Take-Home Points

• The prevalence of preoperative pneumonia is 1.2% among hip fracture patients aged >65 years.
• Preoperative pneumonia is an independent risk factor for mortality and adverse events including renal failure, prolonged ventilator dependence, and prolonged altered mental status after geriatric hip fracture surgery.
• Underweight BMI (<18.5 kg/m²) was associated with higher mortality within 30 days among hip fracture patients admitted with pneumonia.
• The mortality rate normalized to that of patients without pneumonia within 2 weeks of hip fracture surgery.
• Time from admission to surgery was not associated with adverse events or mortality among hip fracture patients admitted with pneumonia.

Preoperative pneumonia remains relatively unexplored as a risk factor for adverse outcomes in geriatric hip fracture surgery. Dated studies report a 0.3% to 3.2% prevalence of “recent pneumonia” in patients presenting with hip fracture but provide neither a definition of pneumonia based on clinical criteria nor a subset analysis of outcomes in the pneumonia group.^1-3 Although active pneumonia has been identified as a preoperative optimization target in the management guidelines for geriatric hip fracture,⁴ we are unaware of any studies that have reported on differences in demographics, comorbidities, delay to surgery, or adverse outcomes between hip fracture patients with and without preoperative pneumonia.

This paucity of information on the effect of preoperative pneumonia in the hip fracture population may be related to low prevalence of preoperative pneumonia and a cadre of variable definitions, which limit identification of a cohort of patients with preoperative pneumonia large enough from which to draw meaningful results. Database studies, especially those using surgical registries rather than administrative or reimbursement data, offer particular advantages for investigation of such rare clinical entities.⁵Medical care of patients with pneumonia alone is known to be facilitated by assessments of mortality risk from clinical and laboratory data. The modified British Thoracic Society rule/CURB-65 (confusion, urea, respiratory rate, blood pressure) score is strongly predictive of mortality in hospitalized adults with pneumonia (odds ratio [OR], 4.59; 95% confidence interval [CI], 1.42-14.85; P = .011) and may guide antibiotic therapy, laboratory investigations, and the decision to intubate in a patient with pneumonia.^6-8 This score is predictive of adverse events (AEs), hospital length of stay, and use of intensive care services.^6,7,9-13 We hypothesized that preoperative clinical indicators assessed by pneumonia severity scores as well as patient demographics and baseline comorbidities may also have prognostic value for risk of AEs in a cohort of geriatric hip fracture surgery patients with preoperative pneumonia.

In this article, we first describe the prevalence of preoperative pneumonia in geriatric hip fracture surgery patients as well as demographic and operative differences between patients with and without the disease. We then ask 3 questions: Is preoperative pneumonia an independent risk factor for mortality and adverse outcomes in geriatric hip fracture surgery? Is there a postoperative interval during which the unadjusted mortality rate is higher among patients with preoperative pneumonia? In patients with preoperative pneumonia, what are the predictors of morbidity and mortality?

Methods

Yale University’s Human Investigations Committee approved this retrospective cohort study, which used the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database for the period 2005 to 2012. ACS-NSQIP is a prospective, multi-institutional outcomes program that collects data on preoperative comorbidities, intraoperative variables, and 30-day postoperative outcomes for patients undergoing surgical procedures in inpatient and outpatient settings.¹⁴

Unlike administrative databases, which are based on reimbursement data, ACS-NSQIP data are collected by trained surgical clinical reviewers for the purposes of quality improvement and clinical research, and data quality is ensured with routine auditing.¹⁵ The program has gained a high degree of respect as a powerful and valid data source in both general¹⁶ and orthopedic¹⁷ surgery literature. The database offers a particular advantage with respect to the study of preoperative pneumonia: Only patients with new or recently diagnosed pneumonia on antibiotic therapy who meet strict criteria for characteristic findings on chest radiography, clinical signs and symptoms of respiratory illness, and positive cultures are coded as having actively treated pneumonia at time of surgery.¹⁵

To identify hip fracture patients over the age of 65 years who underwent operative fixation of a hip fracture, we used Current Procedural Terminology (CPT) hip fracture codes, including 27235 (percutaneous screw fixation), 27236 or 27244 (plate-and-screw fixation), and 27245 (intramedullary device), as well as 27125 (hemiarthroplasty) and 27130 (arthroplasty) for patients with a postoperative International Classification of Disease, Ninth Revision (ICD-9) diagnosis code (820.x, 820.2x, or 820.8) consistent with acute hip fracture.^18,19 Procedure type, anesthesia type, and delay from admission to surgery were captured for all procedures.

Preoperative demographics included age, sex, transfer origin, functional status, and body mass index (BMI) category. Binary comorbidities were classified as preoperative anemia (hematocrit, <0.41 for men, <0.36 for women), confusion, dyspnea at rest, uremia (blood urea nitrogen, >6.8 mmol/L), history of cardiovascular disease (congestive heart failure, myocardial infarction, percutaneous coronary intervention, angina pectoris, medically treated hypertension, peripheral vascular disease, or resting claudication), chronic obstructive pulmonary disease, diabetes, renal disease (renal failure or dialysis), and cigarette use in preceding 12 months.^20,21 Although preoperative hypotension and respiratory rate are often considered in patients with pneumonia, these variables were not available from the ACS-NSQIP data.^6,22Pearson χ² test for categorical variables was used to compare baseline demographics and operative characteristics between patients with and without pneumonia, and Student t test was used to compare intervals from hospital admission to hip fracture surgery, surgery start to surgery stop, and surgery to discharge between patients with and without preoperative pneumonia.

Binary outcome measures were compared between patients with and without preoperative pneumonia. “Any AE” included any serious AE (SAE) or any minor AE. SAEs included death, acute renal failure, ventilator use >48 hours, unplanned intubation, septic shock, sepsis, return to operating room, coma >24 hours, cardiac arrest requiring cardiopulmonary resuscitation, myocardial infarction, thromboembolic event (deep vein thrombosis or pulmonary embolism), and stroke/cerebrovascular accident. Minor AEs included progressive renal insufficiency, urinary tract infection, organ/space infection, superficial surgical-site infection, deep surgical-site infection, and wound dehiscence. Other binary outcome measures included discharge destination and unplanned readmission within 30 days after hip fracture surgery.²³Poisson regression with robust error variance as described by Zou²⁴ was used to compare the rates of any, minor, and individual AEs, and any SAEs, between patients with and without pneumonia. Multivariate analysis accounted for the baseline variables in Table 1. AEs that occurred more than once in each group were included in the analyses.

Results

Of the 7128 geriatric hip fracture patients in this study, 82 (1.2%) had active pneumonia at time of surgery (Table 1). Age, BMI, preoperative uremia, history of cardiovascular disease, diabetes, renal disease, and smoking were similar between groups. In addition, there was no difference in anesthesia type or fixation procedure between the pneumonia and no-pneumonia groups. Patients with preoperative pneumonia differed significantly with respect to sex, transfer from facility, preoperative functional dependence, anemia, confusion, dyspnea at rest, and history of chronic obstructive pulmonary disease (Table 1).

Interval from admission to surgery was longer (P < .001) for geriatric hip fracture patients with preoperative pneumonia (mean, 6.8 days; 95% CI, 2.5-11.1 days) than for those without pneumonia (mean, 1.5 days; CI, 1.4-1.5 days). There was no difference (P = .124) in operative time between the pneumonia group (mean, 72.8 min; CI, 64.0-81.5 min) and the no-pneumonia group (mean, 66.1 min; CI, 61.2-67.0 min). Interval from surgery to discharge was longer (P < .001) for patients with preoperative pneumonia (mean, 10.1 days; CI, 6.9-13.4 days) than for those without pneumonia (mean, 6.3 days; CI, 6.1-6.4 days).

Adverse outcomes of geriatric hip fracture surgery are listed in Table 2. In the multivariate analysis, preoperative pneumonia was significantly associated with any AE (relative risk [RR]) = 1.44) and any SAE (RR = 1.79).

Discussion

In the general US population, pneumonia accounts for 1.4% of deaths in people 65 years to 74 years old, 2.1% in people 75 years to 84 years, and 3.1% in people 85 years or older. In total, 3.4% of hospital inpatient deaths are attributed to pneumonia.²⁵ In hospitalized general orthopedic surgical patients as well as hip fracture patients, pneumonia is strongly associated with increased mortality.^26,27

We identified a preoperative pneumonia prevalence of 1.2%, which is comparable to the rates reported in the literature (0.3%-3.2%).^1-3 To our knowledge, our study represents the largest series of patients with preoperative pneumonia at time of hip fracture repair, and the first to independently associate preoperative pneumonia with increased incidence of AEs, including death.

This study had its limitations. First, the ACS-NSQIP morbidity and mortality data, which are limited to the first 30 postoperative days, may be skewed because AEs that occurred after that interval are not captured. Second, coding of pneumonia in ACS-NSQIP does not convey specific information about the disease and its severity—infectious organism(s) responsible; acquisition setting (healthcare or community); treatment given, including antibiotic(s) selection, steroid use, dosing, and duration; and measures of treatment efficacy—limiting interpretation of the difference in delay to surgery. We cannot say whether the longer interval in patients with pneumonia reflects medical optimization, or whether the delay itself or any interventions during that time positively or negatively affected outcomes. In addition, despite using a large national database, we obtained a relatively small sample of patients (82) who had pneumonia before surgical hip fracture repair.

Multivariate analysis controlling for baseline demographics and comorbidities revealed that multiple SAEs were independently associated with preoperative pneumonia (overall SAE, RR = 1.79). Postoperative use of ventilator support for longer than 48 hours (RR = 6.48) and coma longer than 24 hours (RR = 7.31) are expected given the severity of pulmonary compromise in the study cohort.^28,29 Acute renal failure (RR = 14.61) can occur in both hip fracture patients and community-acquired pneumonia patients and may be a multifactorial complication of the pulmonary infection, of the anesthesia, or of the surgical intervention in this cohort.^30-32Unadjusted mortality in hip fracture takes months to a year to normalize to that of age-matched controls.^32-34 In our series, the unadjusted death rate in the pneumonia cohort (Figure) was transiently elevated during the first weeks after surgery but then drew nearer the rate in the nondiseased hip fracture cohort by the end of the first month. Early death in the pneumonia group likely was multifactorial, potentially influenced by the increased burden of comorbidities in the pneumonia group at baseline, and the longer delay to surgery,^35-38 as well as by the natural history of treated pneumonia in hospital patients, who, compared with age-matched hospitalized controls, also exhibit higher mortality during only the first 2 to 4 months of hospitalization for pneumonia.³⁹ We regret that quality improvement strategies in the treatment of geriatric hip fracture surgery with pneumonia cannot be extrapolated from these results.

Similarly, the utility of BMI <18.5 kg/m² as an actionable preoperative finding cannot be assessed from these results. However, we propose that underweight geriatric hip fracture patients with pneumonia may benefit from more aggressive preoperative optimization that does not delay surgery. Higher acuity of postoperative care, including more intensive nursing care and early coordination of care with respiratory therapists and medical comanagement teams, may also be beneficial.

Anesthesia type did not differ between patients with and without preoperative pneumonia and was not associated with AEs in patients with preoperative pneumonia. Consistent with our findings, multiple studies have reported no significant differences in short-term outcomes of hip fracture repair between general and spinal anesthesia, though no other study has compared the benefits of general and spinal anesthesia for patients with preoperative pneumonia.^40-44 Although spinal anesthesia (relative to general anesthesia) has been reported to have benefits in hip and knee arthroplasty, these benefits appear not to translate to hip fracture repair.^45-50 The results of the present study suggest that general and spinal anesthesia may be equivalent in terms of risk for the geriatric hip fracture patient with preoperative pneumonia.^43,44Our attempt to evaluate the CURB-65 pneumonia severity score as a prognosticator of AEs was thwarted by the absence of required variables in the ACS-NSQIP dataset (confusion, uremia, dyspnea, and age were available; hypotension and blood pressure were not). In our analysis, we did include, individually, variables previously found to predict AEs in the medical pneumonia population (confusion, uremia, dyspnea at rest, anemia).^9-11,32 However, these clinical findings are nonspecific in hip fracture patients, who may become anemic, confused, dyspneic, or uremic from a multitude of factors related to their injury and unrelated to pneumonia, including but not limited to hemorrhage, muscle damage, renal injury, and pulmonary embolism. It is not surprising that confusion, uremia, dyspnea at rest, and anemia were not individually predictive of AEs or death within 30 days after surgery in the cohort of geriatric hip fracture patients with pneumonia.

There is no literature that argues for or against delaying hip fracture surgery in geriatric hip fracture patients with pneumonia. The surgical delay observed in this population is ostensibly related to medical optimization of the pneumonia and/or underlying comorbidities. However, we did not find a morbidity or mortality detriment or benefit in delaying surgery by 1 to 4 days in this population. Delay of surgery is a poor covariate, given extensive confounding by medical management and preoperative optimizing of comorbid conditions (reflected in our independent variable and covariates) as well as institutional and surgeon variations in policy and behavior and other unaccounted influences. Although some authors have found no difference in mortality or major AEs between hip fracture patients who had a surgical delay and those who did not,^31,51-53 other series and meta-analyses have suggested a mortality detriment in a surgical delay of more than 2 days^36,54 or 4 days⁵⁵ from admission. Given our data, we cannot recommend against immediate hip fracture repair in the subpopulation of geriatric hip fracture patients with pneumonia.

Our study findings suggest that preoperative pneumonia is a rare independent risk factor for AEs after hip fracture surgery in geriatric patients. Underweight BMI is predictive of death in geriatric hip fracture surgery patients who present with pneumonia, whereas early surgical repair appears not to be associated with adverse outcomes. Further investigation is warranted to determine if such patients benefit from specific preoperative and postoperative strategies for optimizing medical and surgical care based on these findings.

Am J Orthop. 2017;46(3):E177-E185. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• The prevalence of preoperative pneumonia is 1.2% among hip fracture patients aged >65 years.
• Preoperative pneumonia is an independent risk factor for mortality and adverse events including renal failure, prolonged ventilator dependence, and prolonged altered mental status after geriatric hip fracture surgery.
• Underweight BMI (<18.5 kg/m²) was associated with higher mortality within 30 days among hip fracture patients admitted with pneumonia.
• The mortality rate normalized to that of patients without pneumonia within 2 weeks of hip fracture surgery.
• Time from admission to surgery was not associated with adverse events or mortality among hip fracture patients admitted with pneumonia.

Preoperative pneumonia remains relatively unexplored as a risk factor for adverse outcomes in geriatric hip fracture surgery. Dated studies report a 0.3% to 3.2% prevalence of “recent pneumonia” in patients presenting with hip fracture but provide neither a definition of pneumonia based on clinical criteria nor a subset analysis of outcomes in the pneumonia group.^1-3 Although active pneumonia has been identified as a preoperative optimization target in the management guidelines for geriatric hip fracture,⁴ we are unaware of any studies that have reported on differences in demographics, comorbidities, delay to surgery, or adverse outcomes between hip fracture patients with and without preoperative pneumonia.

