographic assessments that may be completed based on clinical presentation.

Several available studies provide insight into methods of protocol creation and possible barriers to timely management. Previous research showed that an FN protocol for pediatric oncology patients aimed at antibiotic administration within 1 hour showed significant improvement from 35.0% to 55.4% of patients being treated on time.^3,4 Prescribers became more comfortable in using the protocol, and timing improved as the study progressed. Barriers noted were inconsistent ED triage, rotating ED staff, and limited understanding of the protocol.³ Yoshida and colleagues worked with the same population. Over the course of 1 year, 60% of patients were receiving antibiotics within 1 hour. The mean time decreased from 83 to 65 minutes, which the study investigators noted would continue to decrease with increased protocol comfort and use.⁵ Mattison and colleagues used nursing staff to identify patients with FN and begin antibiotic treatment. On triage, nurses took note of a temperature of > 38 °C or a sepsislike clinical picture that initiated their antibiotic proforma.^4,6 This resulted in 48.1% of patients receiving antibiotics within 15 minutes and 63.3% overall within 30 minutes of arrival.⁵ Other barriers to consider are ED crowding and the admission of higher acuity patients, which may delay the treatment of patients with FN.

The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana is a level 1A facility serving about 62,000 veterans annually and more than 13,000 unique veterans visiting the ED. RLRVAMC ED staff rotate often so the creation of a process will facilitate appropriate treatment as quickly as possible. The purpose of this protocol was to improve the mean time from triage to administration of antibiotics for patients with FN presenting to the ED.

Implementation

To quantify the perceived delay in antibiotic prescribing, a pre- and postprotocol retrospective chart review of patients who presented with FN to the RLRVAMC ED was conducted. Patients were identified through the electronic health record (EHR) based on 3 criteria: recorded/reported fever as defined above, ANC < 1000 cells/mm³, and administration of cancer treatment (IV and oral) within 4 weeks. The data collected in the postimplementation phase were identical to the pre-implementation phase. This included timing of blood cultures, choice/appropriateness of antibiotics based on guidelines, and length of admission. The pre-implementation period started on August 1, 2018, and ended on August 1, 2019, to allow for an adequate pre-implementation sample size. The protocol was then implemented on October 1, 2019, and data collection for the postimplementation phase began on October 1,2019, and ended on October 1, 2020.

The protocol was accompanied by EHR order sets initiated by both nurses and health care practitioners (HCPs), including physicians, nurse practitioners, and physician assistants. The nursing order set consisted of vitals and appropriate laboratory monitoring, and the practitioner order set housed medication orders and additional clinical monitoring for more patient-specific scenarios. On identification of at-risk patients, the nursing staff could initiate the neutropenic fever protocol without consulting an HCP. The patient was then assigned a higher acuity rank, and the HCP was tasked with seeing the patient immediately. In conjunction with a complete physical assessment, the HCP ordered appropriate antibiotics through the designated order set to streamline antibiotic selection. Antibiotic options included cefepime or piperacillin-tazobactam, and vancomycin when clinically indicated. Alternatives for patients allergic to penicillin also were available. The protocol intended to streamline workup and antibiotic selection but was not designed as a substitute for solid clinical decision making and complete assessment on behalf of the HCP; therefore, additional workup may have been necessary and documented in the EHR.

Findings

This patient population comprised 17 patients pre-implementation and 12 patients postimplementation, most of whom had solid tumor malignancies (88.2% and 83.3%, respectively) receiving platinum, taxane, or antimetabolite-based chemotherapy. In the pre-implementation group, most patients (70.5%) coming through the ED were treated with palliative intent. Only 25% of these received any prophylactic granulocyte-colony stimulating factor (G-CSF) based on risk for FN. The mean time from triage to the first dose of antibiotics decreased from 3.3 hours before protocol implementation to 2.3 hours after. Only 6% in the pre-implementation group compared with 17% in the postimplementation group received the first dose of antibiotics within the recommended 1-hour interval from triage. The most common antibiotics administered were cefepime and vancomycin. Eleven patients in each group (65% and 92%, respectively) were admitted to the inpatient service for further care, with 10 and 8 patients, respectively, experiencing a hospitalization > 72 hours. Of note, 41% of patients died pre-implementation vs 17% postimplementation.

Interpretation

The goal of this protocol was to optimize ED care of patients presenting with FN to better align with guideline-recommended time lines and antibiotics. The mean time from triage to administration of antibiotics decreased by 1.0 hour from the pre- to postimplementation phase, similar to the study by Mattison and colleagues.³ When removing an outlier from the postimplementation group, the mean time from triage to first dose further decreased to 1.8 hours. The percentage of patients receiving antibiotics within 1 hour of triage nearly tripled from 6% to 17%. Additionally, the percentage of patients empirically treated with appropriate antibiotics consistent with NCCN/ASCO/IDSA guidelines increased from 65% to 83%. Although goals for the optimization of care have not yet been reached, this protocol is the first step in the right direction.

Limitations

Several limitations and concerns arise when implementing a new protocol or workflow process. Overall, these limitations may contribute to delays, such as the willingness of team members to use an unfamiliar protocol or issues locating a new protocol. The nursing staff is challenged to triage patients quickly, which may add to an already busy environment. Frequent physician turnover may require more frequent education sessions. Also, a lag time between implementation and using the protocol may result in decreased protocol use during the designated postimplementation data collection phase.

On review, ED staff were excited to find a protocol that streamlined decision making and increased awareness for patients at risk. The COVID-19 pandemic may have been a confounder for the postimplementation phase. Data may have been skewed as some patients might have elected to stay at home to avoid potential COVID-19 exposure in the ED. Additionally, increased ED use by patients with COVID-19 may have resulted in longer wait times for an available bed, thereby minimizing the impact of the protocol on time from triage to administration of antibiotics. COVID-19 may also have contributed to postimplementation mortality. Of note, barcode medication administration (BCMA) was implemented in the ED in May 2019, which may account for undocumented delays in antibiotic administration as staff may have been unfamiliar with BCMA workflow.

Due to the retrospective nature of a chart review, the data rely on the timely input and accuracy of documented information. Data after the patient’s ED encounter (except inpatient hospitalization and deaths during the implementation period) were not collected due to the scope of the program being limited to the ED only. Last, this protocol was implemented at a single site, and the generalizability to implement the same protocol at other VA medical centers may be limited. After reaching out to other VA sites and several non-VA facilities, we were unable to find a site with a similar protocol or program emphasizing the importance of timely care, although there may have been established laboratory test and medication order sets within the EHR.

Future Direction

The newly established FN order sets will continue to streamline clinical decision making and antibiotic selection in this population. In our study, we learned that most patients coming through the ED were being treated with palliative intent. As a result, these patients also may have a higher risk for complications like FN. We hope to further analyze the impact on this group and consider the role of empiric dose reduction or increased G-CSF support to minimize FN.

More than half of the patients who were admitted to the inpatient service, remained in extended care for > 72 hours. Inpatient recovery time may cause delays in future cancer treatment cycles, dose reductions, and contribute to an overall decline in performance status. Six patients in the pre-implementation phase and 1 in the postimplementation phase were eligible for outpatient management per independent Multinational Association of Supportive Care in Cancer assessment. To increase comfort, a future goal would be to create an outpatient treatment order set on discharge from the ED to help identify and outline treatment options for low-risk patients. In addition to the ED, training staff in clinics with a similar protocol may enhance the identification of patients with FN. This may require a tailored protocol for this location using health technicians in taking vital signs before the HCP visit.

This protocol helped establish “code sepsis.” Code sepsis alerts are broadcast to alert pertinent members of the health care team to provide immediate medical attention to the veteran. Pharmacy can expedite the compounding of antibiotics and record review while radiology prioritizes the portable X-ray for quick and efficient imaging. The nursing team comes ready to administer antibiotics once cultures are drawn. The HCP's attention is focused on the physical examination to determine any additional steps/care that need to be accomplished. At our site, we plan to continue HCP, nursing, and other team member education on this oncologic emergency and the availability of a streamlined protocol. We would like to re-assess the data with a long team study now that the protocol has been in place for 3 years. We hope to continue to provide strong patient care with enhanced adherence to guidelines for patients with FN presenting to RLRVAMC.

Conclusions

Early identification and timely empiric antibiotic therapy are critical to improving outcomes for patients presenting to the ED with FN. The neutropenic fever protocol reduced time to antibiotics by about 1 hour with a higher percentage of patients receiving them in < 1 hour. Additional optimization of the order sets along with increased protocol comfort and staff education will help further reduce the time to antibiotic administration in alignment with guideline recommendations.

Febrile neutropenia (FN) is a life-threatening oncologic emergency requiring timely evaluation and treatment. Chemotherapy-induced neutropenia is a major risk for life-threatening infection, and fever may be the only sign.^1,2 Unrecognized fever can progress to sepsis and may result in increased morbidity and mortality. FN is defined as the presence of fever with a single temperature of  ≥ 38.3 °C or a sustained temperature > 38 °C sustained over 1 hour with an absolute neutrophil count (ANC) of < 500 cells/mm³ or < 1000 cells/mm³ and expected to decrease to < 500 within 48 hours.^2,3 It is critical to quickly identify these patients on presentation to the emergency department (ED) and take appropriate steps to initiate treatment as soon as possible. To streamline care, the American Society of Clinical Oncology (ASCO) recommends that laboratory assessments be initiated within 15 minutes of triage and empiric antibiotic therapy be administered within 1 hour.²

In alignment with the Infectious Disease Society of America (IDSA) guidelines, the National Comprehensive Cancer Network (NCCN) highlights the importance of the initial assessment of fever and neutropenia and presents available treatment options for both inpatient and outpatient management of FN.¹ Once patients are identified, the appropriate laboratory tests and physical assessments should be initiated immediately. These tests include a complete blood count with differential, complete metabolic panel (CMP), and blood cultures from 2 separate IV sites.^1-3 The guidelines offer additional suggestions for cultures and radiographic assessments that may be completed based on clinical presentation.

Several available studies provide insight into methods of protocol creation and possible barriers to timely management. Previous research showed that an FN protocol for pediatric oncology patients aimed at antibiotic administration within 1 hour showed significant improvement from 35.0% to 55.4% of patients being treated on time.^3,4 Prescribers became more comfortable in using the protocol, and timing improved as the study progressed. Barriers noted were inconsistent ED triage, rotating ED staff, and limited understanding of the protocol.³ Yoshida and colleagues worked with the same population. Over the course of 1 year, 60% of patients were receiving antibiotics within 1 hour. The mean time decreased from 83 to 65 minutes, which the study investigators noted would continue to decrease with increased protocol comfort and use.⁵ Mattison and colleagues used nursing staff to identify patients with FN and begin antibiotic treatment. On triage, nurses took note of a temperature of > 38 °C or a sepsislike clinical picture that initiated their antibiotic proforma.^4,6 This resulted in 48.1% of patients receiving antibiotics within 15 minutes and 63.3% overall within 30 minutes of arrival.⁵ Other barriers to consider are ED crowding and the admission of higher acuity patients, which may delay the treatment of patients with FN.

The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana is a level 1A facility serving about 62,000 veterans annually and more than 13,000 unique veterans visiting the ED. RLRVAMC ED staff rotate often so the creation of a process will facilitate appropriate treatment as quickly as possible. The purpose of this protocol was to improve the mean time from triage to administration of antibiotics for patients with FN presenting to the ED.

Implementation

To quantify the perceived delay in antibiotic prescribing, a pre- and postprotocol retrospective chart review of patients who presented with FN to the RLRVAMC ED was conducted. Patients were identified through the electronic health record (EHR) based on 3 criteria: recorded/reported fever as defined above, ANC < 1000 cells/mm³, and administration of cancer treatment (IV and oral) within 4 weeks. The data collected in the postimplementation phase were identical to the pre-implementation phase. This included timing of blood cultures, choice/appropriateness of antibiotics based on guidelines, and length of admission. The pre-implementation period started on August 1, 2018, and ended on August 1, 2019, to allow for an adequate pre-implementation sample size. The protocol was then implemented on October 1, 2019, and data collection for the postimplementation phase began on October 1,2019, and ended on October 1, 2020.

The protocol was accompanied by EHR order sets initiated by both nurses and health care practitioners (HCPs), including physicians, nurse practitioners, and physician assistants. The nursing order set consisted of vitals and appropriate laboratory monitoring, and the practitioner order set housed medication orders and additional clinical monitoring for more patient-specific scenarios. On identification of at-risk patients, the nursing staff could initiate the neutropenic fever protocol without consulting an HCP. The patient was then assigned a higher acuity rank, and the HCP was tasked with seeing the patient immediately. In conjunction with a complete physical assessment, the HCP ordered appropriate antibiotics through the designated order set to streamline antibiotic selection. Antibiotic options included cefepime or piperacillin-tazobactam, and vancomycin when clinically indicated. Alternatives for patients allergic to penicillin also were available. The protocol intended to streamline workup and antibiotic selection but was not designed as a substitute for solid clinical decision making and complete assessment on behalf of the HCP; therefore, additional workup may have been necessary and documented in the EHR.

Findings

This patient population comprised 17 patients pre-implementation and 12 patients postimplementation, most of whom had solid tumor malignancies (88.2% and 83.3%, respectively) receiving platinum, taxane, or antimetabolite-based chemotherapy. In the pre-implementation group, most patients (70.5%) coming through the ED were treated with palliative intent. Only 25% of these received any prophylactic granulocyte-colony stimulating factor (G-CSF) based on risk for FN. The mean time from triage to the first dose of antibiotics decreased from 3.3 hours before protocol implementation to 2.3 hours after. Only 6% in the pre-implementation group compared with 17% in the postimplementation group received the first dose of antibiotics within the recommended 1-hour interval from triage. The most common antibiotics administered were cefepime and vancomycin. Eleven patients in each group (65% and 92%, respectively) were admitted to the inpatient service for further care, with 10 and 8 patients, respectively, experiencing a hospitalization > 72 hours. Of note, 41% of patients died pre-implementation vs 17% postimplementation.

Interpretation

The goal of this protocol was to optimize ED care of patients presenting with FN to better align with guideline-recommended time lines and antibiotics. The mean time from triage to administration of antibiotics decreased by 1.0 hour from the pre- to postimplementation phase, similar to the study by Mattison and colleagues.³ When removing an outlier from the postimplementation group, the mean time from triage to first dose further decreased to 1.8 hours. The percentage of patients receiving antibiotics within 1 hour of triage nearly tripled from 6% to 17%. Additionally, the percentage of patients empirically treated with appropriate antibiotics consistent with NCCN/ASCO/IDSA guidelines increased from 65% to 83%. Although goals for the optimization of care have not yet been reached, this protocol is the first step in the right direction.

Limitations

Several limitations and concerns arise when implementing a new protocol or workflow process. Overall, these limitations may contribute to delays, such as the willingness of team members to use an unfamiliar protocol or issues locating a new protocol. The nursing staff is challenged to triage patients quickly, which may add to an already busy environment. Frequent physician turnover may require more frequent education sessions. Also, a lag time between implementation and using the protocol may result in decreased protocol use during the designated postimplementation data collection phase.

On review, ED staff were excited to find a protocol that streamlined decision making and increased awareness for patients at risk. The COVID-19 pandemic may have been a confounder for the postimplementation phase. Data may have been skewed as some patients might have elected to stay at home to avoid potential COVID-19 exposure in the ED. Additionally, increased ED use by patients with COVID-19 may have resulted in longer wait times for an available bed, thereby minimizing the impact of the protocol on time from triage to administration of antibiotics. COVID-19 may also have contributed to postimplementation mortality. Of note, barcode medication administration (BCMA) was implemented in the ED in May 2019, which may account for undocumented delays in antibiotic administration as staff may have been unfamiliar with BCMA workflow.

Due to the retrospective nature of a chart review, the data rely on the timely input and accuracy of documented information. Data after the patient’s ED encounter (except inpatient hospitalization and deaths during the implementation period) were not collected due to the scope of the program being limited to the ED only. Last, this protocol was implemented at a single site, and the generalizability to implement the same protocol at other VA medical centers may be limited. After reaching out to other VA sites and several non-VA facilities, we were unable to find a site with a similar protocol or program emphasizing the importance of timely care, although there may have been established laboratory test and medication order sets within the EHR.

Future Direction

The newly established FN order sets will continue to streamline clinical decision making and antibiotic selection in this population. In our study, we learned that most patients coming through the ED were being treated with palliative intent. As a result, these patients also may have a higher risk for complications like FN. We hope to further analyze the impact on this group and consider the role of empiric dose reduction or increased G-CSF support to minimize FN.

More than half of the patients who were admitted to the inpatient service, remained in extended care for > 72 hours. Inpatient recovery time may cause delays in future cancer treatment cycles, dose reductions, and contribute to an overall decline in performance status. Six patients in the pre-implementation phase and 1 in the postimplementation phase were eligible for outpatient management per independent Multinational Association of Supportive Care in Cancer assessment. To increase comfort, a future goal would be to create an outpatient treatment order set on discharge from the ED to help identify and outline treatment options for low-risk patients. In addition to the ED, training staff in clinics with a similar protocol may enhance the identification of patients with FN. This may require a tailored protocol for this location using health technicians in taking vital signs before the HCP visit.

This protocol helped establish “code sepsis.” Code sepsis alerts are broadcast to alert pertinent members of the health care team to provide immediate medical attention to the veteran. Pharmacy can expedite the compounding of antibiotics and record review while radiology prioritizes the portable X-ray for quick and efficient imaging. The nursing team comes ready to administer antibiotics once cultures are drawn. The HCP's attention is focused on the physical examination to determine any additional steps/care that need to be accomplished. At our site, we plan to continue HCP, nursing, and other team member education on this oncologic emergency and the availability of a streamlined protocol. We would like to re-assess the data with a long team study now that the protocol has been in place for 3 years. We hope to continue to provide strong patient care with enhanced adherence to guidelines for patients with FN presenting to RLRVAMC.

Conclusions

Early identification and timely empiric antibiotic therapy are critical to improving outcomes for patients presenting to the ED with FN. The neutropenic fever protocol reduced time to antibiotics by about 1 hour with a higher percentage of patients receiving them in < 1 hour. Additional optimization of the order sets along with increased protocol comfort and staff education will help further reduce the time to antibiotic administration in alignment with guideline recommendations.

Febrile neutropenia (FN) is a life-threatening oncologic emergency requiring timely evaluation and treatment. Chemotherapy-induced neutropenia is a major risk for life-threatening infection, and fever may be the only sign.^1,2 Unrecognized fever can progress to sepsis and may result in increased morbidity and mortality. FN is defined as the presence of fever with a single temperature of  ≥ 38.3 °C or a sustained temperature > 38 °C sustained over 1 hour with an absolute neutrophil count (ANC) of < 500 cells/mm³ or < 1000 cells/mm³ and expected to decrease to < 500 within 48 hours.^2,3 It is critical to quickly identify these patients on presentation to the emergency department (ED) and take appropriate steps to initiate treatment as soon as possible. To streamline care, the American Society of Clinical Oncology (ASCO) recommends that laboratory assessments be initiated within 15 minutes of triage and empiric antibiotic therapy be administered within 1 hour.²

In alignment with the Infectious Disease Society of America (IDSA) guidelines, the National Comprehensive Cancer Network (NCCN) highlights the importance of the initial assessment of fever and neutropenia and presents available treatment options for both inpatient and outpatient management of FN.¹ Once patients are identified, the appropriate laboratory tests and physical assessments should be initiated immediately. These tests include a complete blood count with differential, complete metabolic panel (CMP), and blood cultures from 2 separate IV sites.^1-3 The guidelines offer additional suggestions for cultures and radiographic assessments that may be completed based on clinical presentation.

Several available studies provide insight into methods of protocol creation and possible barriers to timely management. Previous research showed that an FN protocol for pediatric oncology patients aimed at antibiotic administration within 1 hour showed significant improvement from 35.0% to 55.4% of patients being treated on time.^3,4 Prescribers became more comfortable in using the protocol, and timing improved as the study progressed. Barriers noted were inconsistent ED triage, rotating ED staff, and limited understanding of the protocol.³ Yoshida and colleagues worked with the same population. Over the course of 1 year, 60% of patients were receiving antibiotics within 1 hour. The mean time decreased from 83 to 65 minutes, which the study investigators noted would continue to decrease with increased protocol comfort and use.⁵ Mattison and colleagues used nursing staff to identify patients with FN and begin antibiotic treatment. On triage, nurses took note of a temperature of > 38 °C or a sepsislike clinical picture that initiated their antibiotic proforma.^4,6 This resulted in 48.1% of patients receiving antibiotics within 15 minutes and 63.3% overall within 30 minutes of arrival.⁵ Other barriers to consider are ED crowding and the admission of higher acuity patients, which may delay the treatment of patients with FN.