This paucity of information on the effect of preoperative pneumonia in the hip fracture population may be related to low prevalence of preoperative pneumonia and a cadre of variable definitions, which limit identification of a cohort of patients with preoperative pneumonia large enough from which to draw meaningful results. Database studies, especially those using surgical registries rather than administrative or reimbursement data, offer particular advantages for investigation of such rare clinical entities.⁵Medical care of patients with pneumonia alone is known to be facilitated by assessments of mortality risk from clinical and laboratory data. The modified British Thoracic Society rule/CURB-65 (confusion, urea, respiratory rate, blood pressure) score is strongly predictive of mortality in hospitalized adults with pneumonia (odds ratio [OR], 4.59; 95% confidence interval [CI], 1.42-14.85; P = .011) and may guide antibiotic therapy, laboratory investigations, and the decision to intubate in a patient with pneumonia.^6-8 This score is predictive of adverse events (AEs), hospital length of stay, and use of intensive care services.^6,7,9-13 We hypothesized that preoperative clinical indicators assessed by pneumonia severity scores as well as patient demographics and baseline comorbidities may also have prognostic value for risk of AEs in a cohort of geriatric hip fracture surgery patients with preoperative pneumonia.

In this article, we first describe the prevalence of preoperative pneumonia in geriatric hip fracture surgery patients as well as demographic and operative differences between patients with and without the disease. We then ask 3 questions: Is preoperative pneumonia an independent risk factor for mortality and adverse outcomes in geriatric hip fracture surgery? Is there a postoperative interval during which the unadjusted mortality rate is higher among patients with preoperative pneumonia? In patients with preoperative pneumonia, what are the predictors of morbidity and mortality?

Methods

Yale University’s Human Investigations Committee approved this retrospective cohort study, which used the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database for the period 2005 to 2012. ACS-NSQIP is a prospective, multi-institutional outcomes program that collects data on preoperative comorbidities, intraoperative variables, and 30-day postoperative outcomes for patients undergoing surgical procedures in inpatient and outpatient settings.¹⁴

Unlike administrative databases, which are based on reimbursement data, ACS-NSQIP data are collected by trained surgical clinical reviewers for the purposes of quality improvement and clinical research, and data quality is ensured with routine auditing.¹⁵ The program has gained a high degree of respect as a powerful and valid data source in both general¹⁶ and orthopedic¹⁷ surgery literature. The database offers a particular advantage with respect to the study of preoperative pneumonia: Only patients with new or recently diagnosed pneumonia on antibiotic therapy who meet strict criteria for characteristic findings on chest radiography, clinical signs and symptoms of respiratory illness, and positive cultures are coded as having actively treated pneumonia at time of surgery.¹⁵

To identify hip fracture patients over the age of 65 years who underwent operative fixation of a hip fracture, we used Current Procedural Terminology (CPT) hip fracture codes, including 27235 (percutaneous screw fixation), 27236 or 27244 (plate-and-screw fixation), and 27245 (intramedullary device), as well as 27125 (hemiarthroplasty) and 27130 (arthroplasty) for patients with a postoperative International Classification of Disease, Ninth Revision (ICD-9) diagnosis code (820.x, 820.2x, or 820.8) consistent with acute hip fracture.^18,19 Procedure type, anesthesia type, and delay from admission to surgery were captured for all procedures.

Preoperative demographics included age, sex, transfer origin, functional status, and body mass index (BMI) category. Binary comorbidities were classified as preoperative anemia (hematocrit, <0.41 for men, <0.36 for women), confusion, dyspnea at rest, uremia (blood urea nitrogen, >6.8 mmol/L), history of cardiovascular disease (congestive heart failure, myocardial infarction, percutaneous coronary intervention, angina pectoris, medically treated hypertension, peripheral vascular disease, or resting claudication), chronic obstructive pulmonary disease, diabetes, renal disease (renal failure or dialysis), and cigarette use in preceding 12 months.^20,21 Although preoperative hypotension and respiratory rate are often considered in patients with pneumonia, these variables were not available from the ACS-NSQIP data.^6,22Pearson χ² test for categorical variables was used to compare baseline demographics and operative characteristics between patients with and without pneumonia, and Student t test was used to compare intervals from hospital admission to hip fracture surgery, surgery start to surgery stop, and surgery to discharge between patients with and without preoperative pneumonia.

Binary outcome measures were compared between patients with and without preoperative pneumonia. “Any AE” included any serious AE (SAE) or any minor AE. SAEs included death, acute renal failure, ventilator use >48 hours, unplanned intubation, septic shock, sepsis, return to operating room, coma >24 hours, cardiac arrest requiring cardiopulmonary resuscitation, myocardial infarction, thromboembolic event (deep vein thrombosis or pulmonary embolism), and stroke/cerebrovascular accident. Minor AEs included progressive renal insufficiency, urinary tract infection, organ/space infection, superficial surgical-site infection, deep surgical-site infection, and wound dehiscence. Other binary outcome measures included discharge destination and unplanned readmission within 30 days after hip fracture surgery.²³Poisson regression with robust error variance as described by Zou²⁴ was used to compare the rates of any, minor, and individual AEs, and any SAEs, between patients with and without pneumonia. Multivariate analysis accounted for the baseline variables in Table 1. AEs that occurred more than once in each group were included in the analyses.

Results

Of the 7128 geriatric hip fracture patients in this study, 82 (1.2%) had active pneumonia at time of surgery (Table 1). Age, BMI, preoperative uremia, history of cardiovascular disease, diabetes, renal disease, and smoking were similar between groups. In addition, there was no difference in anesthesia type or fixation procedure between the pneumonia and no-pneumonia groups. Patients with preoperative pneumonia differed significantly with respect to sex, transfer from facility, preoperative functional dependence, anemia, confusion, dyspnea at rest, and history of chronic obstructive pulmonary disease (Table 1).

Interval from admission to surgery was longer (P < .001) for geriatric hip fracture patients with preoperative pneumonia (mean, 6.8 days; 95% CI, 2.5-11.1 days) than for those without pneumonia (mean, 1.5 days; CI, 1.4-1.5 days). There was no difference (P = .124) in operative time between the pneumonia group (mean, 72.8 min; CI, 64.0-81.5 min) and the no-pneumonia group (mean, 66.1 min; CI, 61.2-67.0 min). Interval from surgery to discharge was longer (P < .001) for patients with preoperative pneumonia (mean, 10.1 days; CI, 6.9-13.4 days) than for those without pneumonia (mean, 6.3 days; CI, 6.1-6.4 days).

Adverse outcomes of geriatric hip fracture surgery are listed in Table 2. In the multivariate analysis, preoperative pneumonia was significantly associated with any AE (relative risk [RR]) = 1.44) and any SAE (RR = 1.79).

Discussion

In the general US population, pneumonia accounts for 1.4% of deaths in people 65 years to 74 years old, 2.1% in people 75 years to 84 years, and 3.1% in people 85 years or older. In total, 3.4% of hospital inpatient deaths are attributed to pneumonia.²⁵ In hospitalized general orthopedic surgical patients as well as hip fracture patients, pneumonia is strongly associated with increased mortality.^26,27

We identified a preoperative pneumonia prevalence of 1.2%, which is comparable to the rates reported in the literature (0.3%-3.2%).^1-3 To our knowledge, our study represents the largest series of patients with preoperative pneumonia at time of hip fracture repair, and the first to independently associate preoperative pneumonia with increased incidence of AEs, including death.

This study had its limitations. First, the ACS-NSQIP morbidity and mortality data, which are limited to the first 30 postoperative days, may be skewed because AEs that occurred after that interval are not captured. Second, coding of pneumonia in ACS-NSQIP does not convey specific information about the disease and its severity—infectious organism(s) responsible; acquisition setting (healthcare or community); treatment given, including antibiotic(s) selection, steroid use, dosing, and duration; and measures of treatment efficacy—limiting interpretation of the difference in delay to surgery. We cannot say whether the longer interval in patients with pneumonia reflects medical optimization, or whether the delay itself or any interventions during that time positively or negatively affected outcomes. In addition, despite using a large national database, we obtained a relatively small sample of patients (82) who had pneumonia before surgical hip fracture repair.

Multivariate analysis controlling for baseline demographics and comorbidities revealed that multiple SAEs were independently associated with preoperative pneumonia (overall SAE, RR = 1.79). Postoperative use of ventilator support for longer than 48 hours (RR = 6.48) and coma longer than 24 hours (RR = 7.31) are expected given the severity of pulmonary compromise in the study cohort.^28,29 Acute renal failure (RR = 14.61) can occur in both hip fracture patients and community-acquired pneumonia patients and may be a multifactorial complication of the pulmonary infection, of the anesthesia, or of the surgical intervention in this cohort.^30-32Unadjusted mortality in hip fracture takes months to a year to normalize to that of age-matched controls.^32-34 In our series, the unadjusted death rate in the pneumonia cohort (Figure) was transiently elevated during the first weeks after surgery but then drew nearer the rate in the nondiseased hip fracture cohort by the end of the first month. Early death in the pneumonia group likely was multifactorial, potentially influenced by the increased burden of comorbidities in the pneumonia group at baseline, and the longer delay to surgery,^35-38 as well as by the natural history of treated pneumonia in hospital patients, who, compared with age-matched hospitalized controls, also exhibit higher mortality during only the first 2 to 4 months of hospitalization for pneumonia.³⁹ We regret that quality improvement strategies in the treatment of geriatric hip fracture surgery with pneumonia cannot be extrapolated from these results.

Similarly, the utility of BMI <18.5 kg/m² as an actionable preoperative finding cannot be assessed from these results. However, we propose that underweight geriatric hip fracture patients with pneumonia may benefit from more aggressive preoperative optimization that does not delay surgery. Higher acuity of postoperative care, including more intensive nursing care and early coordination of care with respiratory therapists and medical comanagement teams, may also be beneficial.

Anesthesia type did not differ between patients with and without preoperative pneumonia and was not associated with AEs in patients with preoperative pneumonia. Consistent with our findings, multiple studies have reported no significant differences in short-term outcomes of hip fracture repair between general and spinal anesthesia, though no other study has compared the benefits of general and spinal anesthesia for patients with preoperative pneumonia.^40-44 Although spinal anesthesia (relative to general anesthesia) has been reported to have benefits in hip and knee arthroplasty, these benefits appear not to translate to hip fracture repair.^45-50 The results of the present study suggest that general and spinal anesthesia may be equivalent in terms of risk for the geriatric hip fracture patient with preoperative pneumonia.^43,44Our attempt to evaluate the CURB-65 pneumonia severity score as a prognosticator of AEs was thwarted by the absence of required variables in the ACS-NSQIP dataset (confusion, uremia, dyspnea, and age were available; hypotension and blood pressure were not). In our analysis, we did include, individually, variables previously found to predict AEs in the medical pneumonia population (confusion, uremia, dyspnea at rest, anemia).^9-11,32 However, these clinical findings are nonspecific in hip fracture patients, who may become anemic, confused, dyspneic, or uremic from a multitude of factors related to their injury and unrelated to pneumonia, including but not limited to hemorrhage, muscle damage, renal injury, and pulmonary embolism. It is not surprising that confusion, uremia, dyspnea at rest, and anemia were not individually predictive of AEs or death within 30 days after surgery in the cohort of geriatric hip fracture patients with pneumonia.

There is no literature that argues for or against delaying hip fracture surgery in geriatric hip fracture patients with pneumonia. The surgical delay observed in this population is ostensibly related to medical optimization of the pneumonia and/or underlying comorbidities. However, we did not find a morbidity or mortality detriment or benefit in delaying surgery by 1 to 4 days in this population. Delay of surgery is a poor covariate, given extensive confounding by medical management and preoperative optimizing of comorbid conditions (reflected in our independent variable and covariates) as well as institutional and surgeon variations in policy and behavior and other unaccounted influences. Although some authors have found no difference in mortality or major AEs between hip fracture patients who had a surgical delay and those who did not,^31,51-53 other series and meta-analyses have suggested a mortality detriment in a surgical delay of more than 2 days^36,54 or 4 days⁵⁵ from admission. Given our data, we cannot recommend against immediate hip fracture repair in the subpopulation of geriatric hip fracture patients with pneumonia.

Our study findings suggest that preoperative pneumonia is a rare independent risk factor for AEs after hip fracture surgery in geriatric patients. Underweight BMI is predictive of death in geriatric hip fracture surgery patients who present with pneumonia, whereas early surgical repair appears not to be associated with adverse outcomes. Further investigation is warranted to determine if such patients benefit from specific preoperative and postoperative strategies for optimizing medical and surgical care based on these findings.

Am J Orthop. 2017;46(3):E177-E185. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

Take-Home Points

• The prevalence of preoperative pneumonia is 1.2% among hip fracture patients aged >65 years.
• Preoperative pneumonia is an independent risk factor for mortality and adverse events including renal failure, prolonged ventilator dependence, and prolonged altered mental status after geriatric hip fracture surgery.
• Underweight BMI (<18.5 kg/m²) was associated with higher mortality within 30 days among hip fracture patients admitted with pneumonia.
• The mortality rate normalized to that of patients without pneumonia within 2 weeks of hip fracture surgery.
• Time from admission to surgery was not associated with adverse events or mortality among hip fracture patients admitted with pneumonia.

Preoperative pneumonia remains relatively unexplored as a risk factor for adverse outcomes in geriatric hip fracture surgery. Dated studies report a 0.3% to 3.2% prevalence of “recent pneumonia” in patients presenting with hip fracture but provide neither a definition of pneumonia based on clinical criteria nor a subset analysis of outcomes in the pneumonia group.^1-3 Although active pneumonia has been identified as a preoperative optimization target in the management guidelines for geriatric hip fracture,⁴ we are unaware of any studies that have reported on differences in demographics, comorbidities, delay to surgery, or adverse outcomes between hip fracture patients with and without preoperative pneumonia.

This paucity of information on the effect of preoperative pneumonia in the hip fracture population may be related to low prevalence of preoperative pneumonia and a cadre of variable definitions, which limit identification of a cohort of patients with preoperative pneumonia large enough from which to draw meaningful results. Database studies, especially those using surgical registries rather than administrative or reimbursement data, offer particular advantages for investigation of such rare clinical entities.⁵Medical care of patients with pneumonia alone is known to be facilitated by assessments of mortality risk from clinical and laboratory data. The modified British Thoracic Society rule/CURB-65 (confusion, urea, respiratory rate, blood pressure) score is strongly predictive of mortality in hospitalized adults with pneumonia (odds ratio [OR], 4.59; 95% confidence interval [CI], 1.42-14.85; P = .011) and may guide antibiotic therapy, laboratory investigations, and the decision to intubate in a patient with pneumonia.^6-8 This score is predictive of adverse events (AEs), hospital length of stay, and use of intensive care services.^6,7,9-13 We hypothesized that preoperative clinical indicators assessed by pneumonia severity scores as well as patient demographics and baseline comorbidities may also have prognostic value for risk of AEs in a cohort of geriatric hip fracture surgery patients with preoperative pneumonia.