The US Department of Veterans Affairs (VA) Richard L. Roudebush VA Medical Center (RLRVAMC) in Indianapolis, Indiana is a level 1A facility serving about 62,000 veterans annually and more than 13,000 unique veterans visiting the ED. RLRVAMC ED staff rotate often so the creation of a process will facilitate appropriate treatment as quickly as possible. The purpose of this protocol was to improve the mean time from triage to administration of antibiotics for patients with FN presenting to the ED.

Implementation

To quantify the perceived delay in antibiotic prescribing, a pre- and postprotocol retrospective chart review of patients who presented with FN to the RLRVAMC ED was conducted. Patients were identified through the electronic health record (EHR) based on 3 criteria: recorded/reported fever as defined above, ANC < 1000 cells/mm³, and administration of cancer treatment (IV and oral) within 4 weeks. The data collected in the postimplementation phase were identical to the pre-implementation phase. This included timing of blood cultures, choice/appropriateness of antibiotics based on guidelines, and length of admission. The pre-implementation period started on August 1, 2018, and ended on August 1, 2019, to allow for an adequate pre-implementation sample size. The protocol was then implemented on October 1, 2019, and data collection for the postimplementation phase began on October 1,2019, and ended on October 1, 2020.

The protocol was accompanied by EHR order sets initiated by both nurses and health care practitioners (HCPs), including physicians, nurse practitioners, and physician assistants. The nursing order set consisted of vitals and appropriate laboratory monitoring, and the practitioner order set housed medication orders and additional clinical monitoring for more patient-specific scenarios. On identification of at-risk patients, the nursing staff could initiate the neutropenic fever protocol without consulting an HCP. The patient was then assigned a higher acuity rank, and the HCP was tasked with seeing the patient immediately. In conjunction with a complete physical assessment, the HCP ordered appropriate antibiotics through the designated order set to streamline antibiotic selection. Antibiotic options included cefepime or piperacillin-tazobactam, and vancomycin when clinically indicated. Alternatives for patients allergic to penicillin also were available. The protocol intended to streamline workup and antibiotic selection but was not designed as a substitute for solid clinical decision making and complete assessment on behalf of the HCP; therefore, additional workup may have been necessary and documented in the EHR.

Findings

This patient population comprised 17 patients pre-implementation and 12 patients postimplementation, most of whom had solid tumor malignancies (88.2% and 83.3%, respectively) receiving platinum, taxane, or antimetabolite-based chemotherapy. In the pre-implementation group, most patients (70.5%) coming through the ED were treated with palliative intent. Only 25% of these received any prophylactic granulocyte-colony stimulating factor (G-CSF) based on risk for FN. The mean time from triage to the first dose of antibiotics decreased from 3.3 hours before protocol implementation to 2.3 hours after. Only 6% in the pre-implementation group compared with 17% in the postimplementation group received the first dose of antibiotics within the recommended 1-hour interval from triage. The most common antibiotics administered were cefepime and vancomycin. Eleven patients in each group (65% and 92%, respectively) were admitted to the inpatient service for further care, with 10 and 8 patients, respectively, experiencing a hospitalization > 72 hours. Of note, 41% of patients died pre-implementation vs 17% postimplementation.

Interpretation

The goal of this protocol was to optimize ED care of patients presenting with FN to better align with guideline-recommended time lines and antibiotics. The mean time from triage to administration of antibiotics decreased by 1.0 hour from the pre- to postimplementation phase, similar to the study by Mattison and colleagues.³ When removing an outlier from the postimplementation group, the mean time from triage to first dose further decreased to 1.8 hours. The percentage of patients receiving antibiotics within 1 hour of triage nearly tripled from 6% to 17%. Additionally, the percentage of patients empirically treated with appropriate antibiotics consistent with NCCN/ASCO/IDSA guidelines increased from 65% to 83%. Although goals for the optimization of care have not yet been reached, this protocol is the first step in the right direction.

Limitations

Several limitations and concerns arise when implementing a new protocol or workflow process. Overall, these limitations may contribute to delays, such as the willingness of team members to use an unfamiliar protocol or issues locating a new protocol. The nursing staff is challenged to triage patients quickly, which may add to an already busy environment. Frequent physician turnover may require more frequent education sessions. Also, a lag time between implementation and using the protocol may result in decreased protocol use during the designated postimplementation data collection phase.

On review, ED staff were excited to find a protocol that streamlined decision making and increased awareness for patients at risk. The COVID-19 pandemic may have been a confounder for the postimplementation phase. Data may have been skewed as some patients might have elected to stay at home to avoid potential COVID-19 exposure in the ED. Additionally, increased ED use by patients with COVID-19 may have resulted in longer wait times for an available bed, thereby minimizing the impact of the protocol on time from triage to administration of antibiotics. COVID-19 may also have contributed to postimplementation mortality. Of note, barcode medication administration (BCMA) was implemented in the ED in May 2019, which may account for undocumented delays in antibiotic administration as staff may have been unfamiliar with BCMA workflow.

Due to the retrospective nature of a chart review, the data rely on the timely input and accuracy of documented information. Data after the patient’s ED encounter (except inpatient hospitalization and deaths during the implementation period) were not collected due to the scope of the program being limited to the ED only. Last, this protocol was implemented at a single site, and the generalizability to implement the same protocol at other VA medical centers may be limited. After reaching out to other VA sites and several non-VA facilities, we were unable to find a site with a similar protocol or program emphasizing the importance of timely care, although there may have been established laboratory test and medication order sets within the EHR.

Future Direction

The newly established FN order sets will continue to streamline clinical decision making and antibiotic selection in this population. In our study, we learned that most patients coming through the ED were being treated with palliative intent. As a result, these patients also may have a higher risk for complications like FN. We hope to further analyze the impact on this group and consider the role of empiric dose reduction or increased G-CSF support to minimize FN.

More than half of the patients who were admitted to the inpatient service, remained in extended care for > 72 hours. Inpatient recovery time may cause delays in future cancer treatment cycles, dose reductions, and contribute to an overall decline in performance status. Six patients in the pre-implementation phase and 1 in the postimplementation phase were eligible for outpatient management per independent Multinational Association of Supportive Care in Cancer assessment. To increase comfort, a future goal would be to create an outpatient treatment order set on discharge from the ED to help identify and outline treatment options for low-risk patients. In addition to the ED, training staff in clinics with a similar protocol may enhance the identification of patients with FN. This may require a tailored protocol for this location using health technicians in taking vital signs before the HCP visit.

This protocol helped establish “code sepsis.” Code sepsis alerts are broadcast to alert pertinent members of the health care team to provide immediate medical attention to the veteran. Pharmacy can expedite the compounding of antibiotics and record review while radiology prioritizes the portable X-ray for quick and efficient imaging. The nursing team comes ready to administer antibiotics once cultures are drawn. The HCP's attention is focused on the physical examination to determine any additional steps/care that need to be accomplished. At our site, we plan to continue HCP, nursing, and other team member education on this oncologic emergency and the availability of a streamlined protocol. We would like to re-assess the data with a long team study now that the protocol has been in place for 3 years. We hope to continue to provide strong patient care with enhanced adherence to guidelines for patients with FN presenting to RLRVAMC.

Conclusions

Early identification and timely empiric antibiotic therapy are critical to improving outcomes for patients presenting to the ED with FN. The neutropenic fever protocol reduced time to antibiotics by about 1 hour with a higher percentage of patients receiving them in < 1 hour. Additional optimization of the order sets along with increased protocol comfort and staff education will help further reduce the time to antibiotic administration in alignment with guideline recommendations.

The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.

Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.¹ With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.²

In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.

AML: Historical perspective

AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.² These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.

Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.¹ In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.

However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.² These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.

Novel therapeutics in AML

Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.² Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.

Acute promyelocytic leukemia

APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.² Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.

Core binding factor AML

CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.

Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).

Intensive chemotherapy in younger/fit AML

St Bartholomew&#039;s Hospital/Science Source

Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.

Older/unfit patients with AML: Low-intensity therapy

Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.

Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.

Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.

Other FDA-approved therapies in AML

CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.

Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.

Expert perspectives: Future of AML therapy

Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.¹

“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”

Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.

“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.

“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.

They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.

Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.

References

1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.

2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.

The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.

Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.¹ With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.²

In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.

AML: Historical perspective

AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.² These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.

Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.¹ In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.

However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.² These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.

Novel therapeutics in AML

Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.² Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.

Acute promyelocytic leukemia

APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.² Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.

Core binding factor AML

CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.

Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).

Intensive chemotherapy in younger/fit AML

St Bartholomew&#039;s Hospital/Science Source

Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.

Older/unfit patients with AML: Low-intensity therapy

Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.

Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.

Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.

Other FDA-approved therapies in AML

CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.

Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.

Expert perspectives: Future of AML therapy

Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.¹

“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”

Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.

“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.

“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.

They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.

Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.

References

1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.

2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.

The emergence of precision medicine has ushered in a groundbreaking era for the treatment of myeloid malignancies, with the ability to integrate individual molecular data into patient care.

Over the past decade, insights from research focusing on the mutations driving the malignant transformation of myeloid cells have provided the basis for the development of novel targeted therapies.¹ With the recent U.S. Food and Drug Administration approval of several novel therapies for different acute myeloid leukemia (AML) indications, the current treatment landscape for AML is evolving rapidly.²

In addition, there has been substantial progress in the development of novel therapeutic strategies for other myeloid neoplasms, with numerous molecularly based therapies in early clinical trials in myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). These advancements have been translated into optimized algorithms for diagnosis, prognostication, and treatment.

AML: Historical perspective

AML comprises a heterogeneous group of blood cell malignancies that require different treatment approaches and confer different prognoses.² These include acute promyelocytic leukemia (APL) and core binding factor (CBF) AML, both of which have high rates of remission and prolonged survival. The remaining non-APL, non-CBF types can be divided by their cytogenetic-molecular profiles, as well as fitness for intensive chemotherapy. AML can also arise secondary to other myeloid neoplasms, especially after exposure to hypomethylating agents (HMAs), chemotherapy, or irradiation as prior treatment for the primary malignancy.

Historically, anthracycline- and cytarabine-based chemotherapy with or without allogeneic hematopoietic stem-cell transplant (allo-HSCT) was the standard of care in AML treatment with curative intent.¹ In the palliative setting, low-dose cytarabine or HMAs were also treatment options. Despite 5 decades of clinical use of these options, researchers have continued to evaluate different dosing schedules of cytosine arabinoside (cytarabine or ara-C) and daunorubicin – the first two agents approved for the treatment of AML – during induction and consolidation treatment phases.

However, recent discoveries have led to the clinical development of targeted agents directed at isocitrate dehydrogenase (IDH), FMS-like tyrosine kinase 3 (FLT3), and BCL2.² These developments, and the highly anticipated combinations arising from them, continue to challenge traditional treatment approaches, raising the question of whether intensive chemotherapy should remain the optimal standard of care.

Novel therapeutics in AML

Since 2017, several new therapies have been approved for the treatment of AML, including gemtuzumab ozogamicin, two FLT3 inhibitors (gilteritinib and midostaurin), two IDH inhibitors (ivosidenib and enasidenib), a BCL2 inhibitor (venetoclax), an oral HMA agent (azacitidine), a hedgehog inhibitor (glasdegib), and a liposomal formulation of CPX351. In addition, oral decitabine/cedazuridine may be used as an alternative oral HMA in AML, but it is currently the only FDA-approved treatment for chronic myelomonocytic leukemia (CMML) and MDS.² Because AML subsets are very heterogeneous, an open question remains about how to best integrate these new agents into frontline and salvage combination regimens.

Acute promyelocytic leukemia

APL composes 5%-10% of AML and is characterized by the cytogenetic translocation between chromosomes 15 and 17, which leads to the PML-RAR alpha fusion oncogene and its encoded oncoprotein.² Two therapies, all-trans retinoic acid (ATRA) and arsenic trioxide, when administered in combination with chemotherapy during induction, have been shown to improve outcomes in APL. At present, the combination of idarubicin and ATRA is the standard-of-care treatment for APL. In addition, patients with high-risk disease have been shown to benefit from the addition of gemtuzumab ozogamicin or anthracyclines.

Core binding factor AML

CBF AML includes patients with the cytogenetic-molecular subsets of inversion 16. Chemotherapy combined with gemtuzumab ozogamicin results in cure rates of 75% or higher and an estimated 5-year survival of 75%. Fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin during induction and consolidation, and an alternative treatment modality (for example, allo-HSCT), for persistent minimal residual disease (MRD) in patients who achieve complete response (CR) is a commonly used regimen. Patients who cannot tolerate this regimen or who have persistent MRD may be treated with an HMA (for instance, decitabine or azacitidine) in combination with venetoclax and gemtuzumab ozogamicin, with the treatment duration adjusted according to MRD status or for 12 months or longer.

Mutations, such as N/KRAS (30%-50%), KIT (25%-30%), and FLT3 (15%-20%), also occur in CBF AML. Targeted agents may also be considered in some cases (for example, dasatinib or avapritinib for KIT mutations; FLT3 inhibitors for FLT3 mutations).

Intensive chemotherapy in younger/fit AML

St Bartholomew&#039;s Hospital/Science Source

Several AML regimens have demonstrated better outcomes than the conventional “3 + 7 regimen” (3 days of daunorubicin plus 7 days of cytarabine). Recently, the treatment paradigm has shifted from intensive chemotherapy alone to multidrug combination regimens, including regimens that incorporate targeted therapies, such as FLT3 inhibitors in FLT3-mutated AML, and venetoclax and/or IDH inhibitors as indicated. In addition, the recent FDA approval of oral azacitidine as maintenance therapy for patients in first CR (CR duration, 4 months or less; patients unable to complete the curative intensive chemotherapy) may allow for expanded combination regimens.

Older/unfit patients with AML: Low-intensity therapy

Prior to 2000, the majority of older/unfit patients with AML were offered supportive/palliative treatment. Today, the HMAs azacitidine and decitabine are the most commonly used drugs for the treatment of older/unfit AML. Recently, the FDA approved an oral formulation of decitabine plus oral cedazuridine for the treatment of CMML and MDS. This could provide an opportunity to investigate and develop an effective oral therapy regimen for older/unfit AML, such as oral decitabine/cedazuridine in combination with venetoclax, which may ease administration and improve quality of life for patients in CR post induction in the community setting.

Other studies have shown benefit for combining an HMA with venetoclax in patients with TP53-mutated AML. In addition, triplet regimens may also improve outcomes, with combinations such as HMA plus FLT3 inhibitor (for instance, midostaurin or gilteritinib) with or without venetoclax now being investigated. However, the potential increased risk of myelosuppression also needs to be considered with use of triplet regimens. The results of these and other combinatorial trials are greatly anticipated.

Two oral IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor) were recently FDA approved as monotherapy for the treatment of IDH-mutated AML. Combination regimens of IDH inhibitors with chemotherapy are currently being investigated in patients with IDH-mutated AML and appear promising based on preliminary data demonstrating improved response rates and event-free survival.

Other FDA-approved therapies in AML

CPX-351 is a nanoscale liposome with a fixed 5:1 molar ratio of cytarabine and daunorubicin. Results from a phase 3 trial showed that CPX-351 resulted in higher response rates and longer survival compared with 3 + 7 chemotherapy in patients with secondary AML, a subgroup of patients with a very poor prognosis. Additional studies are ongoing, combining CPX-351 with gemtuzumab ozogamicin, venetoclax, and other targeted agents.

Results from a phase 2 trial led to the FDA approval of the hedgehog inhibitor glasdegib when given with low-dose cytarabine. The combination improved survival compared with low-dose cytarabine alone in older/unfit AML and high-risk MDS. However, because of poor survival relative to venetoclax-based combinations, glasdegib is not widely used in clinical practice; other trials exploring combinations with azacitidine and with intensive chemotherapy are ongoing.

Expert perspectives: Future of AML therapy

Amir T. Fathi, MD, associate professor of medicine at Harvard Medical School, Boston, and Farhad Ravandi, MD, professor of medicine at the University of Texas MD Anderson Cancer Center, Houston, are coauthors of a recent review that summarized the current treatment landscape in AML, including areas of evolving research.¹

“In the next several years, I am hopeful there will be a series of regulatory approvals of novel, effective agents for myeloid malignancies,” Dr. Fathi explained. “Even if approvals are not as numerous as we’ve seen in AML, any additional effective options would be very welcome.”

Dr. Ravandi also noted that increased understanding of the biology underlying myeloid neoplasms has helped to develop novel therapies.

“As we’ve increased our understanding of the biology of these blood cancers, particularly the mechanisms of leukemogenesis and neoplastic change, we’ve been able to develop more effective therapies in AML,” Dr. Ravandi said.

“In the future, we are likely to see a similar trend in other myeloid neoplasms, such as MDSs and MPNs, as we better understand their underlying pathogenesis,” he further explained.

They both acknowledged that the future treatment paradigm in AML will focus on maximizing the potential of new drug approvals, largely through the development of new combination regimens; however, this could be limited by timely validation and regulatory concerns as the disease has become increasingly segmented into smaller subgroups, each with access to a variety of potentially effective therapies.

Dr. Fathi reported consulting/advisory services for Agios, BMS/Celgene, Astellas, and a variety of other pharmaceutical and biotechnology companies. He also reported receiving research support from Agios, BMS/Celgene, and AbbVie. Dr. Ravandi reported no conflicts of interest.

References

1. Westermann J and Bullinger L. Cancer Biol. 2021 April;S1044-579X(21)00084-5.

2. Kantarjian HM et al. Clin Lymphoma Myeloma Leuk. 2021 Sept;21(9):580-97.

Hypertension affects more than 65 million individuals in the U.S., accounting for nearly 30% of the adult population.¹ Less than 50% of those with hypertension are taking appropriate pharmacotherapy.² Hypertension contributes to cardiovascular events, including cerebrovascular accident, transient ischemic attack, hypertensive retinopathy, renal failure, myocardial infarction, and heart failure.¹ Chronic hypertension mainly is an asymptomatic condition, earning the nickname “the silent killer.”² An acute, symptomatic elevation in blood pressure (BP) often is referred to as hypertensive emergency. Symptoms of end-organ damage can include headache, blurry vision, chest pain, shortness of breath, altered mental status, epistaxis, and oliguria.² Although rare, hypertensive emergencies should be treated immediately. The Seventh Report of the Joint National Committee (JNC 7), and the more recent JNC 8, have published guidelines on managing chronic hypertension.^3,4 However, neither report provides guidance on hypertensive emergency or the appropriate actions in cases of extremely elevated BP in an asymptomatic patient.^3,4

Acute hypertensive episodes—often referred to as hypertensive crises—are responsible for nearly 8 million hospitalizations each year and 20 million visits to the emergency department (ED).^5,6 Most of these visits are same-day “treat-and-release” events.⁵ There is no universally accepted BP value associated with a hypertensive crisis, but most resources state that a BP ≥ 180/110 mm Hg requires attention.^2,7 Without other symptoms, elevated BP is not an emergency, yet ED referral for acute management is common.⁷

Three terms fall under the umbrella of hypertensive crises: hypertensive emergency, hypertensive urgency, and asymptomatic hypertension (AH).² In a 2007 article, the American College of Chest Physicians defined hypertensive emergency as BP ≥ 180/110 mm Hg with evidence of end-organ damage.² Symptoms are almost always present in true hypertensive emergencies, and immediate medical intervention is required to halt further organ damage. In the same article, hypertensive urgency is defined as BP ≥ 180/110 mm Hg without end-organ damage.² The definition of hypertensive urgency could be further refined to include the presence of cardiovascular and renal risk factors, although this additional point is not consistent across the literature. Asymptomatic hypertension is similar to hypertensive urgency; however, there is an absence of signs or symptoms of end-organ damage.² There is ambiguity in the literature concerning managing hypertensive urgency and AH, but both share a basic tenet: Immediate BP reduction is not essential. Gradual dosage adjustment(s) of oral medications, preferably by a primary care provider (PCP), and follow-up within 7 days are recommended.⁷

Limited evidence exists to guide ED providers in managing AH. Long-term outcomes and guidelines intended for the primary care setting should not be extrapolated to acute management in the ED. With limited treatment guidelines, providers might be more likely to refer patients with AH to the ED for evaluation. In 2013, the American College of Emergency Physicians (ACEP) created a clinical policy concerning AH in the ED. The ACEP concluded that screening for target organ injury and medical intervention in the ED does not reduce rates of adverse events (AEs) and could lead to overtreatment and acute hypoperfusion.⁷ More recently, Patel and colleagues published findings on hypertensive urgency in the ambulatory care setting, which similarly found that referral to the ED was associated with increased use of health care resources and no change in short-term major AEs.⁸ The ACEP recommends that patients presenting with AH be referred to primary care clinics where long-term monitoring and medication adjustments can be achieved more cost-effectively.⁷

The objective of this retrospective evaluation was to assess the incidence and management of AH within a VA ED. The authors aimed to provide insight into how these patients are managed and discuss alternatives to ED use.

Methods

This retrospective observational study was conducted within the North Florida/South Georgia Veterans Health System (NFSGVHS), which provides patient care at 2 medical centers in Gainesville and Lake City, Florida, as well as 11 outpatient clinics located throughout North Florida and South Georgia. The NFSGVHS serves rural and urban veteran populations. Study approval was granted by the NFSGVHS Institutional Review Board and Research and Development Committee.

Inclusion/Exclusion Criteria

Adult patients who were ordered at least 1 antihypertensive medication in the ED from July 1, 2011 to July 1, 2014, in addition to being asymptomatic with BP ≥ 180/110 mm Hg at ED triage were included. Based on clinical experience, the authors estimated that 3 years would provide a sample size of more than 100 patients. Patients were excluded if they presented with any acute symptoms or were hospitalized for further management.

Data Collection

Baseline demographics were collected for all participants. During the ED encounter, pre- and postintervention vital signs were recorded and prespecified laboratory data obtained. Interrater reliability was accounted for by performing random reviews of previously collected data to ensure consistency during the chart review process. Renal end-organ damage was defined using Acute Kidney Injury Network criteria, a serum creatinine 50% above baseline, or an absolute increase in baseline serum creatinine by 0.3 mg/dL.⁹ Additional laboratory markers of organ damage included cardiac troponin levels. Urinalysis results also were assessed to determine the presence of hematuria or proteinuria. Patient-reported nonadherence with medications was determined by reviewing ED provider and/or nurse documentation notes for the index ED encounter.

Investigators documented the route (IV or oral) and antihypertensive(s) medication selected for each patient. Adverse effects and any changes to patients’ outpatient medication regimens were noted. Investigators also assessed days to next medical contact after ED discharge to determine whether follow-up occurred according to the recommended standard of 7 days.⁹ Days to next medical contact was defined as any contact—in person or by telephone—that was documented in the electronic health record after the index ED visit.

Statistical Analysis

Descriptive statistics, including mean, median, and standard deviation, were used to analyze data.

Results

A total of 1,052 patients presented with BP ≥ 180/110 mm Hg and for whom antihypertensive medication was ordered but not necessarily given in the ED. Of the total, 724 patients were excluded because of hospital admission for other primary diagnoses; however, 6 of these patients were admitted for hypertensive urgency. The final analysis included 132 patients who presented with the primary condition of elevated BP without any accompanying symptoms. Among these patients, 2 had repeat ED visits for AH during the specified time frame.

Most patients were male with an average age of 63 years and documented history of hypertension. Nearly all patients had established primary care within the NFSGVHS. The most common comorbidity was diabetes mellitus (36%), followed by coronary artery disease (27%) and chronic kidney disease (CKD) (21%) (Table 1). About one-third of patients presented to the ED on their own volition, and slightly more than half were referred to the ED by primary care or specialty clinics.

In the ED, 130 patients received BP treatment (Table 2). Medication was ordered for 2 patients who did not receive treatment. In total, 12 different medication classes were used for treating patients with AH in the ED (Figure). 

Treatment in the ED resulted in an average BP and heart rate reduction of 27/20 mm Hg and 5 beats per minute, respectively. About 80% of patients had a basic metabolic panel drawn, and there were no instances of acute kidney injury. Of the patients in the study 38% had cardiac enzymes collected, and only 1 patient had a positive result, which was determined to be unrelated to acute coronary syndrome. Forty-one (31%) of patients had a urinalysis; 12 has positive results for hematuria, and 18 revealed proteinuria. Of note, the 6 patients who were hospitalized for hypertensive urgency had neither symptoms at presentation to the ED nor laboratory findings indicating end-organ damage. The reason these patients were admitted is unclear.

At discharge, ED providers made changes to 54% of patients’ outpatient antihypertensive regimens. These changes included adding a new medication (68%), increasing the dosage of an existing medication (24%), or multiple changes (8%). Refills were provided for 18% of prescriptions. Follow-up within 7 days from ED discharge was recorded for 34% of patients. One patient received follow-up outside the NFSGVHS and was not included in this analysis.

Discussion

The aim of this retrospective study was to determine the incidence of AH in a VA ED and describe how these patients were managed. Overall, the rate of patients presenting to the ED with AH during the study period was about 1 patient every 8 days or 45 patients per year. By comparison, more than 30,000 patients are seen at the NFSGVHS ED annually. Although AH seems to be an uncommon occurrence, study findings raise questions about the value of managing the condition in the ED.

This study found several management strategies as well as noteworthy trends. For example, laboratory tests were not ordered routinely for all patients, suggesting that some ED providers question their use for AH. There were no patients with acute elevations in serum creatinine that indicated acute kidney injury, and although hematuria and proteinuria were common findings, neither were specific for acute injury. However, there were findings typical of chronic hypertension, and urinalysis may provide little benefit when testing for acute kidney injury. Only 1 patient showed elevated cardiac enzymes, which was determined to be a result of CKD.

Although not included in the final analysis, the 6 patients who were hospitalized for hypertensive urgency were similar in that they had neither symptoms at presentation to the ED nor laboratory findings indicating end-organ damage. Collectively, these findings support existing literature that questions the utility of laboratory testing of patients with AH in the ED.¹⁰

Patients also were treated with a variety of antihypertensive agents in the ED. One explanation might be outpatient nonadherence with medications. In patients with AH, it is common to provide doses of chronic medications that the patient might have missed and should be taking on a regular basis. Therefore, assessing adherence with current medications before modifying chronic therapy is an important initial step when managing AH.

Although oral agents primarily were used, IV antihypertensives were administered to about one-third of patients. Preference for IV administration in the ED might be related to its ability to lower BP quickly. The practice of obtaining IV access for medication in a patient with AH is costly, unnecessary, and potentially harmful.⁷ The authors theorize that this practice is performed, in many cases, as an attempt to expedite ED discharge after an acceptable BP reading is documented.

Rapid reductions in BP can precipitate hypoperfusion inadvertently and are more likely to occur with IV agents than with oral ones. Therefore, the safety, convenience, and cost savings associated with oral administration make it the preferred route for managing AH. 

Best Practices

Primary care clinics are best suited to manage AH because medication adjustments and long-term monitoring are easier to perform and at substantially lower costs when compared with that of the ED. Rather than immediately referring a patient to the ED, clinicians should consider factors that could elevate BP, such as medication nonadherence, anxiety, acute pain, recent tobacco or caffeine use, or white coat syndrome. Staff should be well educated on proper BP measurement and instructed to repeat the reading for confirmation. Before measuring BP, allow the patient to sit quietly for 5 minutes with the feet flat on the floor and arm supported.³ Ideally, the measurement used should be the average of 3 BP readings on an automated device.¹¹ If BP readings are high, staff should ask the patient about medication adherence and missed medication(s) should be administered.

It also is reasonable to have the patient rest quietly for up to 30 minutes because rest has been shown to reduce BP in some patients.¹² The drawback to the prolonged rest strategy is the potential to cause delays in care for other patients. However, it is important to remember that wait times in the ED often are measured in hours, which causes frustration for patients referred to the ED for AH management. Before completing the office visit, the provider should recheck BP using proper technique and confirm that the patient has antihypertensive medication(s) in his/her possession; a follow-up appointment should be scheduled for no later than 1 week.

Primary care providers might be concerned about taking on additional liability and could favor ED referral, but legislation makes it difficult for EDs to defer nonemergent issues to primary care clinics. The Emergency Medical Treatment and Labor Act states that hospitals are prohibited from denying a patient care during an emergency.¹³ Despite evidence that AH is not an emergency, many patients continue to be referred to the ED. One-third of patients presented to the ED on their own volition and more than one-half were referred by health care personnel. This strongly suggests that both patients and health care personnel consider AH an emergency medical condition requiring immediate attention. However, patients with AH rarely are found to have any acute end-organ damage; therefore, acute treatment and extensive laboratory or diagnostic testing in the ED provides little, if any, benefit.¹⁰ The authors believe the ACEP clinical policy should be adopted into mainstream practice to help reduce health care costs and preserve ED resources for patients with true emergencies.

Another pervasive issue that could contribute to inappropriate AH referrals to the ED is the shortage of PCPs and limited same-day appointments for nonemergent conditions. In a 2017 survey, the average wait time for a PCP appointment ranged between 12 and 109 days, depending on the metropolitan area. The national average wait time conducted by this survey was 29.3 days.¹⁴ When primary care appointments are unavailable, triage staff could recommend that patients seek care in the ED. Additionally, patients might choose to seek ED care rather than wait for the next available PCP appointment. Clinic proximity to an ED could influence referral rates. In other words, medical centers or health systems with primary care clinics and ED services under one roof could experience more frequent ED referrals.

A promising strategy to help overcome the challenges of addressing AH and avoiding ED referrals is increasing patient access to and use of qualified, nonphysician providers, such as clinical pharmacists and nurse practitioners. Large health systems such as the VA and Kaiser Permanente have employed clinical pharmacist providers to reduce follow-up times for patients in primary care settings.¹⁵ Furthermore, there is substantial evidence that supports the cost-effectiveness and clinical success of pharmacist-driven hypertension clinics.^16-18 Nurse-driven efforts to improve hypertension control have been successfully implemented in health systems.¹⁹ Both clinical pharmacist and nurse-managed hypertension clinics are effective solutions to manage patients with AH who might otherwise use costly ED services.For example, the average cost of a single ED visit is $740 to $3,437.²⁰ In comparison, a 2010 report from the Agency for Healthcare Research and Quality showed the average annual cost of managing hypertension in ambulatory care clinics was $442 per adult, a cost considerably lower than that of the ED.²¹

Limitations

The retrospective and observational design of this study are inherent limitations. This study was not designed to evaluate cardiovascular outcomes after ED encounters. The sample size could have been larger if patients with BP < 180/110 mm Hg at ED triage were included; however, the 180/110 mm Hg threshold was chosen because it was the most widely agreed on BP value in the literature. This study did not capture patients who presented with AH and did not receive any acute treatment in the ED.Prescribing patterns based on provider training (eg, emergency medicine, family medicine, or internal medicine) were not tracked and might have accounted for differences in selection of diagnostic tests, laboratory ordering, and route of drug administration preference.

A small subset of patients reported positive pain scores at triage but did not describe acute pain. Pain scores are highly subjective, and few primary literature sources link chronic pain with increased BP.^22,23 Nevertheless, patients who reported acute pain and elevated BP were excluded in order to identify truly asymptomatic patients. VA hospitals are unique health systems and data obtained from this study might not be applicable to other public or private facilities. Last, the study did not take into account patients’ psychosocial circumstances that might have fostered a disproportionate reliance on the ED for health care.

Conclusion

Asymptomatic patients with elevated BP are treated in the ED despite no evidence supporting improved outcomes after acute BP lowering in this population. Follow-up after ED encounters for AH did not occur consistently within guideline-recommended 7 days, a trend that also occurs in non-VA systems.⁸ Clinics and health care systems could establish policies to prevent or minimize management of AH in the ED. Ideally, AH should be managed in a clinic setting by a PCP, but growing clinician workload might lead to increasing wait times and difficultly obtaining same-day appointments. Nurse-led clinics and clinical pharmacists operating under a scope of practice and working closely with a PCP are a cost-effective solution to ensure timely treatment and appropriate follow-up of patients with uncontrolled hypertension.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the North Florida South Georgia Veterans Health System in Gainesville, Florida.

Hypertension affects more than 65 million individuals in the U.S., accounting for nearly 30% of the adult population.¹ Less than 50% of those with hypertension are taking appropriate pharmacotherapy.² Hypertension contributes to cardiovascular events, including cerebrovascular accident, transient ischemic attack, hypertensive retinopathy, renal failure, myocardial infarction, and heart failure.¹ Chronic hypertension mainly is an asymptomatic condition, earning the nickname “the silent killer.”² An acute, symptomatic elevation in blood pressure (BP) often is referred to as hypertensive emergency. Symptoms of end-organ damage can include headache, blurry vision, chest pain, shortness of breath, altered mental status, epistaxis, and oliguria.² Although rare, hypertensive emergencies should be treated immediately. The Seventh Report of the Joint National Committee (JNC 7), and the more recent JNC 8, have published guidelines on managing chronic hypertension.^3,4 However, neither report provides guidance on hypertensive emergency or the appropriate actions in cases of extremely elevated BP in an asymptomatic patient.^3,4

Acute hypertensive episodes—often referred to as hypertensive crises—are responsible for nearly 8 million hospitalizations each year and 20 million visits to the emergency department (ED).^5,6 Most of these visits are same-day “treat-and-release” events.⁵ There is no universally accepted BP value associated with a hypertensive crisis, but most resources state that a BP ≥ 180/110 mm Hg requires attention.^2,7 Without other symptoms, elevated BP is not an emergency, yet ED referral for acute management is common.⁷

Three terms fall under the umbrella of hypertensive crises: hypertensive emergency, hypertensive urgency, and asymptomatic hypertension (AH).² In a 2007 article, the American College of Chest Physicians defined hypertensive emergency as BP ≥ 180/110 mm Hg with evidence of end-organ damage.² Symptoms are almost always present in true hypertensive emergencies, and immediate medical intervention is required to halt further organ damage. In the same article, hypertensive urgency is defined as BP ≥ 180/110 mm Hg without end-organ damage.² The definition of hypertensive urgency could be further refined to include the presence of cardiovascular and renal risk factors, although this additional point is not consistent across the literature. Asymptomatic hypertension is similar to hypertensive urgency; however, there is an absence of signs or symptoms of end-organ damage.² There is ambiguity in the literature concerning managing hypertensive urgency and AH, but both share a basic tenet: Immediate BP reduction is not essential. Gradual dosage adjustment(s) of oral medications, preferably by a primary care provider (PCP), and follow-up within 7 days are recommended.⁷

Limited evidence exists to guide ED providers in managing AH. Long-term outcomes and guidelines intended for the primary care setting should not be extrapolated to acute management in the ED. With limited treatment guidelines, providers might be more likely to refer patients with AH to the ED for evaluation. In 2013, the American College of Emergency Physicians (ACEP) created a clinical policy concerning AH in the ED. The ACEP concluded that screening for target organ injury and medical intervention in the ED does not reduce rates of adverse events (AEs) and could lead to overtreatment and acute hypoperfusion.⁷ More recently, Patel and colleagues published findings on hypertensive urgency in the ambulatory care setting, which similarly found that referral to the ED was associated with increased use of health care resources and no change in short-term major AEs.⁸ The ACEP recommends that patients presenting with AH be referred to primary care clinics where long-term monitoring and medication adjustments can be achieved more cost-effectively.⁷

The objective of this retrospective evaluation was to assess the incidence and management of AH within a VA ED. The authors aimed to provide insight into how these patients are managed and discuss alternatives to ED use.

Methods

This retrospective observational study was conducted within the North Florida/South Georgia Veterans Health System (NFSGVHS), which provides patient care at 2 medical centers in Gainesville and Lake City, Florida, as well as 11 outpatient clinics located throughout North Florida and South Georgia. The NFSGVHS serves rural and urban veteran populations. Study approval was granted by the NFSGVHS Institutional Review Board and Research and Development Committee.

Inclusion/Exclusion Criteria

Adult patients who were ordered at least 1 antihypertensive medication in the ED from July 1, 2011 to July 1, 2014, in addition to being asymptomatic with BP ≥ 180/110 mm Hg at ED triage were included. Based on clinical experience, the authors estimated that 3 years would provide a sample size of more than 100 patients. Patients were excluded if they presented with any acute symptoms or were hospitalized for further management.

Data Collection

Baseline demographics were collected for all participants. During the ED encounter, pre- and postintervention vital signs were recorded and prespecified laboratory data obtained. Interrater reliability was accounted for by performing random reviews of previously collected data to ensure consistency during the chart review process. Renal end-organ damage was defined using Acute Kidney Injury Network criteria, a serum creatinine 50% above baseline, or an absolute increase in baseline serum creatinine by 0.3 mg/dL.⁹ Additional laboratory markers of organ damage included cardiac troponin levels. Urinalysis results also were assessed to determine the presence of hematuria or proteinuria. Patient-reported nonadherence with medications was determined by reviewing ED provider and/or nurse documentation notes for the index ED encounter.

Investigators documented the route (IV or oral) and antihypertensive(s) medication selected for each patient. Adverse effects and any changes to patients’ outpatient medication regimens were noted. Investigators also assessed days to next medical contact after ED discharge to determine whether follow-up occurred according to the recommended standard of 7 days.⁹ Days to next medical contact was defined as any contact—in person or by telephone—that was documented in the electronic health record after the index ED visit.

Statistical Analysis

Descriptive statistics, including mean, median, and standard deviation, were used to analyze data.

Results

A total of 1,052 patients presented with BP ≥ 180/110 mm Hg and for whom antihypertensive medication was ordered but not necessarily given in the ED. Of the total, 724 patients were excluded because of hospital admission for other primary diagnoses; however, 6 of these patients were admitted for hypertensive urgency. The final analysis included 132 patients who presented with the primary condition of elevated BP without any accompanying symptoms. Among these patients, 2 had repeat ED visits for AH during the specified time frame.

Most patients were male with an average age of 63 years and documented history of hypertension. Nearly all patients had established primary care within the NFSGVHS. The most common comorbidity was diabetes mellitus (36%), followed by coronary artery disease (27%) and chronic kidney disease (CKD) (21%) (Table 1). About one-third of patients presented to the ED on their own volition, and slightly more than half were referred to the ED by primary care or specialty clinics.

In the ED, 130 patients received BP treatment (Table 2). Medication was ordered for 2 patients who did not receive treatment. In total, 12 different medication classes were used for treating patients with AH in the ED (Figure). 

Treatment in the ED resulted in an average BP and heart rate reduction of 27/20 mm Hg and 5 beats per minute, respectively. About 80% of patients had a basic metabolic panel drawn, and there were no instances of acute kidney injury. Of the patients in the study 38% had cardiac enzymes collected, and only 1 patient had a positive result, which was determined to be unrelated to acute coronary syndrome. Forty-one (31%) of patients had a urinalysis; 12 has positive results for hematuria, and 18 revealed proteinuria. Of note, the 6 patients who were hospitalized for hypertensive urgency had neither symptoms at presentation to the ED nor laboratory findings indicating end-organ damage. The reason these patients were admitted is unclear.

At discharge, ED providers made changes to 54% of patients’ outpatient antihypertensive regimens. These changes included adding a new medication (68%), increasing the dosage of an existing medication (24%), or multiple changes (8%). Refills were provided for 18% of prescriptions. Follow-up within 7 days from ED discharge was recorded for 34% of patients. One patient received follow-up outside the NFSGVHS and was not included in this analysis.

Discussion

The aim of this retrospective study was to determine the incidence of AH in a VA ED and describe how these patients were managed. Overall, the rate of patients presenting to the ED with AH during the study period was about 1 patient every 8 days or 45 patients per year. By comparison, more than 30,000 patients are seen at the NFSGVHS ED annually. Although AH seems to be an uncommon occurrence, study findings raise questions about the value of managing the condition in the ED.

This study found several management strategies as well as noteworthy trends. For example, laboratory tests were not ordered routinely for all patients, suggesting that some ED providers question their use for AH. There were no patients with acute elevations in serum creatinine that indicated acute kidney injury, and although hematuria and proteinuria were common findings, neither were specific for acute injury. However, there were findings typical of chronic hypertension, and urinalysis may provide little benefit when testing for acute kidney injury. Only 1 patient showed elevated cardiac enzymes, which was determined to be a result of CKD.

Although not included in the final analysis, the 6 patients who were hospitalized for hypertensive urgency were similar in that they had neither symptoms at presentation to the ED nor laboratory findings indicating end-organ damage. Collectively, these findings support existing literature that questions the utility of laboratory testing of patients with AH in the ED.¹⁰

Patients also were treated with a variety of antihypertensive agents in the ED. One explanation might be outpatient nonadherence with medications. In patients with AH, it is common to provide doses of chronic medications that the patient might have missed and should be taking on a regular basis. Therefore, assessing adherence with current medications before modifying chronic therapy is an important initial step when managing AH.