In this article, we first describe the prevalence of preoperative pneumonia in geriatric hip fracture surgery patients as well as demographic and operative differences between patients with and without the disease. We then ask 3 questions: Is preoperative pneumonia an independent risk factor for mortality and adverse outcomes in geriatric hip fracture surgery? Is there a postoperative interval during which the unadjusted mortality rate is higher among patients with preoperative pneumonia? In patients with preoperative pneumonia, what are the predictors of morbidity and mortality?

Methods

Yale University’s Human Investigations Committee approved this retrospective cohort study, which used the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database for the period 2005 to 2012. ACS-NSQIP is a prospective, multi-institutional outcomes program that collects data on preoperative comorbidities, intraoperative variables, and 30-day postoperative outcomes for patients undergoing surgical procedures in inpatient and outpatient settings.¹⁴

Unlike administrative databases, which are based on reimbursement data, ACS-NSQIP data are collected by trained surgical clinical reviewers for the purposes of quality improvement and clinical research, and data quality is ensured with routine auditing.¹⁵ The program has gained a high degree of respect as a powerful and valid data source in both general¹⁶ and orthopedic¹⁷ surgery literature. The database offers a particular advantage with respect to the study of preoperative pneumonia: Only patients with new or recently diagnosed pneumonia on antibiotic therapy who meet strict criteria for characteristic findings on chest radiography, clinical signs and symptoms of respiratory illness, and positive cultures are coded as having actively treated pneumonia at time of surgery.¹⁵

To identify hip fracture patients over the age of 65 years who underwent operative fixation of a hip fracture, we used Current Procedural Terminology (CPT) hip fracture codes, including 27235 (percutaneous screw fixation), 27236 or 27244 (plate-and-screw fixation), and 27245 (intramedullary device), as well as 27125 (hemiarthroplasty) and 27130 (arthroplasty) for patients with a postoperative International Classification of Disease, Ninth Revision (ICD-9) diagnosis code (820.x, 820.2x, or 820.8) consistent with acute hip fracture.^18,19 Procedure type, anesthesia type, and delay from admission to surgery were captured for all procedures.

Preoperative demographics included age, sex, transfer origin, functional status, and body mass index (BMI) category. Binary comorbidities were classified as preoperative anemia (hematocrit, <0.41 for men, <0.36 for women), confusion, dyspnea at rest, uremia (blood urea nitrogen, >6.8 mmol/L), history of cardiovascular disease (congestive heart failure, myocardial infarction, percutaneous coronary intervention, angina pectoris, medically treated hypertension, peripheral vascular disease, or resting claudication), chronic obstructive pulmonary disease, diabetes, renal disease (renal failure or dialysis), and cigarette use in preceding 12 months.^20,21 Although preoperative hypotension and respiratory rate are often considered in patients with pneumonia, these variables were not available from the ACS-NSQIP data.^6,22Pearson χ² test for categorical variables was used to compare baseline demographics and operative characteristics between patients with and without pneumonia, and Student t test was used to compare intervals from hospital admission to hip fracture surgery, surgery start to surgery stop, and surgery to discharge between patients with and without preoperative pneumonia.

Binary outcome measures were compared between patients with and without preoperative pneumonia. “Any AE” included any serious AE (SAE) or any minor AE. SAEs included death, acute renal failure, ventilator use >48 hours, unplanned intubation, septic shock, sepsis, return to operating room, coma >24 hours, cardiac arrest requiring cardiopulmonary resuscitation, myocardial infarction, thromboembolic event (deep vein thrombosis or pulmonary embolism), and stroke/cerebrovascular accident. Minor AEs included progressive renal insufficiency, urinary tract infection, organ/space infection, superficial surgical-site infection, deep surgical-site infection, and wound dehiscence. Other binary outcome measures included discharge destination and unplanned readmission within 30 days after hip fracture surgery.²³Poisson regression with robust error variance as described by Zou²⁴ was used to compare the rates of any, minor, and individual AEs, and any SAEs, between patients with and without pneumonia. Multivariate analysis accounted for the baseline variables in Table 1. AEs that occurred more than once in each group were included in the analyses.

Results

Of the 7128 geriatric hip fracture patients in this study, 82 (1.2%) had active pneumonia at time of surgery (Table 1). Age, BMI, preoperative uremia, history of cardiovascular disease, diabetes, renal disease, and smoking were similar between groups. In addition, there was no difference in anesthesia type or fixation procedure between the pneumonia and no-pneumonia groups. Patients with preoperative pneumonia differed significantly with respect to sex, transfer from facility, preoperative functional dependence, anemia, confusion, dyspnea at rest, and history of chronic obstructive pulmonary disease (Table 1).

Interval from admission to surgery was longer (P < .001) for geriatric hip fracture patients with preoperative pneumonia (mean, 6.8 days; 95% CI, 2.5-11.1 days) than for those without pneumonia (mean, 1.5 days; CI, 1.4-1.5 days). There was no difference (P = .124) in operative time between the pneumonia group (mean, 72.8 min; CI, 64.0-81.5 min) and the no-pneumonia group (mean, 66.1 min; CI, 61.2-67.0 min). Interval from surgery to discharge was longer (P < .001) for patients with preoperative pneumonia (mean, 10.1 days; CI, 6.9-13.4 days) than for those without pneumonia (mean, 6.3 days; CI, 6.1-6.4 days).

Adverse outcomes of geriatric hip fracture surgery are listed in Table 2. In the multivariate analysis, preoperative pneumonia was significantly associated with any AE (relative risk [RR]) = 1.44) and any SAE (RR = 1.79).

Discussion

In the general US population, pneumonia accounts for 1.4% of deaths in people 65 years to 74 years old, 2.1% in people 75 years to 84 years, and 3.1% in people 85 years or older. In total, 3.4% of hospital inpatient deaths are attributed to pneumonia.²⁵ In hospitalized general orthopedic surgical patients as well as hip fracture patients, pneumonia is strongly associated with increased mortality.^26,27

We identified a preoperative pneumonia prevalence of 1.2%, which is comparable to the rates reported in the literature (0.3%-3.2%).^1-3 To our knowledge, our study represents the largest series of patients with preoperative pneumonia at time of hip fracture repair, and the first to independently associate preoperative pneumonia with increased incidence of AEs, including death.

This study had its limitations. First, the ACS-NSQIP morbidity and mortality data, which are limited to the first 30 postoperative days, may be skewed because AEs that occurred after that interval are not captured. Second, coding of pneumonia in ACS-NSQIP does not convey specific information about the disease and its severity—infectious organism(s) responsible; acquisition setting (healthcare or community); treatment given, including antibiotic(s) selection, steroid use, dosing, and duration; and measures of treatment efficacy—limiting interpretation of the difference in delay to surgery. We cannot say whether the longer interval in patients with pneumonia reflects medical optimization, or whether the delay itself or any interventions during that time positively or negatively affected outcomes. In addition, despite using a large national database, we obtained a relatively small sample of patients (82) who had pneumonia before surgical hip fracture repair.

Multivariate analysis controlling for baseline demographics and comorbidities revealed that multiple SAEs were independently associated with preoperative pneumonia (overall SAE, RR = 1.79). Postoperative use of ventilator support for longer than 48 hours (RR = 6.48) and coma longer than 24 hours (RR = 7.31) are expected given the severity of pulmonary compromise in the study cohort.^28,29 Acute renal failure (RR = 14.61) can occur in both hip fracture patients and community-acquired pneumonia patients and may be a multifactorial complication of the pulmonary infection, of the anesthesia, or of the surgical intervention in this cohort.^30-32Unadjusted mortality in hip fracture takes months to a year to normalize to that of age-matched controls.^32-34 In our series, the unadjusted death rate in the pneumonia cohort (Figure) was transiently elevated during the first weeks after surgery but then drew nearer the rate in the nondiseased hip fracture cohort by the end of the first month. Early death in the pneumonia group likely was multifactorial, potentially influenced by the increased burden of comorbidities in the pneumonia group at baseline, and the longer delay to surgery,^35-38 as well as by the natural history of treated pneumonia in hospital patients, who, compared with age-matched hospitalized controls, also exhibit higher mortality during only the first 2 to 4 months of hospitalization for pneumonia.³⁹ We regret that quality improvement strategies in the treatment of geriatric hip fracture surgery with pneumonia cannot be extrapolated from these results.

Similarly, the utility of BMI <18.5 kg/m² as an actionable preoperative finding cannot be assessed from these results. However, we propose that underweight geriatric hip fracture patients with pneumonia may benefit from more aggressive preoperative optimization that does not delay surgery. Higher acuity of postoperative care, including more intensive nursing care and early coordination of care with respiratory therapists and medical comanagement teams, may also be beneficial.

Anesthesia type did not differ between patients with and without preoperative pneumonia and was not associated with AEs in patients with preoperative pneumonia. Consistent with our findings, multiple studies have reported no significant differences in short-term outcomes of hip fracture repair between general and spinal anesthesia, though no other study has compared the benefits of general and spinal anesthesia for patients with preoperative pneumonia.^40-44 Although spinal anesthesia (relative to general anesthesia) has been reported to have benefits in hip and knee arthroplasty, these benefits appear not to translate to hip fracture repair.^45-50 The results of the present study suggest that general and spinal anesthesia may be equivalent in terms of risk for the geriatric hip fracture patient with preoperative pneumonia.^43,44Our attempt to evaluate the CURB-65 pneumonia severity score as a prognosticator of AEs was thwarted by the absence of required variables in the ACS-NSQIP dataset (confusion, uremia, dyspnea, and age were available; hypotension and blood pressure were not). In our analysis, we did include, individually, variables previously found to predict AEs in the medical pneumonia population (confusion, uremia, dyspnea at rest, anemia).^9-11,32 However, these clinical findings are nonspecific in hip fracture patients, who may become anemic, confused, dyspneic, or uremic from a multitude of factors related to their injury and unrelated to pneumonia, including but not limited to hemorrhage, muscle damage, renal injury, and pulmonary embolism. It is not surprising that confusion, uremia, dyspnea at rest, and anemia were not individually predictive of AEs or death within 30 days after surgery in the cohort of geriatric hip fracture patients with pneumonia.

There is no literature that argues for or against delaying hip fracture surgery in geriatric hip fracture patients with pneumonia. The surgical delay observed in this population is ostensibly related to medical optimization of the pneumonia and/or underlying comorbidities. However, we did not find a morbidity or mortality detriment or benefit in delaying surgery by 1 to 4 days in this population. Delay of surgery is a poor covariate, given extensive confounding by medical management and preoperative optimizing of comorbid conditions (reflected in our independent variable and covariates) as well as institutional and surgeon variations in policy and behavior and other unaccounted influences. Although some authors have found no difference in mortality or major AEs between hip fracture patients who had a surgical delay and those who did not,^31,51-53 other series and meta-analyses have suggested a mortality detriment in a surgical delay of more than 2 days^36,54 or 4 days⁵⁵ from admission. Given our data, we cannot recommend against immediate hip fracture repair in the subpopulation of geriatric hip fracture patients with pneumonia.

Our study findings suggest that preoperative pneumonia is a rare independent risk factor for AEs after hip fracture surgery in geriatric patients. Underweight BMI is predictive of death in geriatric hip fracture surgery patients who present with pneumonia, whereas early surgical repair appears not to be associated with adverse outcomes. Further investigation is warranted to determine if such patients benefit from specific preoperative and postoperative strategies for optimizing medical and surgical care based on these findings.

Am J Orthop. 2017;46(3):E177-E185. Copyright Frontline Medical Communications Inc. 2017. All rights reserved.

CHICAGO – The standard of care for patients with non–small cell lung cancer positive for the anaplastic lymphoma kinase (ALK) is the ALK inhibitor crizotinib (Xalkori). However, many patients on crizotinib will have disease progression within the first year of therapy, and many will go on to have central nervous system (CNS) metastases.

The multicenter international ALEX trial compared crizotinib with the second-generation ALK inhibitor alectinib (Alecensa). The investigators found that alectinib reduced the risk of progression by 53% and the time to CNS progression by 84%.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, outlines the ALEX trial results, which are being hailed as “practice changing.”

CHICAGO – The standard of care for patients with non–small cell lung cancer positive for the anaplastic lymphoma kinase (ALK) is the ALK inhibitor crizotinib (Xalkori). However, many patients on crizotinib will have disease progression within the first year of therapy, and many will go on to have central nervous system (CNS) metastases.

The multicenter international ALEX trial compared crizotinib with the second-generation ALK inhibitor alectinib (Alecensa). The investigators found that alectinib reduced the risk of progression by 53% and the time to CNS progression by 84%.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, outlines the ALEX trial results, which are being hailed as “practice changing.”

CHICAGO – The standard of care for patients with non–small cell lung cancer positive for the anaplastic lymphoma kinase (ALK) is the ALK inhibitor crizotinib (Xalkori). However, many patients on crizotinib will have disease progression within the first year of therapy, and many will go on to have central nervous system (CNS) metastases.

The multicenter international ALEX trial compared crizotinib with the second-generation ALK inhibitor alectinib (Alecensa). The investigators found that alectinib reduced the risk of progression by 53% and the time to CNS progression by 84%.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Alice T. Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center in Boston, outlines the ALEX trial results, which are being hailed as “practice changing.”

CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.

BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.

CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.

BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.

CHICAGO – Adding an experimental immune-enhancing agent to a checkpoint inhibitor was safe and showed early promise of activity against advanced solid tumors in a phase I/IIa clinical trial.

BMS-986156 is a fully human immunoglobulin G1 agonist monoclonal antibody with high affinity binding for the glucorticoid-induced tumor necrosis factor receptor-related gene. The drug acts synergistically with the programmed-death 1 inhibitor (PD-1) nivolumab (Opdivo) by increasing survival of T effector cells, promoting regulatory T-cell depletion and reduction, and reducing regulatory T cell suppression of T effector cells to produce a more robust antitumor immune response.

In this video interview at the annual meeting of the American Society of Clinical Oncology, Lillian Siu, MD, from the Princess Margaret Hospital, Toronto, describes how the combination has induced durable partial responses in patients with tumors thought to be insensitive to immunotherapy, as well as patients who had disease progression while on a PD-1 inhibitor.

Bob Wachter, MD, created buzz in March 2016 when, at the SHM annual meeting in San Diego, he displayed a slide titled “What did we get wrong?” The slide contained the copy, “Hospitalist shifts run 7 a.m.-7 p.m.; 10 a.m.-10 p.m. 7on/7off” circled in bold red.

Over the last several years, thought leaders in the hospital medicine field have expressed concern that this one-size-fits-all schedule model is a threat to the well-being of many physicians and, by extension, the sustainability of their hospital medicine groups. Despite this, the 2016 State of Hospital Medicine Report reveals relatively little change in the way hospital medicine groups schedule their physicians.

Dr. Eisenstock, MD, FHM, is clinical chief, division of hospital medicine, at the University of Massachusetts Memorial Health Care, Worcester.