Although oral agents primarily were used, IV antihypertensives were administered to about one-third of patients. Preference for IV administration in the ED might be related to its ability to lower BP quickly. The practice of obtaining IV access for medication in a patient with AH is costly, unnecessary, and potentially harmful.⁷ The authors theorize that this practice is performed, in many cases, as an attempt to expedite ED discharge after an acceptable BP reading is documented.

Rapid reductions in BP can precipitate hypoperfusion inadvertently and are more likely to occur with IV agents than with oral ones. Therefore, the safety, convenience, and cost savings associated with oral administration make it the preferred route for managing AH. 

Best Practices

Primary care clinics are best suited to manage AH because medication adjustments and long-term monitoring are easier to perform and at substantially lower costs when compared with that of the ED. Rather than immediately referring a patient to the ED, clinicians should consider factors that could elevate BP, such as medication nonadherence, anxiety, acute pain, recent tobacco or caffeine use, or white coat syndrome. Staff should be well educated on proper BP measurement and instructed to repeat the reading for confirmation. Before measuring BP, allow the patient to sit quietly for 5 minutes with the feet flat on the floor and arm supported.³ Ideally, the measurement used should be the average of 3 BP readings on an automated device.¹¹ If BP readings are high, staff should ask the patient about medication adherence and missed medication(s) should be administered.

It also is reasonable to have the patient rest quietly for up to 30 minutes because rest has been shown to reduce BP in some patients.¹² The drawback to the prolonged rest strategy is the potential to cause delays in care for other patients. However, it is important to remember that wait times in the ED often are measured in hours, which causes frustration for patients referred to the ED for AH management. Before completing the office visit, the provider should recheck BP using proper technique and confirm that the patient has antihypertensive medication(s) in his/her possession; a follow-up appointment should be scheduled for no later than 1 week.

Primary care providers might be concerned about taking on additional liability and could favor ED referral, but legislation makes it difficult for EDs to defer nonemergent issues to primary care clinics. The Emergency Medical Treatment and Labor Act states that hospitals are prohibited from denying a patient care during an emergency.¹³ Despite evidence that AH is not an emergency, many patients continue to be referred to the ED. One-third of patients presented to the ED on their own volition and more than one-half were referred by health care personnel. This strongly suggests that both patients and health care personnel consider AH an emergency medical condition requiring immediate attention. However, patients with AH rarely are found to have any acute end-organ damage; therefore, acute treatment and extensive laboratory or diagnostic testing in the ED provides little, if any, benefit.¹⁰ The authors believe the ACEP clinical policy should be adopted into mainstream practice to help reduce health care costs and preserve ED resources for patients with true emergencies.

Another pervasive issue that could contribute to inappropriate AH referrals to the ED is the shortage of PCPs and limited same-day appointments for nonemergent conditions. In a 2017 survey, the average wait time for a PCP appointment ranged between 12 and 109 days, depending on the metropolitan area. The national average wait time conducted by this survey was 29.3 days.¹⁴ When primary care appointments are unavailable, triage staff could recommend that patients seek care in the ED. Additionally, patients might choose to seek ED care rather than wait for the next available PCP appointment. Clinic proximity to an ED could influence referral rates. In other words, medical centers or health systems with primary care clinics and ED services under one roof could experience more frequent ED referrals.

A promising strategy to help overcome the challenges of addressing AH and avoiding ED referrals is increasing patient access to and use of qualified, nonphysician providers, such as clinical pharmacists and nurse practitioners. Large health systems such as the VA and Kaiser Permanente have employed clinical pharmacist providers to reduce follow-up times for patients in primary care settings.¹⁵ Furthermore, there is substantial evidence that supports the cost-effectiveness and clinical success of pharmacist-driven hypertension clinics.^16-18 Nurse-driven efforts to improve hypertension control have been successfully implemented in health systems.¹⁹ Both clinical pharmacist and nurse-managed hypertension clinics are effective solutions to manage patients with AH who might otherwise use costly ED services.For example, the average cost of a single ED visit is $740 to $3,437.²⁰ In comparison, a 2010 report from the Agency for Healthcare Research and Quality showed the average annual cost of managing hypertension in ambulatory care clinics was $442 per adult, a cost considerably lower than that of the ED.²¹

Limitations

The retrospective and observational design of this study are inherent limitations. This study was not designed to evaluate cardiovascular outcomes after ED encounters. The sample size could have been larger if patients with BP < 180/110 mm Hg at ED triage were included; however, the 180/110 mm Hg threshold was chosen because it was the most widely agreed on BP value in the literature. This study did not capture patients who presented with AH and did not receive any acute treatment in the ED.Prescribing patterns based on provider training (eg, emergency medicine, family medicine, or internal medicine) were not tracked and might have accounted for differences in selection of diagnostic tests, laboratory ordering, and route of drug administration preference.

A small subset of patients reported positive pain scores at triage but did not describe acute pain. Pain scores are highly subjective, and few primary literature sources link chronic pain with increased BP.^22,23 Nevertheless, patients who reported acute pain and elevated BP were excluded in order to identify truly asymptomatic patients. VA hospitals are unique health systems and data obtained from this study might not be applicable to other public or private facilities. Last, the study did not take into account patients’ psychosocial circumstances that might have fostered a disproportionate reliance on the ED for health care.

Conclusion

Asymptomatic patients with elevated BP are treated in the ED despite no evidence supporting improved outcomes after acute BP lowering in this population. Follow-up after ED encounters for AH did not occur consistently within guideline-recommended 7 days, a trend that also occurs in non-VA systems.⁸ Clinics and health care systems could establish policies to prevent or minimize management of AH in the ED. Ideally, AH should be managed in a clinic setting by a PCP, but growing clinician workload might lead to increasing wait times and difficultly obtaining same-day appointments. Nurse-led clinics and clinical pharmacists operating under a scope of practice and working closely with a PCP are a cost-effective solution to ensure timely treatment and appropriate follow-up of patients with uncontrolled hypertension.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the North Florida South Georgia Veterans Health System in Gainesville, Florida.

Hypertension affects more than 65 million individuals in the U.S., accounting for nearly 30% of the adult population.¹ Less than 50% of those with hypertension are taking appropriate pharmacotherapy.² Hypertension contributes to cardiovascular events, including cerebrovascular accident, transient ischemic attack, hypertensive retinopathy, renal failure, myocardial infarction, and heart failure.¹ Chronic hypertension mainly is an asymptomatic condition, earning the nickname “the silent killer.”² An acute, symptomatic elevation in blood pressure (BP) often is referred to as hypertensive emergency. Symptoms of end-organ damage can include headache, blurry vision, chest pain, shortness of breath, altered mental status, epistaxis, and oliguria.² Although rare, hypertensive emergencies should be treated immediately. The Seventh Report of the Joint National Committee (JNC 7), and the more recent JNC 8, have published guidelines on managing chronic hypertension.^3,4 However, neither report provides guidance on hypertensive emergency or the appropriate actions in cases of extremely elevated BP in an asymptomatic patient.^3,4

Acute hypertensive episodes—often referred to as hypertensive crises—are responsible for nearly 8 million hospitalizations each year and 20 million visits to the emergency department (ED).^5,6 Most of these visits are same-day “treat-and-release” events.⁵ There is no universally accepted BP value associated with a hypertensive crisis, but most resources state that a BP ≥ 180/110 mm Hg requires attention.^2,7 Without other symptoms, elevated BP is not an emergency, yet ED referral for acute management is common.⁷

Three terms fall under the umbrella of hypertensive crises: hypertensive emergency, hypertensive urgency, and asymptomatic hypertension (AH).² In a 2007 article, the American College of Chest Physicians defined hypertensive emergency as BP ≥ 180/110 mm Hg with evidence of end-organ damage.² Symptoms are almost always present in true hypertensive emergencies, and immediate medical intervention is required to halt further organ damage. In the same article, hypertensive urgency is defined as BP ≥ 180/110 mm Hg without end-organ damage.² The definition of hypertensive urgency could be further refined to include the presence of cardiovascular and renal risk factors, although this additional point is not consistent across the literature. Asymptomatic hypertension is similar to hypertensive urgency; however, there is an absence of signs or symptoms of end-organ damage.² There is ambiguity in the literature concerning managing hypertensive urgency and AH, but both share a basic tenet: Immediate BP reduction is not essential. Gradual dosage adjustment(s) of oral medications, preferably by a primary care provider (PCP), and follow-up within 7 days are recommended.⁷

Limited evidence exists to guide ED providers in managing AH. Long-term outcomes and guidelines intended for the primary care setting should not be extrapolated to acute management in the ED. With limited treatment guidelines, providers might be more likely to refer patients with AH to the ED for evaluation. In 2013, the American College of Emergency Physicians (ACEP) created a clinical policy concerning AH in the ED. The ACEP concluded that screening for target organ injury and medical intervention in the ED does not reduce rates of adverse events (AEs) and could lead to overtreatment and acute hypoperfusion.⁷ More recently, Patel and colleagues published findings on hypertensive urgency in the ambulatory care setting, which similarly found that referral to the ED was associated with increased use of health care resources and no change in short-term major AEs.⁸ The ACEP recommends that patients presenting with AH be referred to primary care clinics where long-term monitoring and medication adjustments can be achieved more cost-effectively.⁷

The objective of this retrospective evaluation was to assess the incidence and management of AH within a VA ED. The authors aimed to provide insight into how these patients are managed and discuss alternatives to ED use.

Methods

This retrospective observational study was conducted within the North Florida/South Georgia Veterans Health System (NFSGVHS), which provides patient care at 2 medical centers in Gainesville and Lake City, Florida, as well as 11 outpatient clinics located throughout North Florida and South Georgia. The NFSGVHS serves rural and urban veteran populations. Study approval was granted by the NFSGVHS Institutional Review Board and Research and Development Committee.

Inclusion/Exclusion Criteria

Adult patients who were ordered at least 1 antihypertensive medication in the ED from July 1, 2011 to July 1, 2014, in addition to being asymptomatic with BP ≥ 180/110 mm Hg at ED triage were included. Based on clinical experience, the authors estimated that 3 years would provide a sample size of more than 100 patients. Patients were excluded if they presented with any acute symptoms or were hospitalized for further management.

Data Collection

Baseline demographics were collected for all participants. During the ED encounter, pre- and postintervention vital signs were recorded and prespecified laboratory data obtained. Interrater reliability was accounted for by performing random reviews of previously collected data to ensure consistency during the chart review process. Renal end-organ damage was defined using Acute Kidney Injury Network criteria, a serum creatinine 50% above baseline, or an absolute increase in baseline serum creatinine by 0.3 mg/dL.⁹ Additional laboratory markers of organ damage included cardiac troponin levels. Urinalysis results also were assessed to determine the presence of hematuria or proteinuria. Patient-reported nonadherence with medications was determined by reviewing ED provider and/or nurse documentation notes for the index ED encounter.

Investigators documented the route (IV or oral) and antihypertensive(s) medication selected for each patient. Adverse effects and any changes to patients’ outpatient medication regimens were noted. Investigators also assessed days to next medical contact after ED discharge to determine whether follow-up occurred according to the recommended standard of 7 days.⁹ Days to next medical contact was defined as any contact—in person or by telephone—that was documented in the electronic health record after the index ED visit.

Statistical Analysis

Descriptive statistics, including mean, median, and standard deviation, were used to analyze data.

Results

A total of 1,052 patients presented with BP ≥ 180/110 mm Hg and for whom antihypertensive medication was ordered but not necessarily given in the ED. Of the total, 724 patients were excluded because of hospital admission for other primary diagnoses; however, 6 of these patients were admitted for hypertensive urgency. The final analysis included 132 patients who presented with the primary condition of elevated BP without any accompanying symptoms. Among these patients, 2 had repeat ED visits for AH during the specified time frame.

Most patients were male with an average age of 63 years and documented history of hypertension. Nearly all patients had established primary care within the NFSGVHS. The most common comorbidity was diabetes mellitus (36%), followed by coronary artery disease (27%) and chronic kidney disease (CKD) (21%) (Table 1). About one-third of patients presented to the ED on their own volition, and slightly more than half were referred to the ED by primary care or specialty clinics.

In the ED, 130 patients received BP treatment (Table 2). Medication was ordered for 2 patients who did not receive treatment. In total, 12 different medication classes were used for treating patients with AH in the ED (Figure). 

Treatment in the ED resulted in an average BP and heart rate reduction of 27/20 mm Hg and 5 beats per minute, respectively. About 80% of patients had a basic metabolic panel drawn, and there were no instances of acute kidney injury. Of the patients in the study 38% had cardiac enzymes collected, and only 1 patient had a positive result, which was determined to be unrelated to acute coronary syndrome. Forty-one (31%) of patients had a urinalysis; 12 has positive results for hematuria, and 18 revealed proteinuria. Of note, the 6 patients who were hospitalized for hypertensive urgency had neither symptoms at presentation to the ED nor laboratory findings indicating end-organ damage. The reason these patients were admitted is unclear.

At discharge, ED providers made changes to 54% of patients’ outpatient antihypertensive regimens. These changes included adding a new medication (68%), increasing the dosage of an existing medication (24%), or multiple changes (8%). Refills were provided for 18% of prescriptions. Follow-up within 7 days from ED discharge was recorded for 34% of patients. One patient received follow-up outside the NFSGVHS and was not included in this analysis.

Discussion

The aim of this retrospective study was to determine the incidence of AH in a VA ED and describe how these patients were managed. Overall, the rate of patients presenting to the ED with AH during the study period was about 1 patient every 8 days or 45 patients per year. By comparison, more than 30,000 patients are seen at the NFSGVHS ED annually. Although AH seems to be an uncommon occurrence, study findings raise questions about the value of managing the condition in the ED.

This study found several management strategies as well as noteworthy trends. For example, laboratory tests were not ordered routinely for all patients, suggesting that some ED providers question their use for AH. There were no patients with acute elevations in serum creatinine that indicated acute kidney injury, and although hematuria and proteinuria were common findings, neither were specific for acute injury. However, there were findings typical of chronic hypertension, and urinalysis may provide little benefit when testing for acute kidney injury. Only 1 patient showed elevated cardiac enzymes, which was determined to be a result of CKD.

Although not included in the final analysis, the 6 patients who were hospitalized for hypertensive urgency were similar in that they had neither symptoms at presentation to the ED nor laboratory findings indicating end-organ damage. Collectively, these findings support existing literature that questions the utility of laboratory testing of patients with AH in the ED.¹⁰

Patients also were treated with a variety of antihypertensive agents in the ED. One explanation might be outpatient nonadherence with medications. In patients with AH, it is common to provide doses of chronic medications that the patient might have missed and should be taking on a regular basis. Therefore, assessing adherence with current medications before modifying chronic therapy is an important initial step when managing AH.

Although oral agents primarily were used, IV antihypertensives were administered to about one-third of patients. Preference for IV administration in the ED might be related to its ability to lower BP quickly. The practice of obtaining IV access for medication in a patient with AH is costly, unnecessary, and potentially harmful.⁷ The authors theorize that this practice is performed, in many cases, as an attempt to expedite ED discharge after an acceptable BP reading is documented.

Rapid reductions in BP can precipitate hypoperfusion inadvertently and are more likely to occur with IV agents than with oral ones. Therefore, the safety, convenience, and cost savings associated with oral administration make it the preferred route for managing AH. 

Best Practices

Primary care clinics are best suited to manage AH because medication adjustments and long-term monitoring are easier to perform and at substantially lower costs when compared with that of the ED. Rather than immediately referring a patient to the ED, clinicians should consider factors that could elevate BP, such as medication nonadherence, anxiety, acute pain, recent tobacco or caffeine use, or white coat syndrome. Staff should be well educated on proper BP measurement and instructed to repeat the reading for confirmation. Before measuring BP, allow the patient to sit quietly for 5 minutes with the feet flat on the floor and arm supported.³ Ideally, the measurement used should be the average of 3 BP readings on an automated device.¹¹ If BP readings are high, staff should ask the patient about medication adherence and missed medication(s) should be administered.

It also is reasonable to have the patient rest quietly for up to 30 minutes because rest has been shown to reduce BP in some patients.¹² The drawback to the prolonged rest strategy is the potential to cause delays in care for other patients. However, it is important to remember that wait times in the ED often are measured in hours, which causes frustration for patients referred to the ED for AH management. Before completing the office visit, the provider should recheck BP using proper technique and confirm that the patient has antihypertensive medication(s) in his/her possession; a follow-up appointment should be scheduled for no later than 1 week.

Primary care providers might be concerned about taking on additional liability and could favor ED referral, but legislation makes it difficult for EDs to defer nonemergent issues to primary care clinics. The Emergency Medical Treatment and Labor Act states that hospitals are prohibited from denying a patient care during an emergency.¹³ Despite evidence that AH is not an emergency, many patients continue to be referred to the ED. One-third of patients presented to the ED on their own volition and more than one-half were referred by health care personnel. This strongly suggests that both patients and health care personnel consider AH an emergency medical condition requiring immediate attention. However, patients with AH rarely are found to have any acute end-organ damage; therefore, acute treatment and extensive laboratory or diagnostic testing in the ED provides little, if any, benefit.¹⁰ The authors believe the ACEP clinical policy should be adopted into mainstream practice to help reduce health care costs and preserve ED resources for patients with true emergencies.

Another pervasive issue that could contribute to inappropriate AH referrals to the ED is the shortage of PCPs and limited same-day appointments for nonemergent conditions. In a 2017 survey, the average wait time for a PCP appointment ranged between 12 and 109 days, depending on the metropolitan area. The national average wait time conducted by this survey was 29.3 days.¹⁴ When primary care appointments are unavailable, triage staff could recommend that patients seek care in the ED. Additionally, patients might choose to seek ED care rather than wait for the next available PCP appointment. Clinic proximity to an ED could influence referral rates. In other words, medical centers or health systems with primary care clinics and ED services under one roof could experience more frequent ED referrals.

A promising strategy to help overcome the challenges of addressing AH and avoiding ED referrals is increasing patient access to and use of qualified, nonphysician providers, such as clinical pharmacists and nurse practitioners. Large health systems such as the VA and Kaiser Permanente have employed clinical pharmacist providers to reduce follow-up times for patients in primary care settings.¹⁵ Furthermore, there is substantial evidence that supports the cost-effectiveness and clinical success of pharmacist-driven hypertension clinics.^16-18 Nurse-driven efforts to improve hypertension control have been successfully implemented in health systems.¹⁹ Both clinical pharmacist and nurse-managed hypertension clinics are effective solutions to manage patients with AH who might otherwise use costly ED services.For example, the average cost of a single ED visit is $740 to $3,437.²⁰ In comparison, a 2010 report from the Agency for Healthcare Research and Quality showed the average annual cost of managing hypertension in ambulatory care clinics was $442 per adult, a cost considerably lower than that of the ED.²¹

Limitations

The retrospective and observational design of this study are inherent limitations. This study was not designed to evaluate cardiovascular outcomes after ED encounters. The sample size could have been larger if patients with BP < 180/110 mm Hg at ED triage were included; however, the 180/110 mm Hg threshold was chosen because it was the most widely agreed on BP value in the literature. This study did not capture patients who presented with AH and did not receive any acute treatment in the ED.Prescribing patterns based on provider training (eg, emergency medicine, family medicine, or internal medicine) were not tracked and might have accounted for differences in selection of diagnostic tests, laboratory ordering, and route of drug administration preference.

A small subset of patients reported positive pain scores at triage but did not describe acute pain. Pain scores are highly subjective, and few primary literature sources link chronic pain with increased BP.^22,23 Nevertheless, patients who reported acute pain and elevated BP were excluded in order to identify truly asymptomatic patients. VA hospitals are unique health systems and data obtained from this study might not be applicable to other public or private facilities. Last, the study did not take into account patients’ psychosocial circumstances that might have fostered a disproportionate reliance on the ED for health care.

Conclusion

Asymptomatic patients with elevated BP are treated in the ED despite no evidence supporting improved outcomes after acute BP lowering in this population. Follow-up after ED encounters for AH did not occur consistently within guideline-recommended 7 days, a trend that also occurs in non-VA systems.⁸ Clinics and health care systems could establish policies to prevent or minimize management of AH in the ED. Ideally, AH should be managed in a clinic setting by a PCP, but growing clinician workload might lead to increasing wait times and difficultly obtaining same-day appointments. Nurse-led clinics and clinical pharmacists operating under a scope of practice and working closely with a PCP are a cost-effective solution to ensure timely treatment and appropriate follow-up of patients with uncontrolled hypertension.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the North Florida South Georgia Veterans Health System in Gainesville, Florida.