Bob Wachter, MD, created buzz in March 2016 when, at the SHM annual meeting in San Diego, he displayed a slide titled “What did we get wrong?” The slide contained the copy, “Hospitalist shifts run 7 a.m.-7 p.m.; 10 a.m.-10 p.m. 7on/7off” circled in bold red.

Over the last several years, thought leaders in the hospital medicine field have expressed concern that this one-size-fits-all schedule model is a threat to the well-being of many physicians and, by extension, the sustainability of their hospital medicine groups. Despite this, the 2016 State of Hospital Medicine Report reveals relatively little change in the way hospital medicine groups schedule their physicians.

Dr. Eisenstock, MD, FHM, is clinical chief, division of hospital medicine, at the University of Massachusetts Memorial Health Care, Worcester.

Bob Wachter, MD, created buzz in March 2016 when, at the SHM annual meeting in San Diego, he displayed a slide titled “What did we get wrong?” The slide contained the copy, “Hospitalist shifts run 7 a.m.-7 p.m.; 10 a.m.-10 p.m. 7on/7off” circled in bold red.

Over the last several years, thought leaders in the hospital medicine field have expressed concern that this one-size-fits-all schedule model is a threat to the well-being of many physicians and, by extension, the sustainability of their hospital medicine groups. Despite this, the 2016 State of Hospital Medicine Report reveals relatively little change in the way hospital medicine groups schedule their physicians.

Dr. Eisenstock, MD, FHM, is clinical chief, division of hospital medicine, at the University of Massachusetts Memorial Health Care, Worcester.

PARIS – Undetected diabetes and prediabetes are pervasive in patients undergoing percutaneous coronary intervention, and they’re associated with a sharply increased risk of major adverse cardiovascular events, according to the results of the potentially practice-changing BIO-RESORT Silent Diabetes Study, Clemens von Birgelen, MD, PhD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“Our data support screening PCI all-comers for silent diabetes, which may help identify patients with an increased event risk and improve their therapy,” said Dr. von Birgelen, professor of cardiology at the Thoraxcentrum of Twente, a high-volume center for cardiac interventions in Enschede, the Netherlands.

Bruce Jancin/Frontline Medical News

[email protected]

PARIS – Undetected diabetes and prediabetes are pervasive in patients undergoing percutaneous coronary intervention, and they’re associated with a sharply increased risk of major adverse cardiovascular events, according to the results of the potentially practice-changing BIO-RESORT Silent Diabetes Study, Clemens von Birgelen, MD, PhD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“Our data support screening PCI all-comers for silent diabetes, which may help identify patients with an increased event risk and improve their therapy,” said Dr. von Birgelen, professor of cardiology at the Thoraxcentrum of Twente, a high-volume center for cardiac interventions in Enschede, the Netherlands.

Bruce Jancin/Frontline Medical News

[email protected]

PARIS – Undetected diabetes and prediabetes are pervasive in patients undergoing percutaneous coronary intervention, and they’re associated with a sharply increased risk of major adverse cardiovascular events, according to the results of the potentially practice-changing BIO-RESORT Silent Diabetes Study, Clemens von Birgelen, MD, PhD, reported at the annual congress of the European Association of Percutaneous Cardiovascular Interventions.

“Our data support screening PCI all-comers for silent diabetes, which may help identify patients with an increased event risk and improve their therapy,” said Dr. von Birgelen, professor of cardiology at the Thoraxcentrum of Twente, a high-volume center for cardiac interventions in Enschede, the Netherlands.

Bruce Jancin/Frontline Medical News

[email protected]

The use of opioids to treat chronic noncancer pain (CNCP) has become increasingly common over the previous 2 decades. The Office of National Drug Control Policy (ONDCP) reported that from 1997 to 2007, there was a 4-fold increase in the mg per person per year sale of prescription opioids, from 74 mg to 369 mg.¹ The number of opioid prescriptions dispensed by pharmacies also has increased by 48% from 2000 to 2009.² Within the VA population, about half of the 1.44 million patients with a diagnosis of pain (excluding cancer pain) received opioids during 2011, and 57% of these patients received chronic opioid therapy (COT), which is at least 90 days of opioid use in a year.³

Despite this increased use of opioids, data regarding the efficacy of long-term opioid use for noncancer pain remain limited.^1,4-8 Instead, there is a growing body of evidence describing potential adverse effects (AEs) of long-term opioid use at even relatively modest doses, including sexual dysfunction, hyperalgesia, and altered brain structure.^9-11 Additionally, increases in the misuse and abuse of opioids as well as mortality associated with opioid toxicity have been observed.^12-14 Opioid pain relievers were involved in nearly 17,000 deaths in the U.S. in 2010, which represents a 3-fold increase since 1999. This number also represents 75% of all deaths that were attributed to prescription drug poisoning in 2010.¹³ Unfortunately, this alarming trend parallels the aforementioned increases in the utilization of prescription opioids for CNCP.

Given this accumulating data regarding the profound risks and limited benefit of COT, many organizations have advocated a reassessment of the upward trajectory of opioid utilization. In 2009, the American Pain Society (APS) in partnership with the American Academy of Pain Medicine (AAPM) released clinical guidelines for the use of COT in CNCP.⁶ In this guideline, the authors advocate a balanced approach to opioid use: Clinicians consider both the legitimate medical need for opioids in some patients with CNCP as well as the serious public health problem of abuse, addiction, and diversion.⁶ In 2011, the FDA, Drug Enforcement Agency (DEA), and ONDCP enacted the Prescription Drug Abuse Prevention Plan, which focused on 4 major areas: education, prescription monitoring, proper medication disposal, and law enforcement.⁴

In March 2016, the CDC released a new guideline for prescribing opioids for chronic pain that included 12 recommendations based on 3 key principles. First, nonopioids are preferred for chronic pain in all settings except for active cancer, palliative, and end-of-life care. Next, when opioids are used for chronic pain, they always should be prescribed at the lowest possible effective dose to reduce the risk of opioid use disorder and overdose. Finally, clinicians should exercise caution when prescribing opioids and monitor all patients closely for opioid-related risk.¹⁵

Recently, an August 2016 FDA review found that the combined use of opioids and benzodiazepines (BZDs) resulted in serious AEs, including respiratory depression and death. Based on these findings, the FDA requires that updated boxed warnings be added to the labeling of prescription opioid and BZDs.¹⁶

The VHA also has been at the forefront of this national movement to promote the appropriate use of opioids. In 2009, the VHA released a pain management directive that highlighted the risks of COT and required adoption of a stepped-care approach to opioid prescribing that focused on quality of life as the primary determinant of treatment quality.¹⁷ In 2010, the VHA released its guideline on opioid therapy for chronic pain, which also included tools for providers, such as a sample opioid therapy agreement, equivalent potency tables, and a urine drug screening guide.¹⁸ In 2014, the VHA released the Opioid Safety Initiative (OSI), which advocates for a team-based approach to reduce the use of opioids for veterans through a focus on alternate methods to alleviate pain.

At the Ralph H. Johnson VAMC (RHJVAMC) in Charleston, South Carolina, a multidisciplinary pain oversight committee (POC) was tasked with assisting in achieving the goals set forth in the VHA OSI. To reach these goals, the POC sought to develop and implement a population-based initiative targeting modifiable factors that are known to increase the risk of opioid-related toxicity and overdose. These factors included patient utilization of multiple prescribers or multiple pharmacies, high-dose COT (defined in the APS/AAPM guidelines as a morphine equivalent daily dose [MEDD] > 200 mg⁶), and use of concomitant central nervous system-active medications, chiefly BZDs.^19-23 The POC consisted of the RHJVAMC chiefs of mental health, primary care, and pharmacy; a physician specializing in pain and addiction medicine; a pharmacist specializing in pain and palliative care; quality management personnel; a patient advocate; and multiple physicians from the mental health and primary care departments.

Previous studies have described the successful implementation of opioid management initiatives in a variety of health care settings.^2,21,24-27 However, most of this work focused only on strategies to decrease prescribing of high-dose and long-acting opioid formulations. The study presented here sought to add to the existing body of knowledge through evaluation of an initiative aimed at increasing appropriate monitoring as a tool to decrease opioid-related patient risk. The primary aim of this study was to describe the types of interventions implemented by the POC during the study period. The secondary aim was to evaluate the effect of these interventions on the appropriate monitoring of COT as well as the appropriate management of high-risk COT > 200 mg MEDD.

Methods

This study involved a qualitative description of individual POC interventions as well as a retrospective data analysis that examined the clinical impact of these interventions during the study period from April 1, 2012 to September 30, 2015. This study was reviewed and approved by the Medical University of South Carolina Institutional Review Board and the RHJVAMC Research and Development Committee.

Setting

The RHJVAMC is a tertiary care teaching hospital with primary and specialized outpatient services that are provided at the main medical center in Charleston, South Carolina, and at 6 community-based outpatient clinics (CBOCs) located throughout southeastern South Carolina and parts of Georgia. Primary care is delivered by patient aligned care teams (PACTs) based on the patient-centered medical home model.²⁸ The PACT consists of a primary care provider (PCP) who is aided by dedicated nursing, pharmacy, and mental health care providers. In most cases, COT is prescribed and managed in the PACT setting. At the time of this initiative, a broad range of specialty services were available, including a multidisciplinary pain management team, orthopedics, and physical medicine and rehabilitation. In 2012, about 55,000 patients were enrolled and received care at RHJVAMC. The POC interventions were carried out at all clinic sites.

Patients

The study population included all patients prescribed COT at RHJVAMC during the study period. A patient was considered to be prescribed COT if at least 1 opioid-containing medication was dispensed to the patient in a selected fiscal quarter during the study period and the total cumulative supply of opioid-containing medications was ≥ 90 days for both the selected quarter and the prior quarter.

Furthermore, a high-risk COT subpopulation included any patient who satisfied either of the following criteria: (1) Receipt of outpatient prescription(s) for opioid-containing medication(s) (including tramadol) and a benzodiazepine derivative in the same fiscal quarter; patients were included in this subpopulation regardless of whether they met COT criteria; (2) Receipt of outpatient prescription(s) for opioid-containing medication(s) with at least 1 instance in which the MEDD was ≥ 200 mg in the designated quarter (Table 1). The MEDD was calculated for each fill in the fiscal quarter using the following equation:

If medication fills were within 3 days of each other, the prescriptions were considered to be taken together and the MEDD was summed. 

Intervention Descriptions

The primary aim of this study was to qualitatively describe each intervention implemented by the POC. The POC monthly meeting minutes were recorded and reviewed for the study period, and descriptive information regarding each intervention was extracted. Extracted information included implementation date(s), the responsible POC member, and a general description of each intervention. Interventions were then categorized as informatics tool, targeted patient intervention, provider education, or patient education.

Impact of Interventions on Monitoring

In order to characterize the impact of POC interventions on appropriate monitoring of COT, the electronic medical record (EMR) of each patient satisfying COT criteria was queried for the presence of an annual urine drug screen (UDS) result and a note in the chart signaling that a prescription drug monitoring program (PDMP) review had been performed. The authors defined appropriate UDS monitoring and PDMP review as the presence of a UDS result and a PDMP review note in the EMR in the year prior to the query date.

Prior to the start of the POC interventions, 4.1% of RJVAMC patients had an annual PDMP review and 47.8% had an annual UDS. Although more frequent UDS results and PDMP reviews are appropriate in most cases, yearly monitoring was considered by the POC to be a reasonable initial goal. The percentage of veterans receiving COT who had received appropriate monitoring for each measure was collected for each fiscal quarter during the study period. In addition, the difference between the initial and final fiscal quarter during the study period was calculated for each measure.

Impact of Interventions on High-Risk Opioid Prescribing

To assess the impact of POC interventions on appropriate management of high-dose COT, clinical variables were collected for patients who were prescribed high-dose COT and received targeted intervention in the form of a pain clinic e-consult. These variables were MEDD, presence of annual UDS, presence of annual PDMP review, and active BZD prescription. Each variable was assessed on the date of intervention (e-consult submission) and at 6 months postintervention. Changes in each clinical variable between baseline and at 6 months postintervention were then evaluated.

Data Sources

All patient data were obtained from the VHA Corporate Data Warehouse (CDW). The CDW contains extracts from VHA clinical and administrative systems that contain complete clinical data from October 1999 to the present. Population-level data were obtained from the Opioid Safety Initiative Master Dashboard National Report where available. Data not contained in this national dashboard were obtained through local data extractions from the CDW.

Informatics Tool

In September 2014, an e-consult tool was created to enable PCPs to efficiently consult the RHJVAMC pain clinic for advice on opioid-related issues in patients who require specialized attention. On activation of this EMR-based tool, the following patient data autopopulated in the consult: recent and active opioid prescription(s), UDS data from the previous 365 days, and PDMP review data from the previous 365 days. The consulting provider was then required to enter data on concomitant mental health disorders that were deemed pertinent to opioid safety as well as obstructive sleep apnea (OSA) status (OSA diagnosis and continuous positive airway pressure machine receipt and adherence).

The consulting provider was required to indicate whether the patient had an active BZD prescription. If yes, a text field allowed the provider to enter the specific agent(s) prescribed and dose(s). Data were required in all fields for the e-consult to be considered ready for pain clinic review. Common pain clinic recommendations included orders for additional laboratory tests to assess adherence and potential toxicity, drug tapers, and consideration for complementary and alternative medicine (CAM). If a drug taper was recommended (either opioid or BZD), specific taper schedules would be provided by a pharmacist specializing in pain management.

Targeted Patient Intervention

In April 2014, the POC and Mental Health service began a targeted review of all outpatients receiving combination opioid and BZD therapy. First, the POC distributed to each mental health provider a list of patients who were receiving combination opioid and BZD therapy. An opioid/BZD combination risk assessment tool (Table 2) was developed by the POC and made available to assist with these patient reviews. This tool prompted a provider to assess a patient’s stability on the current regimen as well as the presence of any absolute or relative contraindications to concomitant BZD and opioid use. Providers documented whether a discussion regarding the risks and benefits of opioids and BZDs had occurred with the patient. The tool encouraged providers to document a continued indication for combined BZD and opioid therapy use and whether the lowest effective BZD dose was being prescribed. A standardized BZD taper protocol also was developed by the POC to assist providers if a BZD taper was indicated. A total of 222 patients were reviewed over 7 months from April 2014 to October 2015.

Following completion of this targeted review in October 2015, the POC required that starting any patients on opioid and BZD combination therapy would require a specialist consult. For existing COT patients, a mental health consult would be required to initiate BZD therapy. For stable patients on BZD therapy, a pain clinic consult was required before initiating an opioid prescription. The Pharmacy service acted as a gatekeeper for these agents and refused to dispense either new agent until the proper consults had been submitted unless clinical necessity of an agent was apparent (ie, opioid prescription following invasive surgery).