Posttraumatic stress disorder (PTSD) is a mental health condition that may develop in response to a traumatic event, such as that experienced by a soldier during active combat duty. In 2009, more than 495,000 veterans within the VA health care system were treated for PTSD—nearly triple the number a decade earlier.¹ Core symptoms of PTSD include alterations in arousal and reactivity, avoidant behaviors, negative alterations in mood and cognition, and intrusive thoughts and nightmares. All of the symptoms can be debilitating. First-line pharmacotherapy options that target these core symptoms include selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).²

The anxiolytic and sedative effects of benzodiazepines may provide quick relief from many of the secondary symptoms of PTSD, including sleep disturbances, irritability, and panic attacks. However, benzodiazepines potentially interfere with the extinction of conditioned fear—a goal integral to certain types of psychotherapy, such as exposure therapy.^3,4 In addition, the systematic review and meta-analysis by Guina and colleagues revealed that benzodiazepines are ineffective in the treatment of PTSD.⁵ The majority of the evaluated studies that used PTSD-specific measures (eg, Clinician-Administered PTSD Scale [CAPS]) found increased PTSD severity and worse prognosis with use of these medications.⁵ In 2010, the VA and the DoD released a joint guideline for PTSD management.² According to the guideline, benzodiazepines cause harm when used in PTSD and are relatively contraindicated in combat veterans because of the higher incidence of comorbid substance use disorders (SUDs) in these veterans relative to the general population.^2,6

Opioid use also has been linked to poor functional and clinical outcomes in veterans with PTSD. Among patients being treated for opioid use disorder, those with PTSD were less likely to endorse employment as a main source of income and had a higher incidence of recent attempted suicide.⁷ In a large retrospective cohort study, Operation Iraqi Freedom and Operation Enduring Freedom veterans with PTSD who were prescribed opioids were more likely to present to the emergency department (ED) and to be hospitalized for overdoses and injuries.⁸

Despite the risks of benzodiazepine and opioid use in this patient population, these medications are still often prescribed to veterans with PTSD for symptomatic relief. In fiscal year 2009, across the VHA system 37% of veterans diagnosed with PTSD were prescribed a benzodiazepine, 69% of the time by a mental health provider.⁹ Among Iraq and Afghanistan veterans, those with PTSD were significantly more likely to be prescribed an opioid for diagnosed pain—relative to those with a mental health disorder other than PTSD and those without a mental health disorder.⁸ Thus, there seems to be a disconnect between guideline recommendations and current practice.

The authors conducted a study to assess the potential risk of hospitalization for veterans with PTSD prescribed first-line pharmacotherapy and those also prescribed concurrent benzodiazepine and/or opioid therapy since the release of the PTSD guideline in 2010.²

Methods

In this retrospective cohort study, conducted at the Southern Arizona VA Health Care System (SAVAHCS), the authors analyzed electronic medical record data from November 1, 2009 to August 1, 2015. Study inclusion criteria were veteran, aged 18 to 89 years, diagnosis of PTSD (International Classification of Diseases, Ninth Revision, Clinical Modification code 309.81), and SSRI or SNRI newly prescribed between November 1, 2010 and August 1, 2013.

Any veteran prescribed at least one 30-day or longer supply of any benzodiazepine or opioid within 1 year before the SSRI/SNRI initial prescription date was excluded from the study. Also excluded was any patient treated for PTSD at a facility outside SAVAHCS or whose 2-year evaluation period extended past August 1, 2015.

Study Groups

An outpatient prescription was determined to be the initial SSRI/SNRI prescription for a patient who received less than a 30-day cumulative supply of any SSRI or SNRI within 1 year before that prescription date. Citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone, and vortioxetine were the prespecified SSRI/SNRIs included in the study.

Patients who received at least 1 outpatient prescription for any benzodiazepine (minimum 30-day supply) within 1 year after the initial SSRI/SNRI prescription date were determined to be on concurrent SSRI/SNRI and benzodiazepine therapy. Alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, temazepam, and triazolam were the prespecified benzodiazepines included in the study.

Patients who received at least 1 outpatient prescription for any opioid (minimum 30-day supply) within 1 year after the initial SSRI/SNRI prescription date were determined to be on concurrent SSRI/SNRI and opioid therapy. Codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxymorphone, pentazocine, propoxyphene, and tramadol were the prespecified opioids included in this study.

Patients who received at least 1 outpatient prescription for any benzodiazepine and any opioid (minimum 30-day supply) within 1 year after the initial SSRI/SNRI prescription date were determined to be on concurrent SSRI/SNRI, benzodiazepine, and opioid therapy.

The index date was defined as the first date of prescription overlap. If there was no benzodiazepine or opioid prescription within 1 year after the initial SSRI/SNRI prescription date, the patient was categorized as being on SSRI/SNRI monotherapy, and the index date was the date of the initial SSRI/SNRI prescription. For each patient, hospitalization data from the 2-year period after the index date were evaluated.

Outcomes and Data Collection

For evaluation of the primary outcome (2-year overall hospitalization risk), the number of unique mental health and medical/surgical hospitalizations was identified by the number of discharge summaries documented in the patient chart during the evaluation period. Time to first hospitalization was recorded for the survival data analysis. Secondary outcomes were mental health hospitalization risk, medical/surgical hospitalization risk, and all-cause mortality within 2 years.

Demographic data that were collected included age, sex, comorbid mental health disorders, comorbid SUDs, and concomitant use of psychotropic medications at index date (baseline). Select comorbid mental health disorders (anxiety, schizophrenia, depression, bipolar disorder) and substance use disorders (alcohol, opioid, illicit drug) also were identified. Data on insomnia and pain comorbidities (headaches or migraines; neuropathy; head, neck, back, arthritis, or joint pain) were collected, as these comorbidities could be indications for prescribing benzodiazepines and opioids. Concomitant baseline use of classes of psychotropic medications (antipsychotics, non-SSRI/SNRI antidepressants, mood stabilizers, anxiolytics, nonbenzodiazepine sedatives/hypnotics) also were documented. Last, hospitalizations within 6 months before the initial SSRI/SNRI prescription date were noted.

Statistical Analysis

Descriptive statistics were used to analyze all baseline demographic data. Continuous measures were evaluated with 1-way analyses of variance and post hoc Bonferroni-corrected pairwise comparisons, and categorical measures with contingency tables and χ² tests or Fisher exact tests. When the overall χ² test was significant across all 4 study groups, post hoc comparisons were performed between the SSRI/SNRI monotherapy group and each other group with Bonferroni adjusted for 3 comparisons.

Unadjusted and adjusted Weibull proportional hazard regression models were used to estimate hospitalization risk within 2 years after the index date for the different study groups with the SSRI/SNRI monotherapy group as the referent. Robust standard errors were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The Weibull model (and not the Cox model) was used because it does not assume hazard remains constant over time, which is appropriate in this instance, as the risk of an adverse event (AE) may be higher when first starting a medication or combination of medications relative to when doses are stabilized. Models were adjusted for age, sex, baseline mental health disorders, and baseline psychotropic medications. As earlier hospitalizations showed evidence of effect modification when this covariate was tested, hazard analyses were limited to patients not previously hospitalized.

The effect size of differences in hospitalization risk meeting statistical significance was assessed by estimating the number needed to harm (NNH) and 95% CIs (not shown) to observe 1 additional hospitalization in each medication group relative to the SSRI/SNRI monotherapy group over a 90-day period. A 95% CI for NNH that did not include 0 indicated the NNH was significant at the .05 level.¹⁰ All-cause mortality was evaluated with the Fisher exact test with post hoc Bonferroni-corrected comparisons as appropriate.

Results

Of 1,703 patients screened, 613 met all study inclusion criteria (Figure 1). 

Baseline characteristics revealed no significant differences between groups in age or comorbid depression, schizophrenia, or SUDs (Table 1). 

With the SSRI/SNRI monotherapy group as the referent, all concurrent therapy groups were at significantly increased risk for overall hospitalization within 2 years after the index date (Tables 2 & 3, Figure 2). 

Risk for mental health hospitalization was significantly increased in all concurrent therapy groups relative to the referent group.

Discussion

In 2013, Hawkins and colleagues evaluated hospitalization risk in veterans treated for PTSD within the Northwest VISN 20 between 2004 and 2010.¹¹ Compared with patients treated with only an SSRI or SNRI, those treated with 1 of those medications and a benzodiazepine were at significantly higher risk for overall hospitalization (AHR, 1.79; 95% CI, 1.38-2.32; P < .001) and mental health hospitalization (AHR, 1.87; 95% CI, 1.37-2.53; P < .001). Furthermore, those prescribed a benzodiazepine and an opioid along with an SSRI or SNRI were at higher risk for overall hospitalization (AHR, 2.98; 95% CI, 2.22-4.00; P < .001), mental health hospitalization (AHR, 2.00; 95% CI, 1.35-2.98; P < .01), medical/surgical hospitalization (AHR, 4.86; 95% CI, 3.30-7.14; P < .001), and ED visits (AHR, 2.01; 95% CI, 1.53-2.65; P < .001).

Findings from the present study, which covered a period after the newest PTSD guideline was released,support findings reported by Hawkins and colleagues in their retrospective cohort study covering an earlier period.^2,11 In the present study, compared with the monotherapy group, the SSRI/SNRI and benzodiazepine therapy group and the SSRI/SNRI, benzodiazepine, and opioid therapy group were at higher risk for both overall hospitalization and mental health hospitalization within 2 years. However, in a subset of PTSD patients prescribed opioids along with first-line pharmacotherapy, this study found that overall, mental health, and medical/surgical hospitalizations were significantly increased as well. Furthermore, this study found 2-year mortality was significantly higher for the SSRI/SNRI, benzodiazepine, and opioid therapy group than for the SSRI/SNRI monotherapy group.

Adjusted hazard ratios were higher in the present study than those in the study by Hawkins and colleagues,but CIs were wider as well.¹¹ These differences may be attributable to the relatively smaller sample size of the present study and may explain why the HR was higher for the SSRI/SNRI and opioid therapy group than for the SSRI/SNRI, benzodiazepine, and opioid therapy group.

Nevertheless, these results support the growing body of evidence establishing the many risks for AEs when benzodiazepines and opioids are prescribed in the setting of PTSD. Unfortunately, it seems that, against clear guideline recommendations and literature findings, these medications still are being prescribed to this vulnerable, high-risk population.

In the last few months of 2013, the VA health care system launched 2 important medication safety initiatives. The Psychotropic Drug Safety Initiative (PDSI) was established as a quality improvement initiative for evidence-based provision of psychotropic medications. One PDSI metric in particular focused on reducing the proportion of veterans with PTSD being treated with benzodiazepines. The Opioid Safety Initiative (OSI) came as a response to a dramatic increase in the number of fatal overdoses related to prescription opioids—an increase linked to an unprecedented jump in opioid use for nonmalignant pain. As the present study’s inclusion cutoff date of August 1, 2013, preceded the debut of both PDSI and OSI, the benzodiazepine and opioid prescription rates reported here might be higher than those currently being found under the 2 initiatives.

Limitations

This study had several limitations that might affect the interpretation or generalizability of findings. Requiring at least a 30-day supply for prescription eligibility was an attempt to focus on chronic use of medications rather than on, for example, onetime supplies of opioids for dental procedures. However, prescription fill history was not assessed. Therefore, patients could have been included in certain study groups even if their SSRI, SNRI, benzodiazepine, or opioid prescription was not refilled. Furthermore, only VA medical records were used; non-VA prescriptions were not captured.

In addition, this study was limited to patients who at bare minimum were prescribed an SSRI or an SNRI. Some patients may have been prescribed a benzodiazepine and/or an opioid but were not on appropriate first-line pharmacotherapy for PTSD. These patients were excluded from the study, and their relative hospitalization risk went unexplored. Therefore, the magnitude of the issue at hand might have been underestimated.

Although psychotherapy is a first-line treatment option for PTSD, the study did not assess the potential impact of psychotherapy on outcomes or the groups’ relative proportions of patients undergoing psychotherapy. It is unknown whether the groups were equivalent at baseline in regards to psychotherapy participation rates.

This study did not characterize the specific reasons for hospitalization beyond whether it was for a mental health or a medical/surgical issue; thus, no distinction was made between hospitalizations for an elective procedure and hospitalizations for a drug overdose or an injury. Investigators could characterize admission diagnoses to better assess whether hospitalizations are truly associated with study medications or whether patients are being hospitalized for unrelated reasons. In addition, they could elucidate the true nature of hospitalization risk associated with SSRI/SNRI, benzodiazepine, and opioid use by comparing admission diagnoses made before and after initiation of these pharmacologic therapies.

This study also could not assess outcomes for patients who presented to the ED but were not admitted. If the hospital’s floor and ED beds were at full capacity, some patients might have been transferred to an outside facility. However, this scenario is not common at SAVAHCS, where the study was conducted.

Although some comorbid conditions were noted, the study did not evaluate whether its patients had a compelling indication for benzodiazepines in particular. Opioid use is very limited to the treatment of pain, and the majority of the patients on opioid therapy in this study had a diagnosed pain syndrome.

Because of the study’s sample size and power limitations, patients were eligible to be included in a concurrent therapy group if a benzodiazepine, an opioid, or both were added no later than 1 year after SSRI/SNRI initiation. This gap of up to 1 year might have introduced some variability in exposure to risk from earlier prescribed medications. However, sensitivity analyses were performed with multiple constructed Weibull models of time to hospitalization based on subsets with varying overlapping medication gaps. Analyses revealed relatively stable HRs, suggesting that potential bias did not occur.

Future Directions

Investigators could explore the higher all-cause mortality rates in the SSRI/SNRI, benzodiazepine, and opioid therapy group, as this study did not assess cause of death in these patients. Whether any patients died of reasons directly attributable to benzodiazepines or opioids is unknown.

That SSRIs and SNRIs are the only established first-line pharmacologic treatment options for PTSD symptoms partly accounts for the widespread use of benzodiazepines in this population. For that reason, beyond characterizing the many risks associated with using benzodiazepines to manage these symptoms, there is a huge need to research the viability of other pharmacologic agents in treating PTSD. This is especially important given the slower onset to efficacy of the SSRIs and SNRIs; per estimates, only up to 60% of patients respond to SSRIs, and 20% to 30% achieve full remission of PTSD.¹² Furthermore, these rates likely are even lower for combat veterans than those for the general population. Several trials discussed in a 2009 guideline review of the treatment of patients with acute stress disorder and PTSD have called into question the efficacy of SSRIs for combat-related PTSD.¹³ In these randomized, controlled trials, change in PTSD symptom severity as measured with CAPS was not significantly reduced with SSRIs compared with placebo.

A systematic review revealed that, of the nonantidepressants used as adjuncts in treating patients who do not achieve remission with SSRIs, the atypical antipsychotic risperidone may have the strongest supporting evidence.¹² However, the present study found high rates of antipsychotic use in the SSRI/SNRI, benzodiazepine, and opioid therapy group, which also had the highest all-cause mortality rate. The safety of risperidone as an alternative treatment needs further evaluation.

Some prospective studies have suggested that the α₁ blockers doxazosin and prazosin, the latter of which is commonly used for PTSD nightmares, also may improve PTSD symptoms as assessed by CAPS.^14,15 Although these results are promising, the trials to date have been conducted with relatively small sample sizes.

With more veterans being treated for PTSD within the VA health care system, the central treatment goal remains: Adequately address the symptoms of PTSD while minimizing the harm caused by medications. Prescribers should limit benzodiazepine and opioid use in this population and consider safer nonpharmacologic and pharmacologic treatment options when possible.

Conclusion

Combat veterans with PTSD who are prescribed benzodiazepines and/or opioids in addition to first-line pharmacotherapy are at significantly increased risk for overall and mental health hospitalization.

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Posttraumatic stress disorder (PTSD) is a mental health condition that may develop in response to a traumatic event, such as that experienced by a soldier during active combat duty. In 2009, more than 495,000 veterans within the VA health care system were treated for PTSD—nearly triple the number a decade earlier.¹ Core symptoms of PTSD include alterations in arousal and reactivity, avoidant behaviors, negative alterations in mood and cognition, and intrusive thoughts and nightmares. All of the symptoms can be debilitating. First-line pharmacotherapy options that target these core symptoms include selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).²

The anxiolytic and sedative effects of benzodiazepines may provide quick relief from many of the secondary symptoms of PTSD, including sleep disturbances, irritability, and panic attacks. However, benzodiazepines potentially interfere with the extinction of conditioned fear—a goal integral to certain types of psychotherapy, such as exposure therapy.^3,4 In addition, the systematic review and meta-analysis by Guina and colleagues revealed that benzodiazepines are ineffective in the treatment of PTSD.⁵ The majority of the evaluated studies that used PTSD-specific measures (eg, Clinician-Administered PTSD Scale [CAPS]) found increased PTSD severity and worse prognosis with use of these medications.⁵ In 2010, the VA and the DoD released a joint guideline for PTSD management.² According to the guideline, benzodiazepines cause harm when used in PTSD and are relatively contraindicated in combat veterans because of the higher incidence of comorbid substance use disorders (SUDs) in these veterans relative to the general population.^2,6

Opioid use also has been linked to poor functional and clinical outcomes in veterans with PTSD. Among patients being treated for opioid use disorder, those with PTSD were less likely to endorse employment as a main source of income and had a higher incidence of recent attempted suicide.⁷ In a large retrospective cohort study, Operation Iraqi Freedom and Operation Enduring Freedom veterans with PTSD who were prescribed opioids were more likely to present to the emergency department (ED) and to be hospitalized for overdoses and injuries.⁸

Despite the risks of benzodiazepine and opioid use in this patient population, these medications are still often prescribed to veterans with PTSD for symptomatic relief. In fiscal year 2009, across the VHA system 37% of veterans diagnosed with PTSD were prescribed a benzodiazepine, 69% of the time by a mental health provider.⁹ Among Iraq and Afghanistan veterans, those with PTSD were significantly more likely to be prescribed an opioid for diagnosed pain—relative to those with a mental health disorder other than PTSD and those without a mental health disorder.⁸ Thus, there seems to be a disconnect between guideline recommendations and current practice.

The authors conducted a study to assess the potential risk of hospitalization for veterans with PTSD prescribed first-line pharmacotherapy and those also prescribed concurrent benzodiazepine and/or opioid therapy since the release of the PTSD guideline in 2010.²

Methods

In this retrospective cohort study, conducted at the Southern Arizona VA Health Care System (SAVAHCS), the authors analyzed electronic medical record data from November 1, 2009 to August 1, 2015. Study inclusion criteria were veteran, aged 18 to 89 years, diagnosis of PTSD (International Classification of Diseases, Ninth Revision, Clinical Modification code 309.81), and SSRI or SNRI newly prescribed between November 1, 2010 and August 1, 2013.

Any veteran prescribed at least one 30-day or longer supply of any benzodiazepine or opioid within 1 year before the SSRI/SNRI initial prescription date was excluded from the study. Also excluded was any patient treated for PTSD at a facility outside SAVAHCS or whose 2-year evaluation period extended past August 1, 2015.

Study Groups

An outpatient prescription was determined to be the initial SSRI/SNRI prescription for a patient who received less than a 30-day cumulative supply of any SSRI or SNRI within 1 year before that prescription date. Citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone, and vortioxetine were the prespecified SSRI/SNRIs included in the study.

Patients who received at least 1 outpatient prescription for any benzodiazepine (minimum 30-day supply) within 1 year after the initial SSRI/SNRI prescription date were determined to be on concurrent SSRI/SNRI and benzodiazepine therapy. Alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, temazepam, and triazolam were the prespecified benzodiazepines included in the study.

Patients who received at least 1 outpatient prescription for any opioid (minimum 30-day supply) within 1 year after the initial SSRI/SNRI prescription date were determined to be on concurrent SSRI/SNRI and opioid therapy. Codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxymorphone, pentazocine, propoxyphene, and tramadol were the prespecified opioids included in this study.

Patients who received at least 1 outpatient prescription for any benzodiazepine and any opioid (minimum 30-day supply) within 1 year after the initial SSRI/SNRI prescription date were determined to be on concurrent SSRI/SNRI, benzodiazepine, and opioid therapy.

The index date was defined as the first date of prescription overlap. If there was no benzodiazepine or opioid prescription within 1 year after the initial SSRI/SNRI prescription date, the patient was categorized as being on SSRI/SNRI monotherapy, and the index date was the date of the initial SSRI/SNRI prescription. For each patient, hospitalization data from the 2-year period after the index date were evaluated.

Outcomes and Data Collection

For evaluation of the primary outcome (2-year overall hospitalization risk), the number of unique mental health and medical/surgical hospitalizations was identified by the number of discharge summaries documented in the patient chart during the evaluation period. Time to first hospitalization was recorded for the survival data analysis. Secondary outcomes were mental health hospitalization risk, medical/surgical hospitalization risk, and all-cause mortality within 2 years.

Demographic data that were collected included age, sex, comorbid mental health disorders, comorbid SUDs, and concomitant use of psychotropic medications at index date (baseline). Select comorbid mental health disorders (anxiety, schizophrenia, depression, bipolar disorder) and substance use disorders (alcohol, opioid, illicit drug) also were identified. Data on insomnia and pain comorbidities (headaches or migraines; neuropathy; head, neck, back, arthritis, or joint pain) were collected, as these comorbidities could be indications for prescribing benzodiazepines and opioids. Concomitant baseline use of classes of psychotropic medications (antipsychotics, non-SSRI/SNRI antidepressants, mood stabilizers, anxiolytics, nonbenzodiazepine sedatives/hypnotics) also were documented. Last, hospitalizations within 6 months before the initial SSRI/SNRI prescription date were noted.

Statistical Analysis

Descriptive statistics were used to analyze all baseline demographic data. Continuous measures were evaluated with 1-way analyses of variance and post hoc Bonferroni-corrected pairwise comparisons, and categorical measures with contingency tables and χ² tests or Fisher exact tests. When the overall χ² test was significant across all 4 study groups, post hoc comparisons were performed between the SSRI/SNRI monotherapy group and each other group with Bonferroni adjusted for 3 comparisons.

Unadjusted and adjusted Weibull proportional hazard regression models were used to estimate hospitalization risk within 2 years after the index date for the different study groups with the SSRI/SNRI monotherapy group as the referent. Robust standard errors were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The Weibull model (and not the Cox model) was used because it does not assume hazard remains constant over time, which is appropriate in this instance, as the risk of an adverse event (AE) may be higher when first starting a medication or combination of medications relative to when doses are stabilized. Models were adjusted for age, sex, baseline mental health disorders, and baseline psychotropic medications. As earlier hospitalizations showed evidence of effect modification when this covariate was tested, hazard analyses were limited to patients not previously hospitalized.

The effect size of differences in hospitalization risk meeting statistical significance was assessed by estimating the number needed to harm (NNH) and 95% CIs (not shown) to observe 1 additional hospitalization in each medication group relative to the SSRI/SNRI monotherapy group over a 90-day period. A 95% CI for NNH that did not include 0 indicated the NNH was significant at the .05 level.¹⁰ All-cause mortality was evaluated with the Fisher exact test with post hoc Bonferroni-corrected comparisons as appropriate.

Results

Of 1,703 patients screened, 613 met all study inclusion criteria (Figure 1). 

Baseline characteristics revealed no significant differences between groups in age or comorbid depression, schizophrenia, or SUDs (Table 1). 

With the SSRI/SNRI monotherapy group as the referent, all concurrent therapy groups were at significantly increased risk for overall hospitalization within 2 years after the index date (Tables 2 & 3, Figure 2). 

Risk for mental health hospitalization was significantly increased in all concurrent therapy groups relative to the referent group.

Discussion

In 2013, Hawkins and colleagues evaluated hospitalization risk in veterans treated for PTSD within the Northwest VISN 20 between 2004 and 2010.¹¹ Compared with patients treated with only an SSRI or SNRI, those treated with 1 of those medications and a benzodiazepine were at significantly higher risk for overall hospitalization (AHR, 1.79; 95% CI, 1.38-2.32; P < .001) and mental health hospitalization (AHR, 1.87; 95% CI, 1.37-2.53; P < .001). Furthermore, those prescribed a benzodiazepine and an opioid along with an SSRI or SNRI were at higher risk for overall hospitalization (AHR, 2.98; 95% CI, 2.22-4.00; P < .001), mental health hospitalization (AHR, 2.00; 95% CI, 1.35-2.98; P < .01), medical/surgical hospitalization (AHR, 4.86; 95% CI, 3.30-7.14; P < .001), and ED visits (AHR, 2.01; 95% CI, 1.53-2.65; P < .001).

Findings from the present study, which covered a period after the newest PTSD guideline was released,support findings reported by Hawkins and colleagues in their retrospective cohort study covering an earlier period.^2,11 In the present study, compared with the monotherapy group, the SSRI/SNRI and benzodiazepine therapy group and the SSRI/SNRI, benzodiazepine, and opioid therapy group were at higher risk for both overall hospitalization and mental health hospitalization within 2 years. However, in a subset of PTSD patients prescribed opioids along with first-line pharmacotherapy, this study found that overall, mental health, and medical/surgical hospitalizations were significantly increased as well. Furthermore, this study found 2-year mortality was significantly higher for the SSRI/SNRI, benzodiazepine, and opioid therapy group than for the SSRI/SNRI monotherapy group.

Adjusted hazard ratios were higher in the present study than those in the study by Hawkins and colleagues,but CIs were wider as well.¹¹ These differences may be attributable to the relatively smaller sample size of the present study and may explain why the HR was higher for the SSRI/SNRI and opioid therapy group than for the SSRI/SNRI, benzodiazepine, and opioid therapy group.

Nevertheless, these results support the growing body of evidence establishing the many risks for AEs when benzodiazepines and opioids are prescribed in the setting of PTSD. Unfortunately, it seems that, against clear guideline recommendations and literature findings, these medications still are being prescribed to this vulnerable, high-risk population.

In the last few months of 2013, the VA health care system launched 2 important medication safety initiatives. The Psychotropic Drug Safety Initiative (PDSI) was established as a quality improvement initiative for evidence-based provision of psychotropic medications. One PDSI metric in particular focused on reducing the proportion of veterans with PTSD being treated with benzodiazepines. The Opioid Safety Initiative (OSI) came as a response to a dramatic increase in the number of fatal overdoses related to prescription opioids—an increase linked to an unprecedented jump in opioid use for nonmalignant pain. As the present study’s inclusion cutoff date of August 1, 2013, preceded the debut of both PDSI and OSI, the benzodiazepine and opioid prescription rates reported here might be higher than those currently being found under the 2 initiatives.

Limitations

This study had several limitations that might affect the interpretation or generalizability of findings. Requiring at least a 30-day supply for prescription eligibility was an attempt to focus on chronic use of medications rather than on, for example, onetime supplies of opioids for dental procedures. However, prescription fill history was not assessed. Therefore, patients could have been included in certain study groups even if their SSRI, SNRI, benzodiazepine, or opioid prescription was not refilled. Furthermore, only VA medical records were used; non-VA prescriptions were not captured.

In addition, this study was limited to patients who at bare minimum were prescribed an SSRI or an SNRI. Some patients may have been prescribed a benzodiazepine and/or an opioid but were not on appropriate first-line pharmacotherapy for PTSD. These patients were excluded from the study, and their relative hospitalization risk went unexplored. Therefore, the magnitude of the issue at hand might have been underestimated.

Although psychotherapy is a first-line treatment option for PTSD, the study did not assess the potential impact of psychotherapy on outcomes or the groups’ relative proportions of patients undergoing psychotherapy. It is unknown whether the groups were equivalent at baseline in regards to psychotherapy participation rates.

This study did not characterize the specific reasons for hospitalization beyond whether it was for a mental health or a medical/surgical issue; thus, no distinction was made between hospitalizations for an elective procedure and hospitalizations for a drug overdose or an injury. Investigators could characterize admission diagnoses to better assess whether hospitalizations are truly associated with study medications or whether patients are being hospitalized for unrelated reasons. In addition, they could elucidate the true nature of hospitalization risk associated with SSRI/SNRI, benzodiazepine, and opioid use by comparing admission diagnoses made before and after initiation of these pharmacologic therapies.

This study also could not assess outcomes for patients who presented to the ED but were not admitted. If the hospital’s floor and ED beds were at full capacity, some patients might have been transferred to an outside facility. However, this scenario is not common at SAVAHCS, where the study was conducted.

Although some comorbid conditions were noted, the study did not evaluate whether its patients had a compelling indication for benzodiazepines in particular. Opioid use is very limited to the treatment of pain, and the majority of the patients on opioid therapy in this study had a diagnosed pain syndrome.

Because of the study’s sample size and power limitations, patients were eligible to be included in a concurrent therapy group if a benzodiazepine, an opioid, or both were added no later than 1 year after SSRI/SNRI initiation. This gap of up to 1 year might have introduced some variability in exposure to risk from earlier prescribed medications. However, sensitivity analyses were performed with multiple constructed Weibull models of time to hospitalization based on subsets with varying overlapping medication gaps. Analyses revealed relatively stable HRs, suggesting that potential bias did not occur.

Future Directions

Investigators could explore the higher all-cause mortality rates in the SSRI/SNRI, benzodiazepine, and opioid therapy group, as this study did not assess cause of death in these patients. Whether any patients died of reasons directly attributable to benzodiazepines or opioids is unknown.

That SSRIs and SNRIs are the only established first-line pharmacologic treatment options for PTSD symptoms partly accounts for the widespread use of benzodiazepines in this population. For that reason, beyond characterizing the many risks associated with using benzodiazepines to manage these symptoms, there is a huge need to research the viability of other pharmacologic agents in treating PTSD. This is especially important given the slower onset to efficacy of the SSRIs and SNRIs; per estimates, only up to 60% of patients respond to SSRIs, and 20% to 30% achieve full remission of PTSD.¹² Furthermore, these rates likely are even lower for combat veterans than those for the general population. Several trials discussed in a 2009 guideline review of the treatment of patients with acute stress disorder and PTSD have called into question the efficacy of SSRIs for combat-related PTSD.¹³ In these randomized, controlled trials, change in PTSD symptom severity as measured with CAPS was not significantly reduced with SSRIs compared with placebo.

A systematic review revealed that, of the nonantidepressants used as adjuncts in treating patients who do not achieve remission with SSRIs, the atypical antipsychotic risperidone may have the strongest supporting evidence.¹² However, the present study found high rates of antipsychotic use in the SSRI/SNRI, benzodiazepine, and opioid therapy group, which also had the highest all-cause mortality rate. The safety of risperidone as an alternative treatment needs further evaluation.

Some prospective studies have suggested that the α₁ blockers doxazosin and prazosin, the latter of which is commonly used for PTSD nightmares, also may improve PTSD symptoms as assessed by CAPS.^14,15 Although these results are promising, the trials to date have been conducted with relatively small sample sizes.

With more veterans being treated for PTSD within the VA health care system, the central treatment goal remains: Adequately address the symptoms of PTSD while minimizing the harm caused by medications. Prescribers should limit benzodiazepine and opioid use in this population and consider safer nonpharmacologic and pharmacologic treatment options when possible.

Conclusion

Combat veterans with PTSD who are prescribed benzodiazepines and/or opioids in addition to first-line pharmacotherapy are at significantly increased risk for overall and mental health hospitalization.

Click here to read the digital edition.

Posttraumatic stress disorder (PTSD) is a mental health condition that may develop in response to a traumatic event, such as that experienced by a soldier during active combat duty. In 2009, more than 495,000 veterans within the VA health care system were treated for PTSD—nearly triple the number a decade earlier.¹ Core symptoms of PTSD include alterations in arousal and reactivity, avoidant behaviors, negative alterations in mood and cognition, and intrusive thoughts and nightmares. All of the symptoms can be debilitating. First-line pharmacotherapy options that target these core symptoms include selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).²

The anxiolytic and sedative effects of benzodiazepines may provide quick relief from many of the secondary symptoms of PTSD, including sleep disturbances, irritability, and panic attacks. However, benzodiazepines potentially interfere with the extinction of conditioned fear—a goal integral to certain types of psychotherapy, such as exposure therapy.^3,4 In addition, the systematic review and meta-analysis by Guina and colleagues revealed that benzodiazepines are ineffective in the treatment of PTSD.⁵ The majority of the evaluated studies that used PTSD-specific measures (eg, Clinician-Administered PTSD Scale [CAPS]) found increased PTSD severity and worse prognosis with use of these medications.⁵ In 2010, the VA and the DoD released a joint guideline for PTSD management.² According to the guideline, benzodiazepines cause harm when used in PTSD and are relatively contraindicated in combat veterans because of the higher incidence of comorbid substance use disorders (SUDs) in these veterans relative to the general population.^2,6

Opioid use also has been linked to poor functional and clinical outcomes in veterans with PTSD. Among patients being treated for opioid use disorder, those with PTSD were less likely to endorse employment as a main source of income and had a higher incidence of recent attempted suicide.⁷ In a large retrospective cohort study, Operation Iraqi Freedom and Operation Enduring Freedom veterans with PTSD who were prescribed opioids were more likely to present to the emergency department (ED) and to be hospitalized for overdoses and injuries.⁸

Despite the risks of benzodiazepine and opioid use in this patient population, these medications are still often prescribed to veterans with PTSD for symptomatic relief. In fiscal year 2009, across the VHA system 37% of veterans diagnosed with PTSD were prescribed a benzodiazepine, 69% of the time by a mental health provider.⁹ Among Iraq and Afghanistan veterans, those with PTSD were significantly more likely to be prescribed an opioid for diagnosed pain—relative to those with a mental health disorder other than PTSD and those without a mental health disorder.⁸ Thus, there seems to be a disconnect between guideline recommendations and current practice.

The authors conducted a study to assess the potential risk of hospitalization for veterans with PTSD prescribed first-line pharmacotherapy and those also prescribed concurrent benzodiazepine and/or opioid therapy since the release of the PTSD guideline in 2010.²

Methods

In this retrospective cohort study, conducted at the Southern Arizona VA Health Care System (SAVAHCS), the authors analyzed electronic medical record data from November 1, 2009 to August 1, 2015. Study inclusion criteria were veteran, aged 18 to 89 years, diagnosis of PTSD (International Classification of Diseases, Ninth Revision, Clinical Modification code 309.81), and SSRI or SNRI newly prescribed between November 1, 2010 and August 1, 2013.

Any veteran prescribed at least one 30-day or longer supply of any benzodiazepine or opioid within 1 year before the SSRI/SNRI initial prescription date was excluded from the study. Also excluded was any patient treated for PTSD at a facility outside SAVAHCS or whose 2-year evaluation period extended past August 1, 2015.

Study Groups

An outpatient prescription was determined to be the initial SSRI/SNRI prescription for a patient who received less than a 30-day cumulative supply of any SSRI or SNRI within 1 year before that prescription date. Citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone, and vortioxetine were the prespecified SSRI/SNRIs included in the study.

Patients who received at least 1 outpatient prescription for any benzodiazepine (minimum 30-day supply) within 1 year after the initial SSRI/SNRI prescription date were determined to be on concurrent SSRI/SNRI and benzodiazepine therapy. Alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, temazepam, and triazolam were the prespecified benzodiazepines included in the study.

Patients who received at least 1 outpatient prescription for any opioid (minimum 30-day supply) within 1 year after the initial SSRI/SNRI prescription date were determined to be on concurrent SSRI/SNRI and opioid therapy. Codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, oxymorphone, pentazocine, propoxyphene, and tramadol were the prespecified opioids included in this study.

Patients who received at least 1 outpatient prescription for any benzodiazepine and any opioid (minimum 30-day supply) within 1 year after the initial SSRI/SNRI prescription date were determined to be on concurrent SSRI/SNRI, benzodiazepine, and opioid therapy.

The index date was defined as the first date of prescription overlap. If there was no benzodiazepine or opioid prescription within 1 year after the initial SSRI/SNRI prescription date, the patient was categorized as being on SSRI/SNRI monotherapy, and the index date was the date of the initial SSRI/SNRI prescription. For each patient, hospitalization data from the 2-year period after the index date were evaluated.

Outcomes and Data Collection

For evaluation of the primary outcome (2-year overall hospitalization risk), the number of unique mental health and medical/surgical hospitalizations was identified by the number of discharge summaries documented in the patient chart during the evaluation period. Time to first hospitalization was recorded for the survival data analysis. Secondary outcomes were mental health hospitalization risk, medical/surgical hospitalization risk, and all-cause mortality within 2 years.

Demographic data that were collected included age, sex, comorbid mental health disorders, comorbid SUDs, and concomitant use of psychotropic medications at index date (baseline). Select comorbid mental health disorders (anxiety, schizophrenia, depression, bipolar disorder) and substance use disorders (alcohol, opioid, illicit drug) also were identified. Data on insomnia and pain comorbidities (headaches or migraines; neuropathy; head, neck, back, arthritis, or joint pain) were collected, as these comorbidities could be indications for prescribing benzodiazepines and opioids. Concomitant baseline use of classes of psychotropic medications (antipsychotics, non-SSRI/SNRI antidepressants, mood stabilizers, anxiolytics, nonbenzodiazepine sedatives/hypnotics) also were documented. Last, hospitalizations within 6 months before the initial SSRI/SNRI prescription date were noted.

Statistical Analysis

Descriptive statistics were used to analyze all baseline demographic data. Continuous measures were evaluated with 1-way analyses of variance and post hoc Bonferroni-corrected pairwise comparisons, and categorical measures with contingency tables and χ² tests or Fisher exact tests. When the overall χ² test was significant across all 4 study groups, post hoc comparisons were performed between the SSRI/SNRI monotherapy group and each other group with Bonferroni adjusted for 3 comparisons.

Unadjusted and adjusted Weibull proportional hazard regression models were used to estimate hospitalization risk within 2 years after the index date for the different study groups with the SSRI/SNRI monotherapy group as the referent. Robust standard errors were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). The Weibull model (and not the Cox model) was used because it does not assume hazard remains constant over time, which is appropriate in this instance, as the risk of an adverse event (AE) may be higher when first starting a medication or combination of medications relative to when doses are stabilized. Models were adjusted for age, sex, baseline mental health disorders, and baseline psychotropic medications. As earlier hospitalizations showed evidence of effect modification when this covariate was tested, hazard analyses were limited to patients not previously hospitalized.

The effect size of differences in hospitalization risk meeting statistical significance was assessed by estimating the number needed to harm (NNH) and 95% CIs (not shown) to observe 1 additional hospitalization in each medication group relative to the SSRI/SNRI monotherapy group over a 90-day period. A 95% CI for NNH that did not include 0 indicated the NNH was significant at the .05 level.¹⁰ All-cause mortality was evaluated with the Fisher exact test with post hoc Bonferroni-corrected comparisons as appropriate.

Results

Of 1,703 patients screened, 613 met all study inclusion criteria (Figure 1). 

Baseline characteristics revealed no significant differences between groups in age or comorbid depression, schizophrenia, or SUDs (Table 1). 

With the SSRI/SNRI monotherapy group as the referent, all concurrent therapy groups were at significantly increased risk for overall hospitalization within 2 years after the index date (Tables 2 & 3, Figure 2). 

Risk for mental health hospitalization was significantly increased in all concurrent therapy groups relative to the referent group.

Discussion

In 2013, Hawkins and colleagues evaluated hospitalization risk in veterans treated for PTSD within the Northwest VISN 20 between 2004 and 2010.¹¹ Compared with patients treated with only an SSRI or SNRI, those treated with 1 of those medications and a benzodiazepine were at significantly higher risk for overall hospitalization (AHR, 1.79; 95% CI, 1.38-2.32; P < .001) and mental health hospitalization (AHR, 1.87; 95% CI, 1.37-2.53; P < .001). Furthermore, those prescribed a benzodiazepine and an opioid along with an SSRI or SNRI were at higher risk for overall hospitalization (AHR, 2.98; 95% CI, 2.22-4.00; P < .001), mental health hospitalization (AHR, 2.00; 95% CI, 1.35-2.98; P < .01), medical/surgical hospitalization (AHR, 4.86; 95% CI, 3.30-7.14; P < .001), and ED visits (AHR, 2.01; 95% CI, 1.53-2.65; P < .001).

Findings from the present study, which covered a period after the newest PTSD guideline was released,support findings reported by Hawkins and colleagues in their retrospective cohort study covering an earlier period.^2,11 In the present study, compared with the monotherapy group, the SSRI/SNRI and benzodiazepine therapy group and the SSRI/SNRI, benzodiazepine, and opioid therapy group were at higher risk for both overall hospitalization and mental health hospitalization within 2 years. However, in a subset of PTSD patients prescribed opioids along with first-line pharmacotherapy, this study found that overall, mental health, and medical/surgical hospitalizations were significantly increased as well. Furthermore, this study found 2-year mortality was significantly higher for the SSRI/SNRI, benzodiazepine, and opioid therapy group than for the SSRI/SNRI monotherapy group.

Adjusted hazard ratios were higher in the present study than those in the study by Hawkins and colleagues,but CIs were wider as well.¹¹ These differences may be attributable to the relatively smaller sample size of the present study and may explain why the HR was higher for the SSRI/SNRI and opioid therapy group than for the SSRI/SNRI, benzodiazepine, and opioid therapy group.