The final targeted patient intervention occurred following deployment of the opioid safety review e-consult tool in September 2015. To review the highest risk COT patients, each PCP was given a list of their patients who were taking ≥ 200 mg MEDD. With support from the primary care service chief, PCPs were required to submit an e-consult for every patient who did not meet the e-consult exclusion criteria. In the fourth quarter of fiscal year (FY) 2014, and first quarter of FY 2015, 116 RHJVAMC patients received ≥ 200 mg MEDD with 49 meeting the exclusion criteria. Of the 67 patients eligible for pain clinic review, e-consults were placed for 58 patients over a 7-month period. The remaining 9 patients did not receive an e-consult because taper was initiated by the patient’s PCP without pain clinic assistance (6), aberrant patient behavior was identified during data collection (2), and patient was transitioned to palliative care (1).

Provider Education

A primary goal of the POC was to educate PCPs on opioid safety, to ensure that each provider was able to use evidence-based medicine and identify potential high-risk situations during patient encounters. Provider education was delivered by physician and pharmacist pain specialists and took place from September 2013 to January 2015 at existing primary care meetings. Topics included UDS interpretation, opioid/BZD combination risks, the goals and requirements of the VA OSI, and legal requirements of the South Carolina Reporting and Identification Prescription Tracking System (SCRIPTS) PDMP.

Patient Education

Patient education was delivered through informational brochures either mailed or given out during clinic visits. The first brochure was mailed to patients and described the VA OSI goals and its potential impact on patients. A second handout described the risks associated with opioid/BZD combination therapy and encouraged patients to discuss these risks and alternate options with their providers. It was made available to primary care and mental health teams for distribution to patients.

Results

Interventions spanned 19 months, with an average of 1 intervention per month. The highest number of POC interventions in a single month was observed in October 2014, with 3 individual interventions from 3 separate categories.

Impact of POC Interventions on COT Monitoring

During the study period, patients meeting COT criteria who received an annual UDS increased from 47.8% to 75.5%, a 56.7% increase from baseline (Figure 1). During the same period, patients with an annual PDMP review note in their medical record also increased from 4.1% to 19.6%, a 324% increase from baseline (Figure 2). Although the study period began in FY 2012 third quarter, FY 2014 first quarter was the baseline for PDMP review note data collection because VA providers were not legally allowed to access the SCRIPTS database prior to FY 2014.

Impact of Interventions on High-Risk Opioid Prescribing

Patients who received an opioid prescription and a BZD derivative in the same fiscal quarter decreased 41.7% during the study period (Figure 3). A significant improvement was observed in each clinical variable at 6 months postintervention among high-dose COT patients who received an opioid safety review e-consult (Table 3). The median opioid dose per patient decreased 20% from baseline, from 300 mg MEDD to 240 mg MEDD. The number of patients with an annual UDS increased 31.7% from 41 to 54 patients. The number of patients with an annual PDMP review also increased 345%, from 11 patients to 49 patients. Finally, the number of patients with an active BZD order decreased > 75% from 17 patients at baseline to 4 patients at 6-month follow-up.

In the FY 2014 third quarter, prior to activation of the opioid safety review e-consult tool, 100 patients received high-dose COT. Follow-up at the conclusion of fourth quarter FY 2015 revealed 64 such patients, which represented a 36% decrease from baseline.

Discussion

During the study period, the POC used a variety of interventions from 4 distinct categories. Overall, these interventions successfully increased measures of appropriate COT monitoring (ie, UDS and PDMP utilization) and management of high-risk COT. Substantial improvements also were seen in the subgroup of patients receiving high-dose COT following creation and use of the opioid safety review e-consult tool.

Other VHA opioid management improvement initiatives were successful at reducing high-dose opioid prescribing through interventions similar to those described in this study. However, these initiatives did not address opioid monitoring practices or opioid/BZD combination therapy.^25,26 To the authors’ knowledge, no previous opioid management improvement initiatives have reported improvements in provider use of a state PDMP database.

There are a number of factors that also may have helped lead to the successful outcomes observed during the study period. First, the creation of an informatics tool allowed for sustained interventions over time. While targeted interventions and patient/provider education were certainly beneficial, the impact of these efforts wanes as time moves forward. Inevitably, a patient’s and a provider’s focus move to the next important issue, and new patients meet the criteria of the original targeted intervention.

Group Health Cooperative implemented an opioid risk reduction initiative that successfully increased UDS use over a 2-year postimplementation period.^21,26 While this initiative used a number of similar interventions to those implemented in this study (patient and provider education, targeted patient intervention), an informatics tool was not used. The annual UDS rate at the conclusion of the Group Health initiative was 50%, which contrasts with a final rate of 75.5% in this study. Although it is difficult to draw comparisons between the studies given differences in populations studied, periods of evaluation, and varying baseline annual UDS rates, the current study results demonstrate the potential effectiveness of informatics tools to help drive enduring changes in practice.

An additional factor that had a positive impact on outcomes the continued support and advocacy from RHJVAMC clinical and administrative leadership. A targeted review of all patients receiving concomitant BZDs and opioids would not be possible without mental health department leaders who believed in the value of the time consuming undertaking. Furthermore, an e-consult tool is effective only if actually submitted for patients and if a specialist’s recommendations are then followed by a PCP.

Finally, the interdisciplinary nature of the POC contributed to the success of each intervention described in this study. Patients receiving COT often have many complex physical, psychological, and social issues that must be considered in order to make a positive impact on patient care. To appropriately and effectively address these issues requires close collaboration between specialists from multiple disciplines.

Limitations

This study has several important limitations. First, its retrospective nature presents obvious documentation challenges. A second limitation is the brief period of evaluation following a number of POC interventions. For instance, 3 interventions took place in January 2015, leaving only 3 FY quarters of effectiveness data. Furthermore, increased awareness of the risks associated with opioid therapy in the VHA and the health care industry across the study period may have independently impacted the improvements observed in this study.

The lack of an assessment of both patient-centered and clinical outcomes is an additional limitation of this study. Rates of annual UDS and PDMP database reviews and the number of patients receiving high-risk COT are only surrogate metrics that may indicate appropriate prescribing and monitoring of these. Obtaining a UDS or PDMP review is meant to provide a practitioner with additional information to interpret when caring for a patient. These data are only meant to complement—not replace—skilled patient assessment by a provider. Although the authors observed no major patient or clinical adverse events during the study period, the possibility exists that a patient may have been negatively impacted by a population-level initiative to improve surrogate measures of appropriate drug use.

Future studies should assess changes in measures, such as pain scores, legitimate adverse events, and overdose occurrences in order to evaluate whether such opioid improvement initiatives truly benefit the patients who are ultimately affected by each intervention.

Conclusion

This study demonstrates the successful implementation of a VHA-based opioid management initiative to increase appropriate COT monitoring and appropriate management of high-risk patients. It is the authors’ hope that the findings may add to the growing body of literature describing successful opioid improvement initiatives and serve as a tool for other health systems that are confronted with these same issues.

The use of opioids to treat chronic noncancer pain (CNCP) has become increasingly common over the previous 2 decades. The Office of National Drug Control Policy (ONDCP) reported that from 1997 to 2007, there was a 4-fold increase in the mg per person per year sale of prescription opioids, from 74 mg to 369 mg.¹ The number of opioid prescriptions dispensed by pharmacies also has increased by 48% from 2000 to 2009.² Within the VA population, about half of the 1.44 million patients with a diagnosis of pain (excluding cancer pain) received opioids during 2011, and 57% of these patients received chronic opioid therapy (COT), which is at least 90 days of opioid use in a year.³

Despite this increased use of opioids, data regarding the efficacy of long-term opioid use for noncancer pain remain limited.^1,4-8 Instead, there is a growing body of evidence describing potential adverse effects (AEs) of long-term opioid use at even relatively modest doses, including sexual dysfunction, hyperalgesia, and altered brain structure.^9-11 Additionally, increases in the misuse and abuse of opioids as well as mortality associated with opioid toxicity have been observed.^12-14 Opioid pain relievers were involved in nearly 17,000 deaths in the U.S. in 2010, which represents a 3-fold increase since 1999. This number also represents 75% of all deaths that were attributed to prescription drug poisoning in 2010.¹³ Unfortunately, this alarming trend parallels the aforementioned increases in the utilization of prescription opioids for CNCP.

Given this accumulating data regarding the profound risks and limited benefit of COT, many organizations have advocated a reassessment of the upward trajectory of opioid utilization. In 2009, the American Pain Society (APS) in partnership with the American Academy of Pain Medicine (AAPM) released clinical guidelines for the use of COT in CNCP.⁶ In this guideline, the authors advocate a balanced approach to opioid use: Clinicians consider both the legitimate medical need for opioids in some patients with CNCP as well as the serious public health problem of abuse, addiction, and diversion.⁶ In 2011, the FDA, Drug Enforcement Agency (DEA), and ONDCP enacted the Prescription Drug Abuse Prevention Plan, which focused on 4 major areas: education, prescription monitoring, proper medication disposal, and law enforcement.⁴

In March 2016, the CDC released a new guideline for prescribing opioids for chronic pain that included 12 recommendations based on 3 key principles. First, nonopioids are preferred for chronic pain in all settings except for active cancer, palliative, and end-of-life care. Next, when opioids are used for chronic pain, they always should be prescribed at the lowest possible effective dose to reduce the risk of opioid use disorder and overdose. Finally, clinicians should exercise caution when prescribing opioids and monitor all patients closely for opioid-related risk.¹⁵

Recently, an August 2016 FDA review found that the combined use of opioids and benzodiazepines (BZDs) resulted in serious AEs, including respiratory depression and death. Based on these findings, the FDA requires that updated boxed warnings be added to the labeling of prescription opioid and BZDs.¹⁶

The VHA also has been at the forefront of this national movement to promote the appropriate use of opioids. In 2009, the VHA released a pain management directive that highlighted the risks of COT and required adoption of a stepped-care approach to opioid prescribing that focused on quality of life as the primary determinant of treatment quality.¹⁷ In 2010, the VHA released its guideline on opioid therapy for chronic pain, which also included tools for providers, such as a sample opioid therapy agreement, equivalent potency tables, and a urine drug screening guide.¹⁸ In 2014, the VHA released the Opioid Safety Initiative (OSI), which advocates for a team-based approach to reduce the use of opioids for veterans through a focus on alternate methods to alleviate pain.

At the Ralph H. Johnson VAMC (RHJVAMC) in Charleston, South Carolina, a multidisciplinary pain oversight committee (POC) was tasked with assisting in achieving the goals set forth in the VHA OSI. To reach these goals, the POC sought to develop and implement a population-based initiative targeting modifiable factors that are known to increase the risk of opioid-related toxicity and overdose. These factors included patient utilization of multiple prescribers or multiple pharmacies, high-dose COT (defined in the APS/AAPM guidelines as a morphine equivalent daily dose [MEDD] > 200 mg⁶), and use of concomitant central nervous system-active medications, chiefly BZDs.^19-23 The POC consisted of the RHJVAMC chiefs of mental health, primary care, and pharmacy; a physician specializing in pain and addiction medicine; a pharmacist specializing in pain and palliative care; quality management personnel; a patient advocate; and multiple physicians from the mental health and primary care departments.

Previous studies have described the successful implementation of opioid management initiatives in a variety of health care settings.^2,21,24-27 However, most of this work focused only on strategies to decrease prescribing of high-dose and long-acting opioid formulations. The study presented here sought to add to the existing body of knowledge through evaluation of an initiative aimed at increasing appropriate monitoring as a tool to decrease opioid-related patient risk. The primary aim of this study was to describe the types of interventions implemented by the POC during the study period. The secondary aim was to evaluate the effect of these interventions on the appropriate monitoring of COT as well as the appropriate management of high-risk COT > 200 mg MEDD.

Methods

This study involved a qualitative description of individual POC interventions as well as a retrospective data analysis that examined the clinical impact of these interventions during the study period from April 1, 2012 to September 30, 2015. This study was reviewed and approved by the Medical University of South Carolina Institutional Review Board and the RHJVAMC Research and Development Committee.

Setting

The RHJVAMC is a tertiary care teaching hospital with primary and specialized outpatient services that are provided at the main medical center in Charleston, South Carolina, and at 6 community-based outpatient clinics (CBOCs) located throughout southeastern South Carolina and parts of Georgia. Primary care is delivered by patient aligned care teams (PACTs) based on the patient-centered medical home model.²⁸ The PACT consists of a primary care provider (PCP) who is aided by dedicated nursing, pharmacy, and mental health care providers. In most cases, COT is prescribed and managed in the PACT setting. At the time of this initiative, a broad range of specialty services were available, including a multidisciplinary pain management team, orthopedics, and physical medicine and rehabilitation. In 2012, about 55,000 patients were enrolled and received care at RHJVAMC. The POC interventions were carried out at all clinic sites.

Patients

The study population included all patients prescribed COT at RHJVAMC during the study period. A patient was considered to be prescribed COT if at least 1 opioid-containing medication was dispensed to the patient in a selected fiscal quarter during the study period and the total cumulative supply of opioid-containing medications was ≥ 90 days for both the selected quarter and the prior quarter.

Furthermore, a high-risk COT subpopulation included any patient who satisfied either of the following criteria: (1) Receipt of outpatient prescription(s) for opioid-containing medication(s) (including tramadol) and a benzodiazepine derivative in the same fiscal quarter; patients were included in this subpopulation regardless of whether they met COT criteria; (2) Receipt of outpatient prescription(s) for opioid-containing medication(s) with at least 1 instance in which the MEDD was ≥ 200 mg in the designated quarter (Table 1). The MEDD was calculated for each fill in the fiscal quarter using the following equation:

If medication fills were within 3 days of each other, the prescriptions were considered to be taken together and the MEDD was summed. 

Intervention Descriptions

The primary aim of this study was to qualitatively describe each intervention implemented by the POC. The POC monthly meeting minutes were recorded and reviewed for the study period, and descriptive information regarding each intervention was extracted. Extracted information included implementation date(s), the responsible POC member, and a general description of each intervention. Interventions were then categorized as informatics tool, targeted patient intervention, provider education, or patient education.

Impact of Interventions on Monitoring

In order to characterize the impact of POC interventions on appropriate monitoring of COT, the electronic medical record (EMR) of each patient satisfying COT criteria was queried for the presence of an annual urine drug screen (UDS) result and a note in the chart signaling that a prescription drug monitoring program (PDMP) review had been performed. The authors defined appropriate UDS monitoring and PDMP review as the presence of a UDS result and a PDMP review note in the EMR in the year prior to the query date.

Prior to the start of the POC interventions, 4.1% of RJVAMC patients had an annual PDMP review and 47.8% had an annual UDS. Although more frequent UDS results and PDMP reviews are appropriate in most cases, yearly monitoring was considered by the POC to be a reasonable initial goal. The percentage of veterans receiving COT who had received appropriate monitoring for each measure was collected for each fiscal quarter during the study period. In addition, the difference between the initial and final fiscal quarter during the study period was calculated for each measure.

Impact of Interventions on High-Risk Opioid Prescribing

To assess the impact of POC interventions on appropriate management of high-dose COT, clinical variables were collected for patients who were prescribed high-dose COT and received targeted intervention in the form of a pain clinic e-consult. These variables were MEDD, presence of annual UDS, presence of annual PDMP review, and active BZD prescription. Each variable was assessed on the date of intervention (e-consult submission) and at 6 months postintervention. Changes in each clinical variable between baseline and at 6 months postintervention were then evaluated.

Data Sources

All patient data were obtained from the VHA Corporate Data Warehouse (CDW). The CDW contains extracts from VHA clinical and administrative systems that contain complete clinical data from October 1999 to the present. Population-level data were obtained from the Opioid Safety Initiative Master Dashboard National Report where available. Data not contained in this national dashboard were obtained through local data extractions from the CDW.

Informatics Tool

In September 2014, an e-consult tool was created to enable PCPs to efficiently consult the RHJVAMC pain clinic for advice on opioid-related issues in patients who require specialized attention. On activation of this EMR-based tool, the following patient data autopopulated in the consult: recent and active opioid prescription(s), UDS data from the previous 365 days, and PDMP review data from the previous 365 days. The consulting provider was then required to enter data on concomitant mental health disorders that were deemed pertinent to opioid safety as well as obstructive sleep apnea (OSA) status (OSA diagnosis and continuous positive airway pressure machine receipt and adherence).

The consulting provider was required to indicate whether the patient had an active BZD prescription. If yes, a text field allowed the provider to enter the specific agent(s) prescribed and dose(s). Data were required in all fields for the e-consult to be considered ready for pain clinic review. Common pain clinic recommendations included orders for additional laboratory tests to assess adherence and potential toxicity, drug tapers, and consideration for complementary and alternative medicine (CAM). If a drug taper was recommended (either opioid or BZD), specific taper schedules would be provided by a pharmacist specializing in pain management.

Targeted Patient Intervention

In April 2014, the POC and Mental Health service began a targeted review of all outpatients receiving combination opioid and BZD therapy. First, the POC distributed to each mental health provider a list of patients who were receiving combination opioid and BZD therapy. An opioid/BZD combination risk assessment tool (Table 2) was developed by the POC and made available to assist with these patient reviews. This tool prompted a provider to assess a patient’s stability on the current regimen as well as the presence of any absolute or relative contraindications to concomitant BZD and opioid use. Providers documented whether a discussion regarding the risks and benefits of opioids and BZDs had occurred with the patient. The tool encouraged providers to document a continued indication for combined BZD and opioid therapy use and whether the lowest effective BZD dose was being prescribed. A standardized BZD taper protocol also was developed by the POC to assist providers if a BZD taper was indicated. A total of 222 patients were reviewed over 7 months from April 2014 to October 2015.

Following completion of this targeted review in October 2015, the POC required that starting any patients on opioid and BZD combination therapy would require a specialist consult. For existing COT patients, a mental health consult would be required to initiate BZD therapy. For stable patients on BZD therapy, a pain clinic consult was required before initiating an opioid prescription. The Pharmacy service acted as a gatekeeper for these agents and refused to dispense either new agent until the proper consults had been submitted unless clinical necessity of an agent was apparent (ie, opioid prescription following invasive surgery).

The final targeted patient intervention occurred following deployment of the opioid safety review e-consult tool in September 2015. To review the highest risk COT patients, each PCP was given a list of their patients who were taking ≥ 200 mg MEDD. With support from the primary care service chief, PCPs were required to submit an e-consult for every patient who did not meet the e-consult exclusion criteria. In the fourth quarter of fiscal year (FY) 2014, and first quarter of FY 2015, 116 RHJVAMC patients received ≥ 200 mg MEDD with 49 meeting the exclusion criteria. Of the 67 patients eligible for pain clinic review, e-consults were placed for 58 patients over a 7-month period. The remaining 9 patients did not receive an e-consult because taper was initiated by the patient’s PCP without pain clinic assistance (6), aberrant patient behavior was identified during data collection (2), and patient was transitioned to palliative care (1).

Provider Education

A primary goal of the POC was to educate PCPs on opioid safety, to ensure that each provider was able to use evidence-based medicine and identify potential high-risk situations during patient encounters. Provider education was delivered by physician and pharmacist pain specialists and took place from September 2013 to January 2015 at existing primary care meetings. Topics included UDS interpretation, opioid/BZD combination risks, the goals and requirements of the VA OSI, and legal requirements of the South Carolina Reporting and Identification Prescription Tracking System (SCRIPTS) PDMP.

Patient Education

Patient education was delivered through informational brochures either mailed or given out during clinic visits. The first brochure was mailed to patients and described the VA OSI goals and its potential impact on patients. A second handout described the risks associated with opioid/BZD combination therapy and encouraged patients to discuss these risks and alternate options with their providers. It was made available to primary care and mental health teams for distribution to patients.

Results

Interventions spanned 19 months, with an average of 1 intervention per month. The highest number of POC interventions in a single month was observed in October 2014, with 3 individual interventions from 3 separate categories.

Impact of POC Interventions on COT Monitoring

During the study period, patients meeting COT criteria who received an annual UDS increased from 47.8% to 75.5%, a 56.7% increase from baseline (Figure 1). During the same period, patients with an annual PDMP review note in their medical record also increased from 4.1% to 19.6%, a 324% increase from baseline (Figure 2). Although the study period began in FY 2012 third quarter, FY 2014 first quarter was the baseline for PDMP review note data collection because VA providers were not legally allowed to access the SCRIPTS database prior to FY 2014.

Impact of Interventions on High-Risk Opioid Prescribing

Patients who received an opioid prescription and a BZD derivative in the same fiscal quarter decreased 41.7% during the study period (Figure 3). A significant improvement was observed in each clinical variable at 6 months postintervention among high-dose COT patients who received an opioid safety review e-consult (Table 3). The median opioid dose per patient decreased 20% from baseline, from 300 mg MEDD to 240 mg MEDD. The number of patients with an annual UDS increased 31.7% from 41 to 54 patients. The number of patients with an annual PDMP review also increased 345%, from 11 patients to 49 patients. Finally, the number of patients with an active BZD order decreased > 75% from 17 patients at baseline to 4 patients at 6-month follow-up.

In the FY 2014 third quarter, prior to activation of the opioid safety review e-consult tool, 100 patients received high-dose COT. Follow-up at the conclusion of fourth quarter FY 2015 revealed 64 such patients, which represented a 36% decrease from baseline.

Discussion

During the study period, the POC used a variety of interventions from 4 distinct categories. Overall, these interventions successfully increased measures of appropriate COT monitoring (ie, UDS and PDMP utilization) and management of high-risk COT. Substantial improvements also were seen in the subgroup of patients receiving high-dose COT following creation and use of the opioid safety review e-consult tool.

Other VHA opioid management improvement initiatives were successful at reducing high-dose opioid prescribing through interventions similar to those described in this study. However, these initiatives did not address opioid monitoring practices or opioid/BZD combination therapy.^25,26 To the authors’ knowledge, no previous opioid management improvement initiatives have reported improvements in provider use of a state PDMP database.

There are a number of factors that also may have helped lead to the successful outcomes observed during the study period. First, the creation of an informatics tool allowed for sustained interventions over time. While targeted interventions and patient/provider education were certainly beneficial, the impact of these efforts wanes as time moves forward. Inevitably, a patient’s and a provider’s focus move to the next important issue, and new patients meet the criteria of the original targeted intervention.

Group Health Cooperative implemented an opioid risk reduction initiative that successfully increased UDS use over a 2-year postimplementation period.^21,26 While this initiative used a number of similar interventions to those implemented in this study (patient and provider education, targeted patient intervention), an informatics tool was not used. The annual UDS rate at the conclusion of the Group Health initiative was 50%, which contrasts with a final rate of 75.5% in this study. Although it is difficult to draw comparisons between the studies given differences in populations studied, periods of evaluation, and varying baseline annual UDS rates, the current study results demonstrate the potential effectiveness of informatics tools to help drive enduring changes in practice.

An additional factor that had a positive impact on outcomes the continued support and advocacy from RHJVAMC clinical and administrative leadership. A targeted review of all patients receiving concomitant BZDs and opioids would not be possible without mental health department leaders who believed in the value of the time consuming undertaking. Furthermore, an e-consult tool is effective only if actually submitted for patients and if a specialist’s recommendations are then followed by a PCP.

Finally, the interdisciplinary nature of the POC contributed to the success of each intervention described in this study. Patients receiving COT often have many complex physical, psychological, and social issues that must be considered in order to make a positive impact on patient care. To appropriately and effectively address these issues requires close collaboration between specialists from multiple disciplines.

Limitations

This study has several important limitations. First, its retrospective nature presents obvious documentation challenges. A second limitation is the brief period of evaluation following a number of POC interventions. For instance, 3 interventions took place in January 2015, leaving only 3 FY quarters of effectiveness data. Furthermore, increased awareness of the risks associated with opioid therapy in the VHA and the health care industry across the study period may have independently impacted the improvements observed in this study.

The lack of an assessment of both patient-centered and clinical outcomes is an additional limitation of this study. Rates of annual UDS and PDMP database reviews and the number of patients receiving high-risk COT are only surrogate metrics that may indicate appropriate prescribing and monitoring of these. Obtaining a UDS or PDMP review is meant to provide a practitioner with additional information to interpret when caring for a patient. These data are only meant to complement—not replace—skilled patient assessment by a provider. Although the authors observed no major patient or clinical adverse events during the study period, the possibility exists that a patient may have been negatively impacted by a population-level initiative to improve surrogate measures of appropriate drug use.

Future studies should assess changes in measures, such as pain scores, legitimate adverse events, and overdose occurrences in order to evaluate whether such opioid improvement initiatives truly benefit the patients who are ultimately affected by each intervention.

Conclusion

This study demonstrates the successful implementation of a VHA-based opioid management initiative to increase appropriate COT monitoring and appropriate management of high-risk patients. It is the authors’ hope that the findings may add to the growing body of literature describing successful opioid improvement initiatives and serve as a tool for other health systems that are confronted with these same issues.

The use of opioids to treat chronic noncancer pain (CNCP) has become increasingly common over the previous 2 decades. The Office of National Drug Control Policy (ONDCP) reported that from 1997 to 2007, there was a 4-fold increase in the mg per person per year sale of prescription opioids, from 74 mg to 369 mg.¹ The number of opioid prescriptions dispensed by pharmacies also has increased by 48% from 2000 to 2009.² Within the VA population, about half of the 1.44 million patients with a diagnosis of pain (excluding cancer pain) received opioids during 2011, and 57% of these patients received chronic opioid therapy (COT), which is at least 90 days of opioid use in a year.³

Despite this increased use of opioids, data regarding the efficacy of long-term opioid use for noncancer pain remain limited.^1,4-8 Instead, there is a growing body of evidence describing potential adverse effects (AEs) of long-term opioid use at even relatively modest doses, including sexual dysfunction, hyperalgesia, and altered brain structure.^9-11 Additionally, increases in the misuse and abuse of opioids as well as mortality associated with opioid toxicity have been observed.^12-14 Opioid pain relievers were involved in nearly 17,000 deaths in the U.S. in 2010, which represents a 3-fold increase since 1999. This number also represents 75% of all deaths that were attributed to prescription drug poisoning in 2010.¹³ Unfortunately, this alarming trend parallels the aforementioned increases in the utilization of prescription opioids for CNCP.

Given this accumulating data regarding the profound risks and limited benefit of COT, many organizations have advocated a reassessment of the upward trajectory of opioid utilization. In 2009, the American Pain Society (APS) in partnership with the American Academy of Pain Medicine (AAPM) released clinical guidelines for the use of COT in CNCP.⁶ In this guideline, the authors advocate a balanced approach to opioid use: Clinicians consider both the legitimate medical need for opioids in some patients with CNCP as well as the serious public health problem of abuse, addiction, and diversion.⁶ In 2011, the FDA, Drug Enforcement Agency (DEA), and ONDCP enacted the Prescription Drug Abuse Prevention Plan, which focused on 4 major areas: education, prescription monitoring, proper medication disposal, and law enforcement.⁴

In March 2016, the CDC released a new guideline for prescribing opioids for chronic pain that included 12 recommendations based on 3 key principles. First, nonopioids are preferred for chronic pain in all settings except for active cancer, palliative, and end-of-life care. Next, when opioids are used for chronic pain, they always should be prescribed at the lowest possible effective dose to reduce the risk of opioid use disorder and overdose. Finally, clinicians should exercise caution when prescribing opioids and monitor all patients closely for opioid-related risk.¹⁵

Recently, an August 2016 FDA review found that the combined use of opioids and benzodiazepines (BZDs) resulted in serious AEs, including respiratory depression and death. Based on these findings, the FDA requires that updated boxed warnings be added to the labeling of prescription opioid and BZDs.¹⁶

The VHA also has been at the forefront of this national movement to promote the appropriate use of opioids. In 2009, the VHA released a pain management directive that highlighted the risks of COT and required adoption of a stepped-care approach to opioid prescribing that focused on quality of life as the primary determinant of treatment quality.¹⁷ In 2010, the VHA released its guideline on opioid therapy for chronic pain, which also included tools for providers, such as a sample opioid therapy agreement, equivalent potency tables, and a urine drug screening guide.¹⁸ In 2014, the VHA released the Opioid Safety Initiative (OSI), which advocates for a team-based approach to reduce the use of opioids for veterans through a focus on alternate methods to alleviate pain.

At the Ralph H. Johnson VAMC (RHJVAMC) in Charleston, South Carolina, a multidisciplinary pain oversight committee (POC) was tasked with assisting in achieving the goals set forth in the VHA OSI. To reach these goals, the POC sought to develop and implement a population-based initiative targeting modifiable factors that are known to increase the risk of opioid-related toxicity and overdose. These factors included patient utilization of multiple prescribers or multiple pharmacies, high-dose COT (defined in the APS/AAPM guidelines as a morphine equivalent daily dose [MEDD] > 200 mg⁶), and use of concomitant central nervous system-active medications, chiefly BZDs.^19-23 The POC consisted of the RHJVAMC chiefs of mental health, primary care, and pharmacy; a physician specializing in pain and addiction medicine; a pharmacist specializing in pain and palliative care; quality management personnel; a patient advocate; and multiple physicians from the mental health and primary care departments.

Previous studies have described the successful implementation of opioid management initiatives in a variety of health care settings.^2,21,24-27 However, most of this work focused only on strategies to decrease prescribing of high-dose and long-acting opioid formulations. The study presented here sought to add to the existing body of knowledge through evaluation of an initiative aimed at increasing appropriate monitoring as a tool to decrease opioid-related patient risk. The primary aim of this study was to describe the types of interventions implemented by the POC during the study period. The secondary aim was to evaluate the effect of these interventions on the appropriate monitoring of COT as well as the appropriate management of high-risk COT > 200 mg MEDD.

Methods

This study involved a qualitative description of individual POC interventions as well as a retrospective data analysis that examined the clinical impact of these interventions during the study period from April 1, 2012 to September 30, 2015. This study was reviewed and approved by the Medical University of South Carolina Institutional Review Board and the RHJVAMC Research and Development Committee.