Nevertheless, these results support the growing body of evidence establishing the many risks for AEs when benzodiazepines and opioids are prescribed in the setting of PTSD. Unfortunately, it seems that, against clear guideline recommendations and literature findings, these medications still are being prescribed to this vulnerable, high-risk population.

In the last few months of 2013, the VA health care system launched 2 important medication safety initiatives. The Psychotropic Drug Safety Initiative (PDSI) was established as a quality improvement initiative for evidence-based provision of psychotropic medications. One PDSI metric in particular focused on reducing the proportion of veterans with PTSD being treated with benzodiazepines. The Opioid Safety Initiative (OSI) came as a response to a dramatic increase in the number of fatal overdoses related to prescription opioids—an increase linked to an unprecedented jump in opioid use for nonmalignant pain. As the present study’s inclusion cutoff date of August 1, 2013, preceded the debut of both PDSI and OSI, the benzodiazepine and opioid prescription rates reported here might be higher than those currently being found under the 2 initiatives.

Limitations

This study had several limitations that might affect the interpretation or generalizability of findings. Requiring at least a 30-day supply for prescription eligibility was an attempt to focus on chronic use of medications rather than on, for example, onetime supplies of opioids for dental procedures. However, prescription fill history was not assessed. Therefore, patients could have been included in certain study groups even if their SSRI, SNRI, benzodiazepine, or opioid prescription was not refilled. Furthermore, only VA medical records were used; non-VA prescriptions were not captured.

In addition, this study was limited to patients who at bare minimum were prescribed an SSRI or an SNRI. Some patients may have been prescribed a benzodiazepine and/or an opioid but were not on appropriate first-line pharmacotherapy for PTSD. These patients were excluded from the study, and their relative hospitalization risk went unexplored. Therefore, the magnitude of the issue at hand might have been underestimated.

Although psychotherapy is a first-line treatment option for PTSD, the study did not assess the potential impact of psychotherapy on outcomes or the groups’ relative proportions of patients undergoing psychotherapy. It is unknown whether the groups were equivalent at baseline in regards to psychotherapy participation rates.

This study did not characterize the specific reasons for hospitalization beyond whether it was for a mental health or a medical/surgical issue; thus, no distinction was made between hospitalizations for an elective procedure and hospitalizations for a drug overdose or an injury. Investigators could characterize admission diagnoses to better assess whether hospitalizations are truly associated with study medications or whether patients are being hospitalized for unrelated reasons. In addition, they could elucidate the true nature of hospitalization risk associated with SSRI/SNRI, benzodiazepine, and opioid use by comparing admission diagnoses made before and after initiation of these pharmacologic therapies.

This study also could not assess outcomes for patients who presented to the ED but were not admitted. If the hospital’s floor and ED beds were at full capacity, some patients might have been transferred to an outside facility. However, this scenario is not common at SAVAHCS, where the study was conducted.

Although some comorbid conditions were noted, the study did not evaluate whether its patients had a compelling indication for benzodiazepines in particular. Opioid use is very limited to the treatment of pain, and the majority of the patients on opioid therapy in this study had a diagnosed pain syndrome.

Because of the study’s sample size and power limitations, patients were eligible to be included in a concurrent therapy group if a benzodiazepine, an opioid, or both were added no later than 1 year after SSRI/SNRI initiation. This gap of up to 1 year might have introduced some variability in exposure to risk from earlier prescribed medications. However, sensitivity analyses were performed with multiple constructed Weibull models of time to hospitalization based on subsets with varying overlapping medication gaps. Analyses revealed relatively stable HRs, suggesting that potential bias did not occur.

Future Directions

Investigators could explore the higher all-cause mortality rates in the SSRI/SNRI, benzodiazepine, and opioid therapy group, as this study did not assess cause of death in these patients. Whether any patients died of reasons directly attributable to benzodiazepines or opioids is unknown.

That SSRIs and SNRIs are the only established first-line pharmacologic treatment options for PTSD symptoms partly accounts for the widespread use of benzodiazepines in this population. For that reason, beyond characterizing the many risks associated with using benzodiazepines to manage these symptoms, there is a huge need to research the viability of other pharmacologic agents in treating PTSD. This is especially important given the slower onset to efficacy of the SSRIs and SNRIs; per estimates, only up to 60% of patients respond to SSRIs, and 20% to 30% achieve full remission of PTSD.¹² Furthermore, these rates likely are even lower for combat veterans than those for the general population. Several trials discussed in a 2009 guideline review of the treatment of patients with acute stress disorder and PTSD have called into question the efficacy of SSRIs for combat-related PTSD.¹³ In these randomized, controlled trials, change in PTSD symptom severity as measured with CAPS was not significantly reduced with SSRIs compared with placebo.

A systematic review revealed that, of the nonantidepressants used as adjuncts in treating patients who do not achieve remission with SSRIs, the atypical antipsychotic risperidone may have the strongest supporting evidence.¹² However, the present study found high rates of antipsychotic use in the SSRI/SNRI, benzodiazepine, and opioid therapy group, which also had the highest all-cause mortality rate. The safety of risperidone as an alternative treatment needs further evaluation.

Some prospective studies have suggested that the α₁ blockers doxazosin and prazosin, the latter of which is commonly used for PTSD nightmares, also may improve PTSD symptoms as assessed by CAPS.^14,15 Although these results are promising, the trials to date have been conducted with relatively small sample sizes.

With more veterans being treated for PTSD within the VA health care system, the central treatment goal remains: Adequately address the symptoms of PTSD while minimizing the harm caused by medications. Prescribers should limit benzodiazepine and opioid use in this population and consider safer nonpharmacologic and pharmacologic treatment options when possible.

Conclusion

Combat veterans with PTSD who are prescribed benzodiazepines and/or opioids in addition to first-line pharmacotherapy are at significantly increased risk for overall and mental health hospitalization.

Click here to read the digital edition.

From the Wake Forest School of Medicine, Winston-Salem, NC.

Abstract

• Objective: To assess outcomes and pharmacotherapy in a cohort of patients with type 2 diabetes in a university-based family medicine teaching practice.
• Methods: We used ICD-9-CM codes to identify a cohort of patients with diabetes seen in 2006 and 2012. A total of 891 patients were identified who made follow-up visits in both years. We collected data on patient characteristics, pharmacotherapy, and outcomes for glycemia, blood pressure (BP), and low-density lipoprotein (LDL) cholesterol. We determined type and number of medications taken to achieve target outcomes.
• Results: A1C remained constant between 2006 and 2012 (7.6% to 7.7%) along with BMI (34.7 kg/m² to 34.1 kg/m²), while mean LDL cholesterol significantly decreased from 109 mg/dL in 2006 to 98.8 mg/dL in 2012. The number of patients achieving a goal LDL < 100 mg/dL increased from 43.5 % in 2006 to 58.6% in 2012. The largest group with controlled A1C (< 7 %) were taking metformin with a sulfonylurea, DPP-4 inhibitor, glitazone or an injectable GLP-agonist. The majority achieved an LDL goal of < 100 mg/dl. The majority of hypertensive regimens included use of an ACE inhibitor or ARB with overall BP control achieved in at least 45% of patients.
• Conclusion: Multiple medications are necessary to achieve control among patients with type 2 diabetes over time and this cannot be attributed to an increase in BMI. Overall control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications, with the primary agent for LDL reduction being a statin.

Diabetes is an illness that affects an estimated 25.8 million Americans and is quickly becoming a worldwide epidemic [1,2]. Diabetes is a significant cause of both microvascular and macrovascular sequelae, but its frequent association with the comorbid conditions of hypertension and dyslipidemia further increases the risk of heart disease, stroke, peripheral vascular complications, and renal impairment [3–5]. The American Diabetes Association (ADA) publishes consensus guidelines annually to guide management for patients with diabetes. From 2006 to 2012, the accepted standard of medical care included achieving a hemoglobin A1C (A1C) measurement of < 7%, a low-density lipoprotein (LDL) level of < 100 mg/dL, and a blood pressure (BP) of < 130/80 mm Hg [6,7]. The National Health and Nutrition Examination Survey (NHANES) recently reported that the goal of simultaneous control of A1C, LDL and BP is met in only about 19% of diabetes patients [8]. Target glycemic control is relaxed to an A1C < 8% in some patients with multiple comorbidities, limited life span, or risk for hypoglycemia; and in 2013 the BP goal was modified to < 140/80 based on clinical trial evidence [9].

In combination with lifestyle modification, pharmacotherapy is a critical component of chronic disease management. Initial pharmacotherapy treatment recommendations include metformin for diabetes, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) for hypertension, and a statin for dyslipidemia [6,7,9]. In patients who already have a diagnosis of diabetes, achieving control becomes more difficult to accomplish with lifestyle alone, and the benefit of lifestyle intervention on all-cause mortality as well as cardiovascular and microvascular events remains a debated issue [10]. The need for pharmacologic agents in most patients with diabetes is inevitable. Metformin is the agent of choice for initial treatment with drug therapy, with the option of adding a variety of other oral or injectable medications based on clinician decision-making [7]. In this study, we reviewed data from a longitudinal cohort of type 2 diabetes patients and compared medication use and outcomes at 2 different time-points (2006 and 2012) to see how medical management and outcome measures changed over time.

Methods

Setting

Data were obtained from an academic family medicine clinic in the southeastern United States. Approximately 56,000 patient visits to this clinic are conducted annually. Family medicine residents in training, fellows, faculty physicians, physician assistants, a nutritionist, and diabetes educators care for patients seen in this practice.

Data Collection

A cohort of patients was identified using the International Classification of Diseases, 9th Revision, Clinical Modification codes for type 2 diabetes. The cohort comprised patients with diabetes in 2006 and 2012 who made follow-up visits in both years.

The data from both time-points were obtained from electronic medical record (EMR) data capture and structured chart review. Two reviewers reviewed 10% of the charts for accuracy after the data was pre-populated from the EMR. The following data were obtained: demographic variables (patient age, gender, and race), height, weight, insurance, smoking status, A1C, LDL, and BP measurements, pharmacotherapy for glycemia, hypertension, and hyperlipidemia, and number of medications needed for control. For variables that had multiple measures, we calculated an average for the year.

The study protocol was approved by the Institutional Review Board at Wake Forest School of Medicine.

Statistical Analysis

Descriptive statistics were performed to compute means, standard deviations, frequencies, and percentages for demographic variables and for glycemia, BP, LDL includ-ing patient characteristics, diabetes outcomes, and pharmacotherapy medication variables. Paired t tests were used to assess for a difference at the level of the patient in the means of the A1C, BP, and LDL between the 2 study time-points (2-sided alpha = 0.05). The non-parametric McNemar test was used to assess for differences in the proportions of patients at the identified goal for A1C, LDL, and BP for 2006 and 2012.

Results

The number of visits per patient was 5.9 in 2006 and 5.3 in 2012. A1C remained constant between 2006 and 2012 (mean 7.6% vs. 7.7%, ± 1.8) along with body mass index (BMI), while mean LDL cholesterol significantly decreased from 109 ± 36.4 mg/dL in 2006 to 98.8 ± 40.4 mg/dL in 2012 (Table 2). Mean systolic BP marginally increased over the 6-year period from 131.5 ± 14.2 to 134.8 ± 16.1 mm Hg with diastolic BP remaining constant.

The percentage of patients achieving the less stringent A1C goal of < 8% comprised over 50% of the population at both time points; however, compared with 2006, in 2012 there was a lower percentage of patients at the more stringent A1C target of < 7% (43.2% vs. 39.6%). The percentage of patients achieving goal for systolic BP was significantly decreased to 38.6% in 2012 versus 46.5% in 2006 (Table 2). However, the proportion of patients with controlled diastolic BP rose significantly from 70% to 77.6%. The number of patients achieving goal LDL (< 100 mg/dL) increased from 43.5% in 2006 to 58.6% in 2012.

Table 3 shows number of patients at LDL goal of < 100 mg/dL by lipid-lowering agent. There was a large portion (n = 303 or 34%) of the 891 patients that did not have LDL values available in both 2006 and 2012. A total of 89 patients were taking no medications for LDL, with 64% achieving controlled levels. The large majority of patients were controlled on a single statin drug (n = 195, 59%) while those requiring more than a statin drug for control comprised 53% of patients (n = 92).

Table 3 shows achievement of BP < 130/80 by anti-hypertensive regimen. The majority of the hypertensive regimens included the use of an ACEI or an ARB, with overall BP control achieved in at least 45% of patients. The highest BP control (49%) was achieved in the diuretic and CCB–containing regimens without an ACEI or ARB, represented by a smaller group of patients (n = 65). There were 32 patients whose hypertension was controlled without antihypertensive therapy. Ninety-three percent of the cohort had data for evaluation in both years.

Discussion

Despite the availability of evidence-based guidelines and vast knowledge about microvascular and macrovascular complications due to diabetes, clinical goals for diabetes outcomes are not being routinely achieved in practice. More work is needed to achieve national standards of care. NHANES data from 2007 to 2010 revealed that 52.5% of patients with diabetes achieved an A1C of < 7% while 51.1% had a BP < 130/80 and 56.2% had an LDL < 100 mg/dL [8].

Improvement in LDL cholesterol was seen in the current study, and A1C remained constant during the 6-year time period. While mean A1C, BP, and LDL measurements were close to ADA target goals, a smaller proportion of patients were controlled in 2012 compared with 2006. Hoerger and colleagues [11] found using NHANES data 1999 to 2004 that mean A1C levels significantly declined over time, with 55.7% (up from 36.9%) achieving an A1C of < 7% by 2004  [11]. In our sample of patient with diabetes, only 39.6% were at A1C goal in 2012; 8.2% (61/742) achieved control with no medications.

Metformin is first-line therapy according to ADA recommendations. Most regimens in our study included this drug, with a large percentage of patients with controlled A1C taking this very affordable agent [12]. The combination regimens with metformin plus another oral therapy or 2 oral drugs with insulin resulted in a higher percentage of patients controlled  compared to metformin or insulin monotherapy. From our previous chart review [13] of the entire practice of patients with diabetes (n = 1398) from 2006, A1C control was similarly achieved in patients taking insulin (31% vs. 33%) or insulin combinations (19% vs. 20%) from 2006 to 2012, respectively.

For LDL cholesterol control, 9.7% (57/588) of the cohort used no medications to reach goal. Statin use predominated, with 60% of the cohort reaching goal with a single statin agent. Approximately one-third (175/588) of evaluable patients were on  more than 1 cholesterol medication, and about half of these (53%) reached goal. Over the 6-year period, atorvastatin become available generically, which may have impacted the number of patients able to use this statin. Compared with a recent literature review over a 12-year period of LDL attainment in primary care [14], the results of our study show equivalent or better LDL goal achievement among patient with diabetes.

The majority of the patients received an ACEI or ARB. There were a comparable number of patients controlled with ACEI or ARB with a diuretic, versus an ACEI or ARB with a diuretic and CCB. Large-scale clinical trials have shown that using an ACEI or ARB in combination with a CCB is superior to a hydrochlorathiazide-based combination for reducing risk of major cardiovascular events [15]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that serious adverse events attributed to antihypertensive treatment occurred more frequently in the intensive therapy group (< 120/80) than in the standard therapy (< 140/80) group [16]. The stringent systolic BP goal in accord was accomplished using 3.4 medications. Aggressive lowering of BP may be dangerous in patients with diabetes and there is no benefit found in many large-scale studies [17]. The 2013 ADA goal for BP is now < 140/80 mm Hg, and while our data show that a significant increase in BP was seen over a 6-year period, the number of medications needed to control BP will likely be lower with the new ADA target and potentially safer.

In our cohort, over the 6-year period there was an increase in the number of medications needed to achieve glycemic, BP, and LDL goals. During this time, there were no major changes in the way the patients received care in the clinic environment. We cannot comment on whether lifestyle changes or diabetes education may have impacted the need for increased medication use. Limitations to this study include the unavailability of  A1C (17%) and LDL (34%) data at both time points for every patient, inability to verify insurance data for the 2012 time period, and that the data are from a single practice. We also were unable to determine the duration of diabetes diagnosis due to a change in electronic medical record systems and lack of full documentation by providers.

These findings suggest that as patients live longer with type 2 diabetes, they will need increasing numbers of medications to achieve standard of care goals. Research has shown that there are challenges in implementing diabetes guidelines in primary care, including potential inaccuracies contained in electronic patient health information, inadequate coordination among health care providers, physician lack of awareness of guidelines, and clinical inertia [18]. As shown in the current study and other research, intensification of traditional therapies for glycemic control can sustain target outcomes without the risk of significant weight gain [19].

The chronic condition of diabetes is associated with medical complications as well as challenges for providing optimal care, despite advances in pharmacotherapy. As more medications are added to a patient’s regimen, adherence can become challenging. The cost of medications also warrants consideration. Research is needed to understand the impact on quality of life, cost of care, and outcomes of these regimens as well as whether lifestyle modifications can impact the number of medications needed by individual patients. The current study indicates that overall outcome control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications with the primary agent being a statin drug.

Acknowledgements: We would like to thank Drs. Elizabeth Strachan and Madhavi Peechara for their past contributions and diligence in the original chart review.

Corresponding author: Julienne K. Kirk, PharmD, CDE, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1084, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JKK, KL, RWL; analysis and interpretation of data, JKK, SWD, KL, CAH, RWL; drafting of article, JKK, KL, RWL; critical revision of the article, JKK, KL, CAH; provision of study materials or patients, JKK, SWD; statistical expertise, SWD; administrative or technical support, CAH; collection and assembly of data, JKK, KL, CAH.

From the Wake Forest School of Medicine, Winston-Salem, NC.

Abstract

• Objective: To assess outcomes and pharmacotherapy in a cohort of patients with type 2 diabetes in a university-based family medicine teaching practice.
• Methods: We used ICD-9-CM codes to identify a cohort of patients with diabetes seen in 2006 and 2012. A total of 891 patients were identified who made follow-up visits in both years. We collected data on patient characteristics, pharmacotherapy, and outcomes for glycemia, blood pressure (BP), and low-density lipoprotein (LDL) cholesterol. We determined type and number of medications taken to achieve target outcomes.
• Results: A1C remained constant between 2006 and 2012 (7.6% to 7.7%) along with BMI (34.7 kg/m² to 34.1 kg/m²), while mean LDL cholesterol significantly decreased from 109 mg/dL in 2006 to 98.8 mg/dL in 2012. The number of patients achieving a goal LDL < 100 mg/dL increased from 43.5 % in 2006 to 58.6% in 2012. The largest group with controlled A1C (< 7 %) were taking metformin with a sulfonylurea, DPP-4 inhibitor, glitazone or an injectable GLP-agonist. The majority achieved an LDL goal of < 100 mg/dl. The majority of hypertensive regimens included use of an ACE inhibitor or ARB with overall BP control achieved in at least 45% of patients.
• Conclusion: Multiple medications are necessary to achieve control among patients with type 2 diabetes over time and this cannot be attributed to an increase in BMI. Overall control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications, with the primary agent for LDL reduction being a statin.

Diabetes is an illness that affects an estimated 25.8 million Americans and is quickly becoming a worldwide epidemic [1,2]. Diabetes is a significant cause of both microvascular and macrovascular sequelae, but its frequent association with the comorbid conditions of hypertension and dyslipidemia further increases the risk of heart disease, stroke, peripheral vascular complications, and renal impairment [3–5]. The American Diabetes Association (ADA) publishes consensus guidelines annually to guide management for patients with diabetes. From 2006 to 2012, the accepted standard of medical care included achieving a hemoglobin A1C (A1C) measurement of < 7%, a low-density lipoprotein (LDL) level of < 100 mg/dL, and a blood pressure (BP) of < 130/80 mm Hg [6,7]. The National Health and Nutrition Examination Survey (NHANES) recently reported that the goal of simultaneous control of A1C, LDL and BP is met in only about 19% of diabetes patients [8]. Target glycemic control is relaxed to an A1C < 8% in some patients with multiple comorbidities, limited life span, or risk for hypoglycemia; and in 2013 the BP goal was modified to < 140/80 based on clinical trial evidence [9].

In combination with lifestyle modification, pharmacotherapy is a critical component of chronic disease management. Initial pharmacotherapy treatment recommendations include metformin for diabetes, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) for hypertension, and a statin for dyslipidemia [6,7,9]. In patients who already have a diagnosis of diabetes, achieving control becomes more difficult to accomplish with lifestyle alone, and the benefit of lifestyle intervention on all-cause mortality as well as cardiovascular and microvascular events remains a debated issue [10]. The need for pharmacologic agents in most patients with diabetes is inevitable. Metformin is the agent of choice for initial treatment with drug therapy, with the option of adding a variety of other oral or injectable medications based on clinician decision-making [7]. In this study, we reviewed data from a longitudinal cohort of type 2 diabetes patients and compared medication use and outcomes at 2 different time-points (2006 and 2012) to see how medical management and outcome measures changed over time.