Setting

The RHJVAMC is a tertiary care teaching hospital with primary and specialized outpatient services that are provided at the main medical center in Charleston, South Carolina, and at 6 community-based outpatient clinics (CBOCs) located throughout southeastern South Carolina and parts of Georgia. Primary care is delivered by patient aligned care teams (PACTs) based on the patient-centered medical home model.²⁸ The PACT consists of a primary care provider (PCP) who is aided by dedicated nursing, pharmacy, and mental health care providers. In most cases, COT is prescribed and managed in the PACT setting. At the time of this initiative, a broad range of specialty services were available, including a multidisciplinary pain management team, orthopedics, and physical medicine and rehabilitation. In 2012, about 55,000 patients were enrolled and received care at RHJVAMC. The POC interventions were carried out at all clinic sites.

Patients

The study population included all patients prescribed COT at RHJVAMC during the study period. A patient was considered to be prescribed COT if at least 1 opioid-containing medication was dispensed to the patient in a selected fiscal quarter during the study period and the total cumulative supply of opioid-containing medications was ≥ 90 days for both the selected quarter and the prior quarter.

Furthermore, a high-risk COT subpopulation included any patient who satisfied either of the following criteria: (1) Receipt of outpatient prescription(s) for opioid-containing medication(s) (including tramadol) and a benzodiazepine derivative in the same fiscal quarter; patients were included in this subpopulation regardless of whether they met COT criteria; (2) Receipt of outpatient prescription(s) for opioid-containing medication(s) with at least 1 instance in which the MEDD was ≥ 200 mg in the designated quarter (Table 1). The MEDD was calculated for each fill in the fiscal quarter using the following equation:

If medication fills were within 3 days of each other, the prescriptions were considered to be taken together and the MEDD was summed. 

Intervention Descriptions

The primary aim of this study was to qualitatively describe each intervention implemented by the POC. The POC monthly meeting minutes were recorded and reviewed for the study period, and descriptive information regarding each intervention was extracted. Extracted information included implementation date(s), the responsible POC member, and a general description of each intervention. Interventions were then categorized as informatics tool, targeted patient intervention, provider education, or patient education.

Impact of Interventions on Monitoring

In order to characterize the impact of POC interventions on appropriate monitoring of COT, the electronic medical record (EMR) of each patient satisfying COT criteria was queried for the presence of an annual urine drug screen (UDS) result and a note in the chart signaling that a prescription drug monitoring program (PDMP) review had been performed. The authors defined appropriate UDS monitoring and PDMP review as the presence of a UDS result and a PDMP review note in the EMR in the year prior to the query date.

Prior to the start of the POC interventions, 4.1% of RJVAMC patients had an annual PDMP review and 47.8% had an annual UDS. Although more frequent UDS results and PDMP reviews are appropriate in most cases, yearly monitoring was considered by the POC to be a reasonable initial goal. The percentage of veterans receiving COT who had received appropriate monitoring for each measure was collected for each fiscal quarter during the study period. In addition, the difference between the initial and final fiscal quarter during the study period was calculated for each measure.

Impact of Interventions on High-Risk Opioid Prescribing

To assess the impact of POC interventions on appropriate management of high-dose COT, clinical variables were collected for patients who were prescribed high-dose COT and received targeted intervention in the form of a pain clinic e-consult. These variables were MEDD, presence of annual UDS, presence of annual PDMP review, and active BZD prescription. Each variable was assessed on the date of intervention (e-consult submission) and at 6 months postintervention. Changes in each clinical variable between baseline and at 6 months postintervention were then evaluated.

Data Sources

All patient data were obtained from the VHA Corporate Data Warehouse (CDW). The CDW contains extracts from VHA clinical and administrative systems that contain complete clinical data from October 1999 to the present. Population-level data were obtained from the Opioid Safety Initiative Master Dashboard National Report where available. Data not contained in this national dashboard were obtained through local data extractions from the CDW.

Informatics Tool

In September 2014, an e-consult tool was created to enable PCPs to efficiently consult the RHJVAMC pain clinic for advice on opioid-related issues in patients who require specialized attention. On activation of this EMR-based tool, the following patient data autopopulated in the consult: recent and active opioid prescription(s), UDS data from the previous 365 days, and PDMP review data from the previous 365 days. The consulting provider was then required to enter data on concomitant mental health disorders that were deemed pertinent to opioid safety as well as obstructive sleep apnea (OSA) status (OSA diagnosis and continuous positive airway pressure machine receipt and adherence).

The consulting provider was required to indicate whether the patient had an active BZD prescription. If yes, a text field allowed the provider to enter the specific agent(s) prescribed and dose(s). Data were required in all fields for the e-consult to be considered ready for pain clinic review. Common pain clinic recommendations included orders for additional laboratory tests to assess adherence and potential toxicity, drug tapers, and consideration for complementary and alternative medicine (CAM). If a drug taper was recommended (either opioid or BZD), specific taper schedules would be provided by a pharmacist specializing in pain management.

Targeted Patient Intervention

In April 2014, the POC and Mental Health service began a targeted review of all outpatients receiving combination opioid and BZD therapy. First, the POC distributed to each mental health provider a list of patients who were receiving combination opioid and BZD therapy. An opioid/BZD combination risk assessment tool (Table 2) was developed by the POC and made available to assist with these patient reviews. This tool prompted a provider to assess a patient’s stability on the current regimen as well as the presence of any absolute or relative contraindications to concomitant BZD and opioid use. Providers documented whether a discussion regarding the risks and benefits of opioids and BZDs had occurred with the patient. The tool encouraged providers to document a continued indication for combined BZD and opioid therapy use and whether the lowest effective BZD dose was being prescribed. A standardized BZD taper protocol also was developed by the POC to assist providers if a BZD taper was indicated. A total of 222 patients were reviewed over 7 months from April 2014 to October 2015.

Following completion of this targeted review in October 2015, the POC required that starting any patients on opioid and BZD combination therapy would require a specialist consult. For existing COT patients, a mental health consult would be required to initiate BZD therapy. For stable patients on BZD therapy, a pain clinic consult was required before initiating an opioid prescription. The Pharmacy service acted as a gatekeeper for these agents and refused to dispense either new agent until the proper consults had been submitted unless clinical necessity of an agent was apparent (ie, opioid prescription following invasive surgery).

The final targeted patient intervention occurred following deployment of the opioid safety review e-consult tool in September 2015. To review the highest risk COT patients, each PCP was given a list of their patients who were taking ≥ 200 mg MEDD. With support from the primary care service chief, PCPs were required to submit an e-consult for every patient who did not meet the e-consult exclusion criteria. In the fourth quarter of fiscal year (FY) 2014, and first quarter of FY 2015, 116 RHJVAMC patients received ≥ 200 mg MEDD with 49 meeting the exclusion criteria. Of the 67 patients eligible for pain clinic review, e-consults were placed for 58 patients over a 7-month period. The remaining 9 patients did not receive an e-consult because taper was initiated by the patient’s PCP without pain clinic assistance (6), aberrant patient behavior was identified during data collection (2), and patient was transitioned to palliative care (1).

Provider Education

A primary goal of the POC was to educate PCPs on opioid safety, to ensure that each provider was able to use evidence-based medicine and identify potential high-risk situations during patient encounters. Provider education was delivered by physician and pharmacist pain specialists and took place from September 2013 to January 2015 at existing primary care meetings. Topics included UDS interpretation, opioid/BZD combination risks, the goals and requirements of the VA OSI, and legal requirements of the South Carolina Reporting and Identification Prescription Tracking System (SCRIPTS) PDMP.

Patient Education

Patient education was delivered through informational brochures either mailed or given out during clinic visits. The first brochure was mailed to patients and described the VA OSI goals and its potential impact on patients. A second handout described the risks associated with opioid/BZD combination therapy and encouraged patients to discuss these risks and alternate options with their providers. It was made available to primary care and mental health teams for distribution to patients.

Results

Interventions spanned 19 months, with an average of 1 intervention per month. The highest number of POC interventions in a single month was observed in October 2014, with 3 individual interventions from 3 separate categories.

Impact of POC Interventions on COT Monitoring

During the study period, patients meeting COT criteria who received an annual UDS increased from 47.8% to 75.5%, a 56.7% increase from baseline (Figure 1). During the same period, patients with an annual PDMP review note in their medical record also increased from 4.1% to 19.6%, a 324% increase from baseline (Figure 2). Although the study period began in FY 2012 third quarter, FY 2014 first quarter was the baseline for PDMP review note data collection because VA providers were not legally allowed to access the SCRIPTS database prior to FY 2014.

Impact of Interventions on High-Risk Opioid Prescribing

Patients who received an opioid prescription and a BZD derivative in the same fiscal quarter decreased 41.7% during the study period (Figure 3). A significant improvement was observed in each clinical variable at 6 months postintervention among high-dose COT patients who received an opioid safety review e-consult (Table 3). The median opioid dose per patient decreased 20% from baseline, from 300 mg MEDD to 240 mg MEDD. The number of patients with an annual UDS increased 31.7% from 41 to 54 patients. The number of patients with an annual PDMP review also increased 345%, from 11 patients to 49 patients. Finally, the number of patients with an active BZD order decreased > 75% from 17 patients at baseline to 4 patients at 6-month follow-up.

In the FY 2014 third quarter, prior to activation of the opioid safety review e-consult tool, 100 patients received high-dose COT. Follow-up at the conclusion of fourth quarter FY 2015 revealed 64 such patients, which represented a 36% decrease from baseline.

Discussion

During the study period, the POC used a variety of interventions from 4 distinct categories. Overall, these interventions successfully increased measures of appropriate COT monitoring (ie, UDS and PDMP utilization) and management of high-risk COT. Substantial improvements also were seen in the subgroup of patients receiving high-dose COT following creation and use of the opioid safety review e-consult tool.

Other VHA opioid management improvement initiatives were successful at reducing high-dose opioid prescribing through interventions similar to those described in this study. However, these initiatives did not address opioid monitoring practices or opioid/BZD combination therapy.^25,26 To the authors’ knowledge, no previous opioid management improvement initiatives have reported improvements in provider use of a state PDMP database.

There are a number of factors that also may have helped lead to the successful outcomes observed during the study period. First, the creation of an informatics tool allowed for sustained interventions over time. While targeted interventions and patient/provider education were certainly beneficial, the impact of these efforts wanes as time moves forward. Inevitably, a patient’s and a provider’s focus move to the next important issue, and new patients meet the criteria of the original targeted intervention.

Group Health Cooperative implemented an opioid risk reduction initiative that successfully increased UDS use over a 2-year postimplementation period.^21,26 While this initiative used a number of similar interventions to those implemented in this study (patient and provider education, targeted patient intervention), an informatics tool was not used. The annual UDS rate at the conclusion of the Group Health initiative was 50%, which contrasts with a final rate of 75.5% in this study. Although it is difficult to draw comparisons between the studies given differences in populations studied, periods of evaluation, and varying baseline annual UDS rates, the current study results demonstrate the potential effectiveness of informatics tools to help drive enduring changes in practice.

An additional factor that had a positive impact on outcomes the continued support and advocacy from RHJVAMC clinical and administrative leadership. A targeted review of all patients receiving concomitant BZDs and opioids would not be possible without mental health department leaders who believed in the value of the time consuming undertaking. Furthermore, an e-consult tool is effective only if actually submitted for patients and if a specialist’s recommendations are then followed by a PCP.

Finally, the interdisciplinary nature of the POC contributed to the success of each intervention described in this study. Patients receiving COT often have many complex physical, psychological, and social issues that must be considered in order to make a positive impact on patient care. To appropriately and effectively address these issues requires close collaboration between specialists from multiple disciplines.

Limitations

This study has several important limitations. First, its retrospective nature presents obvious documentation challenges. A second limitation is the brief period of evaluation following a number of POC interventions. For instance, 3 interventions took place in January 2015, leaving only 3 FY quarters of effectiveness data. Furthermore, increased awareness of the risks associated with opioid therapy in the VHA and the health care industry across the study period may have independently impacted the improvements observed in this study.

The lack of an assessment of both patient-centered and clinical outcomes is an additional limitation of this study. Rates of annual UDS and PDMP database reviews and the number of patients receiving high-risk COT are only surrogate metrics that may indicate appropriate prescribing and monitoring of these. Obtaining a UDS or PDMP review is meant to provide a practitioner with additional information to interpret when caring for a patient. These data are only meant to complement—not replace—skilled patient assessment by a provider. Although the authors observed no major patient or clinical adverse events during the study period, the possibility exists that a patient may have been negatively impacted by a population-level initiative to improve surrogate measures of appropriate drug use.

Future studies should assess changes in measures, such as pain scores, legitimate adverse events, and overdose occurrences in order to evaluate whether such opioid improvement initiatives truly benefit the patients who are ultimately affected by each intervention.

Conclusion

This study demonstrates the successful implementation of a VHA-based opioid management initiative to increase appropriate COT monitoring and appropriate management of high-risk patients. It is the authors’ hope that the findings may add to the growing body of literature describing successful opioid improvement initiatives and serve as a tool for other health systems that are confronted with these same issues.

The Cherokee Nation has filed a lawsuit against 6 companies, accusing them of “turning a blind eye” to opioids being illegally prescribed to Cherokee adults and children. The lawsuit is the first of its kind filed in the U.S. “As we fight this epidemic in our hospitals, our schools, and our Cherokee homes, we will also use our legal system to make sure the companies, who put profits over people while our society is crippled by this epidemic, are held responsible for their actions,” said Cherokee Nation Principal Chief Bill John Baker.

According to DEA statistics, about 845 mg of opioids were distributed in the 14 counties of the Cherokee Nation in 2015—or between 360 and 720 opioid pills per every prescription. In The Washington Post, one of the lawyers for the Cherokee Nation said the “flood of opioids into Oklahoma has torn apart families and cost the Cherokees hundreds of millions of dollars.” Over the past 3 years, 2,684 opioid-related deaths have been reported in the state, according to Oklahoma Attorney General Mike Hunter.

The lawsuit names McKesson Corporation, Cardinal Health, Inc., and AmerisourceBergen (which together control roughly 85% of prescription drug distribution in the U.S.) as well as CVS, Walgreens, and Walmart. The companies “enabled prescription opioids to fall into illicit distribution channels, failed to alert regulators of extreme volume, and incentivized sales of these drugs with financial bonuses,” said Cherokee Nation Attorney General Todd Hembree. He said the drug distributors and pharmacies knew or should have known that the amount of drugs they were sending and dispensing were suspicious. He charged that the corporations’ profit seeking has unleashed “a plague.”

“Tribal nations have survived disease, removal from our homelands, termination, and other adversities and still we prospered,” said Chief Baker. “However, I fear the opioid epidemic is emerging as the next great challenge of our modern era.”

The full petition is available at www.cherokeecourts.org.