Methods

Setting

Data were obtained from an academic family medicine clinic in the southeastern United States. Approximately 56,000 patient visits to this clinic are conducted annually. Family medicine residents in training, fellows, faculty physicians, physician assistants, a nutritionist, and diabetes educators care for patients seen in this practice.

Data Collection

A cohort of patients was identified using the International Classification of Diseases, 9th Revision, Clinical Modification codes for type 2 diabetes. The cohort comprised patients with diabetes in 2006 and 2012 who made follow-up visits in both years.

The data from both time-points were obtained from electronic medical record (EMR) data capture and structured chart review. Two reviewers reviewed 10% of the charts for accuracy after the data was pre-populated from the EMR. The following data were obtained: demographic variables (patient age, gender, and race), height, weight, insurance, smoking status, A1C, LDL, and BP measurements, pharmacotherapy for glycemia, hypertension, and hyperlipidemia, and number of medications needed for control. For variables that had multiple measures, we calculated an average for the year.

The study protocol was approved by the Institutional Review Board at Wake Forest School of Medicine.

Statistical Analysis

Descriptive statistics were performed to compute means, standard deviations, frequencies, and percentages for demographic variables and for glycemia, BP, LDL includ-ing patient characteristics, diabetes outcomes, and pharmacotherapy medication variables. Paired t tests were used to assess for a difference at the level of the patient in the means of the A1C, BP, and LDL between the 2 study time-points (2-sided alpha = 0.05). The non-parametric McNemar test was used to assess for differences in the proportions of patients at the identified goal for A1C, LDL, and BP for 2006 and 2012.

Results

The number of visits per patient was 5.9 in 2006 and 5.3 in 2012. A1C remained constant between 2006 and 2012 (mean 7.6% vs. 7.7%, ± 1.8) along with body mass index (BMI), while mean LDL cholesterol significantly decreased from 109 ± 36.4 mg/dL in 2006 to 98.8 ± 40.4 mg/dL in 2012 (Table 2). Mean systolic BP marginally increased over the 6-year period from 131.5 ± 14.2 to 134.8 ± 16.1 mm Hg with diastolic BP remaining constant.

The percentage of patients achieving the less stringent A1C goal of < 8% comprised over 50% of the population at both time points; however, compared with 2006, in 2012 there was a lower percentage of patients at the more stringent A1C target of < 7% (43.2% vs. 39.6%). The percentage of patients achieving goal for systolic BP was significantly decreased to 38.6% in 2012 versus 46.5% in 2006 (Table 2). However, the proportion of patients with controlled diastolic BP rose significantly from 70% to 77.6%. The number of patients achieving goal LDL (< 100 mg/dL) increased from 43.5% in 2006 to 58.6% in 2012.

Table 3 shows number of patients at LDL goal of < 100 mg/dL by lipid-lowering agent. There was a large portion (n = 303 or 34%) of the 891 patients that did not have LDL values available in both 2006 and 2012. A total of 89 patients were taking no medications for LDL, with 64% achieving controlled levels. The large majority of patients were controlled on a single statin drug (n = 195, 59%) while those requiring more than a statin drug for control comprised 53% of patients (n = 92).

Table 3 shows achievement of BP < 130/80 by anti-hypertensive regimen. The majority of the hypertensive regimens included the use of an ACEI or an ARB, with overall BP control achieved in at least 45% of patients. The highest BP control (49%) was achieved in the diuretic and CCB–containing regimens without an ACEI or ARB, represented by a smaller group of patients (n = 65). There were 32 patients whose hypertension was controlled without antihypertensive therapy. Ninety-three percent of the cohort had data for evaluation in both years.

Discussion

Despite the availability of evidence-based guidelines and vast knowledge about microvascular and macrovascular complications due to diabetes, clinical goals for diabetes outcomes are not being routinely achieved in practice. More work is needed to achieve national standards of care. NHANES data from 2007 to 2010 revealed that 52.5% of patients with diabetes achieved an A1C of < 7% while 51.1% had a BP < 130/80 and 56.2% had an LDL < 100 mg/dL [8].

Improvement in LDL cholesterol was seen in the current study, and A1C remained constant during the 6-year time period. While mean A1C, BP, and LDL measurements were close to ADA target goals, a smaller proportion of patients were controlled in 2012 compared with 2006. Hoerger and colleagues [11] found using NHANES data 1999 to 2004 that mean A1C levels significantly declined over time, with 55.7% (up from 36.9%) achieving an A1C of < 7% by 2004  [11]. In our sample of patient with diabetes, only 39.6% were at A1C goal in 2012; 8.2% (61/742) achieved control with no medications.

Metformin is first-line therapy according to ADA recommendations. Most regimens in our study included this drug, with a large percentage of patients with controlled A1C taking this very affordable agent [12]. The combination regimens with metformin plus another oral therapy or 2 oral drugs with insulin resulted in a higher percentage of patients controlled  compared to metformin or insulin monotherapy. From our previous chart review [13] of the entire practice of patients with diabetes (n = 1398) from 2006, A1C control was similarly achieved in patients taking insulin (31% vs. 33%) or insulin combinations (19% vs. 20%) from 2006 to 2012, respectively.

For LDL cholesterol control, 9.7% (57/588) of the cohort used no medications to reach goal. Statin use predominated, with 60% of the cohort reaching goal with a single statin agent. Approximately one-third (175/588) of evaluable patients were on  more than 1 cholesterol medication, and about half of these (53%) reached goal. Over the 6-year period, atorvastatin become available generically, which may have impacted the number of patients able to use this statin. Compared with a recent literature review over a 12-year period of LDL attainment in primary care [14], the results of our study show equivalent or better LDL goal achievement among patient with diabetes.

The majority of the patients received an ACEI or ARB. There were a comparable number of patients controlled with ACEI or ARB with a diuretic, versus an ACEI or ARB with a diuretic and CCB. Large-scale clinical trials have shown that using an ACEI or ARB in combination with a CCB is superior to a hydrochlorathiazide-based combination for reducing risk of major cardiovascular events [15]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that serious adverse events attributed to antihypertensive treatment occurred more frequently in the intensive therapy group (< 120/80) than in the standard therapy (< 140/80) group [16]. The stringent systolic BP goal in accord was accomplished using 3.4 medications. Aggressive lowering of BP may be dangerous in patients with diabetes and there is no benefit found in many large-scale studies [17]. The 2013 ADA goal for BP is now < 140/80 mm Hg, and while our data show that a significant increase in BP was seen over a 6-year period, the number of medications needed to control BP will likely be lower with the new ADA target and potentially safer.

In our cohort, over the 6-year period there was an increase in the number of medications needed to achieve glycemic, BP, and LDL goals. During this time, there were no major changes in the way the patients received care in the clinic environment. We cannot comment on whether lifestyle changes or diabetes education may have impacted the need for increased medication use. Limitations to this study include the unavailability of  A1C (17%) and LDL (34%) data at both time points for every patient, inability to verify insurance data for the 2012 time period, and that the data are from a single practice. We also were unable to determine the duration of diabetes diagnosis due to a change in electronic medical record systems and lack of full documentation by providers.

These findings suggest that as patients live longer with type 2 diabetes, they will need increasing numbers of medications to achieve standard of care goals. Research has shown that there are challenges in implementing diabetes guidelines in primary care, including potential inaccuracies contained in electronic patient health information, inadequate coordination among health care providers, physician lack of awareness of guidelines, and clinical inertia [18]. As shown in the current study and other research, intensification of traditional therapies for glycemic control can sustain target outcomes without the risk of significant weight gain [19].

The chronic condition of diabetes is associated with medical complications as well as challenges for providing optimal care, despite advances in pharmacotherapy. As more medications are added to a patient’s regimen, adherence can become challenging. The cost of medications also warrants consideration. Research is needed to understand the impact on quality of life, cost of care, and outcomes of these regimens as well as whether lifestyle modifications can impact the number of medications needed by individual patients. The current study indicates that overall outcome control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications with the primary agent being a statin drug.

Acknowledgements: We would like to thank Drs. Elizabeth Strachan and Madhavi Peechara for their past contributions and diligence in the original chart review.

Corresponding author: Julienne K. Kirk, PharmD, CDE, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1084, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JKK, KL, RWL; analysis and interpretation of data, JKK, SWD, KL, CAH, RWL; drafting of article, JKK, KL, RWL; critical revision of the article, JKK, KL, CAH; provision of study materials or patients, JKK, SWD; statistical expertise, SWD; administrative or technical support, CAH; collection and assembly of data, JKK, KL, CAH.

From the Wake Forest School of Medicine, Winston-Salem, NC.

Abstract

• Objective: To assess outcomes and pharmacotherapy in a cohort of patients with type 2 diabetes in a university-based family medicine teaching practice.
• Methods: We used ICD-9-CM codes to identify a cohort of patients with diabetes seen in 2006 and 2012. A total of 891 patients were identified who made follow-up visits in both years. We collected data on patient characteristics, pharmacotherapy, and outcomes for glycemia, blood pressure (BP), and low-density lipoprotein (LDL) cholesterol. We determined type and number of medications taken to achieve target outcomes.
• Results: A1C remained constant between 2006 and 2012 (7.6% to 7.7%) along with BMI (34.7 kg/m² to 34.1 kg/m²), while mean LDL cholesterol significantly decreased from 109 mg/dL in 2006 to 98.8 mg/dL in 2012. The number of patients achieving a goal LDL < 100 mg/dL increased from 43.5 % in 2006 to 58.6% in 2012. The largest group with controlled A1C (< 7 %) were taking metformin with a sulfonylurea, DPP-4 inhibitor, glitazone or an injectable GLP-agonist. The majority achieved an LDL goal of < 100 mg/dl. The majority of hypertensive regimens included use of an ACE inhibitor or ARB with overall BP control achieved in at least 45% of patients.
• Conclusion: Multiple medications are necessary to achieve control among patients with type 2 diabetes over time and this cannot be attributed to an increase in BMI. Overall control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications, with the primary agent for LDL reduction being a statin.

Diabetes is an illness that affects an estimated 25.8 million Americans and is quickly becoming a worldwide epidemic [1,2]. Diabetes is a significant cause of both microvascular and macrovascular sequelae, but its frequent association with the comorbid conditions of hypertension and dyslipidemia further increases the risk of heart disease, stroke, peripheral vascular complications, and renal impairment [3–5]. The American Diabetes Association (ADA) publishes consensus guidelines annually to guide management for patients with diabetes. From 2006 to 2012, the accepted standard of medical care included achieving a hemoglobin A1C (A1C) measurement of < 7%, a low-density lipoprotein (LDL) level of < 100 mg/dL, and a blood pressure (BP) of < 130/80 mm Hg [6,7]. The National Health and Nutrition Examination Survey (NHANES) recently reported that the goal of simultaneous control of A1C, LDL and BP is met in only about 19% of diabetes patients [8]. Target glycemic control is relaxed to an A1C < 8% in some patients with multiple comorbidities, limited life span, or risk for hypoglycemia; and in 2013 the BP goal was modified to < 140/80 based on clinical trial evidence [9].

In combination with lifestyle modification, pharmacotherapy is a critical component of chronic disease management. Initial pharmacotherapy treatment recommendations include metformin for diabetes, an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) for hypertension, and a statin for dyslipidemia [6,7,9]. In patients who already have a diagnosis of diabetes, achieving control becomes more difficult to accomplish with lifestyle alone, and the benefit of lifestyle intervention on all-cause mortality as well as cardiovascular and microvascular events remains a debated issue [10]. The need for pharmacologic agents in most patients with diabetes is inevitable. Metformin is the agent of choice for initial treatment with drug therapy, with the option of adding a variety of other oral or injectable medications based on clinician decision-making [7]. In this study, we reviewed data from a longitudinal cohort of type 2 diabetes patients and compared medication use and outcomes at 2 different time-points (2006 and 2012) to see how medical management and outcome measures changed over time.

Methods

Setting

Data were obtained from an academic family medicine clinic in the southeastern United States. Approximately 56,000 patient visits to this clinic are conducted annually. Family medicine residents in training, fellows, faculty physicians, physician assistants, a nutritionist, and diabetes educators care for patients seen in this practice.

Data Collection

A cohort of patients was identified using the International Classification of Diseases, 9th Revision, Clinical Modification codes for type 2 diabetes. The cohort comprised patients with diabetes in 2006 and 2012 who made follow-up visits in both years.

The data from both time-points were obtained from electronic medical record (EMR) data capture and structured chart review. Two reviewers reviewed 10% of the charts for accuracy after the data was pre-populated from the EMR. The following data were obtained: demographic variables (patient age, gender, and race), height, weight, insurance, smoking status, A1C, LDL, and BP measurements, pharmacotherapy for glycemia, hypertension, and hyperlipidemia, and number of medications needed for control. For variables that had multiple measures, we calculated an average for the year.

The study protocol was approved by the Institutional Review Board at Wake Forest School of Medicine.

Statistical Analysis

Descriptive statistics were performed to compute means, standard deviations, frequencies, and percentages for demographic variables and for glycemia, BP, LDL includ-ing patient characteristics, diabetes outcomes, and pharmacotherapy medication variables. Paired t tests were used to assess for a difference at the level of the patient in the means of the A1C, BP, and LDL between the 2 study time-points (2-sided alpha = 0.05). The non-parametric McNemar test was used to assess for differences in the proportions of patients at the identified goal for A1C, LDL, and BP for 2006 and 2012.

Results

The number of visits per patient was 5.9 in 2006 and 5.3 in 2012. A1C remained constant between 2006 and 2012 (mean 7.6% vs. 7.7%, ± 1.8) along with body mass index (BMI), while mean LDL cholesterol significantly decreased from 109 ± 36.4 mg/dL in 2006 to 98.8 ± 40.4 mg/dL in 2012 (Table 2). Mean systolic BP marginally increased over the 6-year period from 131.5 ± 14.2 to 134.8 ± 16.1 mm Hg with diastolic BP remaining constant.

The percentage of patients achieving the less stringent A1C goal of < 8% comprised over 50% of the population at both time points; however, compared with 2006, in 2012 there was a lower percentage of patients at the more stringent A1C target of < 7% (43.2% vs. 39.6%). The percentage of patients achieving goal for systolic BP was significantly decreased to 38.6% in 2012 versus 46.5% in 2006 (Table 2). However, the proportion of patients with controlled diastolic BP rose significantly from 70% to 77.6%. The number of patients achieving goal LDL (< 100 mg/dL) increased from 43.5% in 2006 to 58.6% in 2012.

Table 3 shows number of patients at LDL goal of < 100 mg/dL by lipid-lowering agent. There was a large portion (n = 303 or 34%) of the 891 patients that did not have LDL values available in both 2006 and 2012. A total of 89 patients were taking no medications for LDL, with 64% achieving controlled levels. The large majority of patients were controlled on a single statin drug (n = 195, 59%) while those requiring more than a statin drug for control comprised 53% of patients (n = 92).

Table 3 shows achievement of BP < 130/80 by anti-hypertensive regimen. The majority of the hypertensive regimens included the use of an ACEI or an ARB, with overall BP control achieved in at least 45% of patients. The highest BP control (49%) was achieved in the diuretic and CCB–containing regimens without an ACEI or ARB, represented by a smaller group of patients (n = 65). There were 32 patients whose hypertension was controlled without antihypertensive therapy. Ninety-three percent of the cohort had data for evaluation in both years.

Discussion

Despite the availability of evidence-based guidelines and vast knowledge about microvascular and macrovascular complications due to diabetes, clinical goals for diabetes outcomes are not being routinely achieved in practice. More work is needed to achieve national standards of care. NHANES data from 2007 to 2010 revealed that 52.5% of patients with diabetes achieved an A1C of < 7% while 51.1% had a BP < 130/80 and 56.2% had an LDL < 100 mg/dL [8].

Improvement in LDL cholesterol was seen in the current study, and A1C remained constant during the 6-year time period. While mean A1C, BP, and LDL measurements were close to ADA target goals, a smaller proportion of patients were controlled in 2012 compared with 2006. Hoerger and colleagues [11] found using NHANES data 1999 to 2004 that mean A1C levels significantly declined over time, with 55.7% (up from 36.9%) achieving an A1C of < 7% by 2004  [11]. In our sample of patient with diabetes, only 39.6% were at A1C goal in 2012; 8.2% (61/742) achieved control with no medications.

Metformin is first-line therapy according to ADA recommendations. Most regimens in our study included this drug, with a large percentage of patients with controlled A1C taking this very affordable agent [12]. The combination regimens with metformin plus another oral therapy or 2 oral drugs with insulin resulted in a higher percentage of patients controlled  compared to metformin or insulin monotherapy. From our previous chart review [13] of the entire practice of patients with diabetes (n = 1398) from 2006, A1C control was similarly achieved in patients taking insulin (31% vs. 33%) or insulin combinations (19% vs. 20%) from 2006 to 2012, respectively.

For LDL cholesterol control, 9.7% (57/588) of the cohort used no medications to reach goal. Statin use predominated, with 60% of the cohort reaching goal with a single statin agent. Approximately one-third (175/588) of evaluable patients were on  more than 1 cholesterol medication, and about half of these (53%) reached goal. Over the 6-year period, atorvastatin become available generically, which may have impacted the number of patients able to use this statin. Compared with a recent literature review over a 12-year period of LDL attainment in primary care [14], the results of our study show equivalent or better LDL goal achievement among patient with diabetes.

The majority of the patients received an ACEI or ARB. There were a comparable number of patients controlled with ACEI or ARB with a diuretic, versus an ACEI or ARB with a diuretic and CCB. Large-scale clinical trials have shown that using an ACEI or ARB in combination with a CCB is superior to a hydrochlorathiazide-based combination for reducing risk of major cardiovascular events [15]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed that serious adverse events attributed to antihypertensive treatment occurred more frequently in the intensive therapy group (< 120/80) than in the standard therapy (< 140/80) group [16]. The stringent systolic BP goal in accord was accomplished using 3.4 medications. Aggressive lowering of BP may be dangerous in patients with diabetes and there is no benefit found in many large-scale studies [17]. The 2013 ADA goal for BP is now < 140/80 mm Hg, and while our data show that a significant increase in BP was seen over a 6-year period, the number of medications needed to control BP will likely be lower with the new ADA target and potentially safer.

In our cohort, over the 6-year period there was an increase in the number of medications needed to achieve glycemic, BP, and LDL goals. During this time, there were no major changes in the way the patients received care in the clinic environment. We cannot comment on whether lifestyle changes or diabetes education may have impacted the need for increased medication use. Limitations to this study include the unavailability of  A1C (17%) and LDL (34%) data at both time points for every patient, inability to verify insurance data for the 2012 time period, and that the data are from a single practice. We also were unable to determine the duration of diabetes diagnosis due to a change in electronic medical record systems and lack of full documentation by providers.

These findings suggest that as patients live longer with type 2 diabetes, they will need increasing numbers of medications to achieve standard of care goals. Research has shown that there are challenges in implementing diabetes guidelines in primary care, including potential inaccuracies contained in electronic patient health information, inadequate coordination among health care providers, physician lack of awareness of guidelines, and clinical inertia [18]. As shown in the current study and other research, intensification of traditional therapies for glycemic control can sustain target outcomes without the risk of significant weight gain [19].

The chronic condition of diabetes is associated with medical complications as well as challenges for providing optimal care, despite advances in pharmacotherapy. As more medications are added to a patient’s regimen, adherence can become challenging. The cost of medications also warrants consideration. Research is needed to understand the impact on quality of life, cost of care, and outcomes of these regimens as well as whether lifestyle modifications can impact the number of medications needed by individual patients. The current study indicates that overall outcome control for A1C and BP can be sustained and significantly decreased for LDL cholesterol using multiple medications with the primary agent being a statin drug.

Acknowledgements: We would like to thank Drs. Elizabeth Strachan and Madhavi Peechara for their past contributions and diligence in the original chart review.

Corresponding author: Julienne K. Kirk, PharmD, CDE, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1084, [email protected].

Financial disclosures: None.

Author contributions: conception and design, JKK, KL, RWL; analysis and interpretation of data, JKK, SWD, KL, CAH, RWL; drafting of article, JKK, KL, RWL; critical revision of the article, JKK, KL, CAH; provision of study materials or patients, JKK, SWD; statistical expertise, SWD; administrative or technical support, CAH; collection and assembly of data, JKK, KL, CAH.