The Cherokee Nation has filed a lawsuit against 6 companies, accusing them of “turning a blind eye” to opioids being illegally prescribed to Cherokee adults and children. The lawsuit is the first of its kind filed in the U.S. “As we fight this epidemic in our hospitals, our schools, and our Cherokee homes, we will also use our legal system to make sure the companies, who put profits over people while our society is crippled by this epidemic, are held responsible for their actions,” said Cherokee Nation Principal Chief Bill John Baker.

According to DEA statistics, about 845 mg of opioids were distributed in the 14 counties of the Cherokee Nation in 2015—or between 360 and 720 opioid pills per every prescription. In The Washington Post, one of the lawyers for the Cherokee Nation said the “flood of opioids into Oklahoma has torn apart families and cost the Cherokees hundreds of millions of dollars.” Over the past 3 years, 2,684 opioid-related deaths have been reported in the state, according to Oklahoma Attorney General Mike Hunter.

The lawsuit names McKesson Corporation, Cardinal Health, Inc., and AmerisourceBergen (which together control roughly 85% of prescription drug distribution in the U.S.) as well as CVS, Walgreens, and Walmart. The companies “enabled prescription opioids to fall into illicit distribution channels, failed to alert regulators of extreme volume, and incentivized sales of these drugs with financial bonuses,” said Cherokee Nation Attorney General Todd Hembree. He said the drug distributors and pharmacies knew or should have known that the amount of drugs they were sending and dispensing were suspicious. He charged that the corporations’ profit seeking has unleashed “a plague.”

“Tribal nations have survived disease, removal from our homelands, termination, and other adversities and still we prospered,” said Chief Baker. “However, I fear the opioid epidemic is emerging as the next great challenge of our modern era.”

The full petition is available at www.cherokeecourts.org.

The Cherokee Nation has filed a lawsuit against 6 companies, accusing them of “turning a blind eye” to opioids being illegally prescribed to Cherokee adults and children. The lawsuit is the first of its kind filed in the U.S. “As we fight this epidemic in our hospitals, our schools, and our Cherokee homes, we will also use our legal system to make sure the companies, who put profits over people while our society is crippled by this epidemic, are held responsible for their actions,” said Cherokee Nation Principal Chief Bill John Baker.

According to DEA statistics, about 845 mg of opioids were distributed in the 14 counties of the Cherokee Nation in 2015—or between 360 and 720 opioid pills per every prescription. In The Washington Post, one of the lawyers for the Cherokee Nation said the “flood of opioids into Oklahoma has torn apart families and cost the Cherokees hundreds of millions of dollars.” Over the past 3 years, 2,684 opioid-related deaths have been reported in the state, according to Oklahoma Attorney General Mike Hunter.

The lawsuit names McKesson Corporation, Cardinal Health, Inc., and AmerisourceBergen (which together control roughly 85% of prescription drug distribution in the U.S.) as well as CVS, Walgreens, and Walmart. The companies “enabled prescription opioids to fall into illicit distribution channels, failed to alert regulators of extreme volume, and incentivized sales of these drugs with financial bonuses,” said Cherokee Nation Attorney General Todd Hembree. He said the drug distributors and pharmacies knew or should have known that the amount of drugs they were sending and dispensing were suspicious. He charged that the corporations’ profit seeking has unleashed “a plague.”

“Tribal nations have survived disease, removal from our homelands, termination, and other adversities and still we prospered,” said Chief Baker. “However, I fear the opioid epidemic is emerging as the next great challenge of our modern era.”

The full petition is available at www.cherokeecourts.org.

Follicular lymphoma (FL), which accounts for about 20% to 30% of all non-Hodgkin lymphomas, is an incurable disease. Although people with FL are living longer, the median overall survival (OS) had been about 10 years—until recently. According to researchers from the Spanish Lymphoma Oncology Group, OS may be changing. In their long-term study of 1,074 patients with newly diagnosed FL, median OS was more than 20 years.

Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies

The difference, the researchers say, may be chemoimmunotherapy, specifically, the anti-CD20 monoclonal antibody rituximab. Patients were enrolled between 1980 and 2013 and followed for a median of 55 months. The researchers note that rituximab was added to the treatment options in 2003. When the researchers analyzed the patients who were still alive 10 years beyond the diagnosis, they found that 118 of 166 were free of evident clinical disease.

The prognostic factors the researchers enumerate are similar to those of other studies. The variables significantly associated with survival at 10 years were stage great than II, aged < 60 years, low Follicular Lymphoma International Prognostic Index, normal β2 microglobulin, no B symptoms on diagnosis, Performance Status 0 to 1, and treatment with anthracyclines and rituximab. But their data, the researchers add, support the conclusion that the initial combined treatment with rituximab and anthracyclines “could be considered key factors.” They note that randomized studies and meta-analyses have repeatedly made improvements in the survival of patients with FL.

Related: New Treatments Offer Hope in Diffuse Large B-Cell Lymphoma

“We believe that the weight of the introduction of [rituximab] in a young population, associated with chemotherapy,” the researchers say, “has given these high rates of survival in an unselected population.” They conclude, “in the [rituximab] era, the strategy of ‘wait and watch’ remains valid for patients with favorable prognostic factors and low-grade tumors.”

Source:
Provencio M, Sabín P, Gomez-Codina J, et al. PLoS One. 2017;12(5):e0177204.
doi: 10.1371/journal.pone.0177204

Follicular lymphoma (FL), which accounts for about 20% to 30% of all non-Hodgkin lymphomas, is an incurable disease. Although people with FL are living longer, the median overall survival (OS) had been about 10 years—until recently. According to researchers from the Spanish Lymphoma Oncology Group, OS may be changing. In their long-term study of 1,074 patients with newly diagnosed FL, median OS was more than 20 years.

Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies

The difference, the researchers say, may be chemoimmunotherapy, specifically, the anti-CD20 monoclonal antibody rituximab. Patients were enrolled between 1980 and 2013 and followed for a median of 55 months. The researchers note that rituximab was added to the treatment options in 2003. When the researchers analyzed the patients who were still alive 10 years beyond the diagnosis, they found that 118 of 166 were free of evident clinical disease.

The prognostic factors the researchers enumerate are similar to those of other studies. The variables significantly associated with survival at 10 years were stage great than II, aged < 60 years, low Follicular Lymphoma International Prognostic Index, normal β2 microglobulin, no B symptoms on diagnosis, Performance Status 0 to 1, and treatment with anthracyclines and rituximab. But their data, the researchers add, support the conclusion that the initial combined treatment with rituximab and anthracyclines “could be considered key factors.” They note that randomized studies and meta-analyses have repeatedly made improvements in the survival of patients with FL.

Related: New Treatments Offer Hope in Diffuse Large B-Cell Lymphoma

“We believe that the weight of the introduction of [rituximab] in a young population, associated with chemotherapy,” the researchers say, “has given these high rates of survival in an unselected population.” They conclude, “in the [rituximab] era, the strategy of ‘wait and watch’ remains valid for patients with favorable prognostic factors and low-grade tumors.”

Source:
Provencio M, Sabín P, Gomez-Codina J, et al. PLoS One. 2017;12(5):e0177204.
doi: 10.1371/journal.pone.0177204

Follicular lymphoma (FL), which accounts for about 20% to 30% of all non-Hodgkin lymphomas, is an incurable disease. Although people with FL are living longer, the median overall survival (OS) had been about 10 years—until recently. According to researchers from the Spanish Lymphoma Oncology Group, OS may be changing. In their long-term study of 1,074 patients with newly diagnosed FL, median OS was more than 20 years.

Related: Six Open Clinical Trials That Are Expanding Our Understanding of Immunotherapies

The difference, the researchers say, may be chemoimmunotherapy, specifically, the anti-CD20 monoclonal antibody rituximab. Patients were enrolled between 1980 and 2013 and followed for a median of 55 months. The researchers note that rituximab was added to the treatment options in 2003. When the researchers analyzed the patients who were still alive 10 years beyond the diagnosis, they found that 118 of 166 were free of evident clinical disease.

The prognostic factors the researchers enumerate are similar to those of other studies. The variables significantly associated with survival at 10 years were stage great than II, aged < 60 years, low Follicular Lymphoma International Prognostic Index, normal β2 microglobulin, no B symptoms on diagnosis, Performance Status 0 to 1, and treatment with anthracyclines and rituximab. But their data, the researchers add, support the conclusion that the initial combined treatment with rituximab and anthracyclines “could be considered key factors.” They note that randomized studies and meta-analyses have repeatedly made improvements in the survival of patients with FL.

Related: New Treatments Offer Hope in Diffuse Large B-Cell Lymphoma

“We believe that the weight of the introduction of [rituximab] in a young population, associated with chemotherapy,” the researchers say, “has given these high rates of survival in an unselected population.” They conclude, “in the [rituximab] era, the strategy of ‘wait and watch’ remains valid for patients with favorable prognostic factors and low-grade tumors.”

Source:
Provencio M, Sabín P, Gomez-Codina J, et al. PLoS One. 2017;12(5):e0177204.
doi: 10.1371/journal.pone.0177204

Federal Practitioner is inviting VA, DoD, and PHS health care providers and researchers to contribute to a special issue that will be published in November 2017 and will examine cardiovascular disease treatments, such as heart failure, atrial fibrillation, anticoagulation treatments, and other related conditions.

Interested authors should submit a brief 2 to 3 sentence abstract to [email protected] by July 7, 2017. Federal Practitioner welcomes case studies, literature reviews, original research, program profiles, guest editorials, and other evidence-based articles. The updated and complete submission guidelines, including details about the style and format, can be found here: 

http://www.mdedge.com/fedprac/page/submission-guidelines

Federal Practitioner uses Editorial Manager, a web-based manuscript submission and review system. All manuscripts must be submitted through this system.

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editor-in-Chief (or, in the event of a potential conflict of interest, a designated surrogate from the journal’s Editorial Advisory Association). 

Federal Practitioner is inviting VA, DoD, and PHS health care providers and researchers to contribute to a special issue that will be published in November 2017 and will examine cardiovascular disease treatments, such as heart failure, atrial fibrillation, anticoagulation treatments, and other related conditions.

Interested authors should submit a brief 2 to 3 sentence abstract to [email protected] by July 7, 2017. Federal Practitioner welcomes case studies, literature reviews, original research, program profiles, guest editorials, and other evidence-based articles. The updated and complete submission guidelines, including details about the style and format, can be found here: 

http://www.mdedge.com/fedprac/page/submission-guidelines

Federal Practitioner uses Editorial Manager, a web-based manuscript submission and review system. All manuscripts must be submitted through this system.

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editor-in-Chief (or, in the event of a potential conflict of interest, a designated surrogate from the journal’s Editorial Advisory Association). 

Federal Practitioner is inviting VA, DoD, and PHS health care providers and researchers to contribute to a special issue that will be published in November 2017 and will examine cardiovascular disease treatments, such as heart failure, atrial fibrillation, anticoagulation treatments, and other related conditions.

Interested authors should submit a brief 2 to 3 sentence abstract to [email protected] by July 7, 2017. Federal Practitioner welcomes case studies, literature reviews, original research, program profiles, guest editorials, and other evidence-based articles. The updated and complete submission guidelines, including details about the style and format, can be found here: 

http://www.mdedge.com/fedprac/page/submission-guidelines

Federal Practitioner uses Editorial Manager, a web-based manuscript submission and review system. All manuscripts must be submitted through this system.

All manuscripts submitted to Federal Practitioner for both special and regular issues will be subject to peer review. Peer reviews are conducted in a double-blind fashion, and the reviewers are asked to comment on the manuscript’s importance, accuracy, relevance, clarity, timeliness, balance, and reference citation. Final decisions on all submitted manuscripts are made by the Editor-in-Chief (or, in the event of a potential conflict of interest, a designated surrogate from the journal’s Editorial Advisory Association). 

Photo © ASCO/David Eulitt 2017

CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).

BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.

This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.

“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of  Nanjing Legend Biotech in China, the developer of LCAR-B38M.

“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.

To date the objective response rate is 100%.

The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.

The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.

Efficacy

Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.

One patient who achieved a VGPR relapsed due to an extramedullary lesion.

Investigators observed no evidence of relapse among patients who achieved sCR.

Five patients have been followed for more than a year and all have maintained sCR.

Safety

Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).

Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.

Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.

A clinical trial of LCAR-B38M is planned in the United States.

Photo © ASCO/David Eulitt 2017

CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).

BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.

This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.

“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of  Nanjing Legend Biotech in China, the developer of LCAR-B38M.

“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.

To date the objective response rate is 100%.

The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.

The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.

Efficacy

Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.

One patient who achieved a VGPR relapsed due to an extramedullary lesion.

Investigators observed no evidence of relapse among patients who achieved sCR.

Five patients have been followed for more than a year and all have maintained sCR.

Safety

Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).

Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.

Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.

A clinical trial of LCAR-B38M is planned in the United States.

Photo © ASCO/David Eulitt 2017

CHICAGO—A new type of chimeric antigen receptor (CAR) T cell, one that is specific for the B-cell maturation antigen (BCMA), has produced durable remissions in patients with multiple myeloma (MM), according to research reported at the 2017 ASCO Annual Meeting (abstract LBA3001).

BCMA is a cell surface antigen universally expressed on malignant plasma cells. It plays a role in the progression of MM and is turning out to be a highly selective antigen to target in novel treatments for MM.

This trial of LCAR-B38M is one of the first clinical trials of CAR T cells to target BCMA.

“[W]hat makes our CAR T different from other CAR T all over the world is we are truly a bispecific CAR T modality,” Frank (Xiaohu) Fan, MD, PhD, explained in a media briefing, “especially our antigen-binding units compared to single domain antibodies.” Dr Fan is CSO of  Nanjing Legend Biotech in China, the developer of LCAR-B38M.

“We believe targeting BCMA alone should be enough to get a good efficacy,” he said.

To date the objective response rate is 100%.

The investigators treated 35 relapsed/refractory MM patients thus far with LCAR-B38M. Patients received the modified CAR T cells in 3 doses, on days 0, 2, and 6.

The investigators reported on 19 patients who they followed for more than 4 months, a criterion established by the International Myeloma Working Group for full efficacy evaluation.

Efficacy

Of the 19 patients, 14 (74%) achieved a stringent complete response (sCR), 4 (21%) a very good partial response (VGPR), and 1 (5%) a PR.

One patient who achieved a VGPR relapsed due to an extramedullary lesion.

Investigators observed no evidence of relapse among patients who achieved sCR.

Five patients have been followed for more than a year and all have maintained sCR.

Safety

Safety is a major issue with CAR T-cell therapies, with a frequent and major adverse event being cytokine release syndrome (CRS).

Of the 35 patients treated, 6 experienced no CRS, 17 had grade 1, 10 had grade 2, and 2 had grade 3 CRS. No patient experienced grade 4 CRS or any grade 5 event.

Because LCAR-B38M demonstrates “outstanding” efficacy with a “great” safety profile, the investigators believe this technology raises the hope of cure for MM patients.

A clinical trial of LCAR-B38M is planned in the United States.