From Grant Medical Center (Dr. Wasielewski, Dr. Polonia, Ms. Barca, Ms. Cebriak, Ms. Lucki), and OhioHealth Group (Mr. Rogers, Ms. St. John, Dr. Gascon), Columbus, OH.

Abstract

• Background: Organizations participating in the Centers for Medicare and Medicaid Services (CMS) Bundled Payment for Care Improvement (BPCI) initiative enter into payment arrangements that include financial and performance accountability for episodes of care. There is growing evidence that the use of these payment incentives reduces spending for episodes of care while maintaining or improving quality. A recent study of BPCI and quality outcomes in joint replacement episodes found that nearly all the reduction in spending within BPCI hospitals was generated from the reduced use of institutional post-acute care (eg, skilled nursing facilities [SNF], long-term care facilities, and inpatient rehabilitation facilities).
• Objective: To describe a pilot program designed to reduce the utilization of institutional post-acute care for total joint replacement surgical patients.
• Methods: A multidisciplinary intervention team optimized scheduling, preadmission testing, patient communication, and patient education along a total joint replacement care pathway.
• Results: Among Medicare patients, total discharges to a SNF fell from 39.5% (70/177) in the baseline period to 17.7% (34/192) in the performance period. The risk of SNF utilization among patients in the intervention period was nearly half (0.45; 95% confidence interval, 0.314-0.639) that of patients in the baseline period. Using Fisher’s exact test and a 2-tailed test, this reduction was found to be significant (P < 0.0001). The readmission rate was substantially lower than national norms.
• Conclusion: Optimizing patient care throughout the care pathway using the concerted efforts of a multidisciplinary team is possible given a common vision, shared goals, and clearly communicated expectations.

Keywords: arthroplasty; readmissions; Medicare; post-acute care; Bundled Payment for Care Improvement.

Quality improvement in health care is partially dependent upon processes that standardize episodes of care. This is especially true in the post–acute care setting, where efforts to increase patient engagement and care coordination can improve a patient’s recovery process. One framework for optimizing patient care across an episode of care is the Centers for Medicare and Medicaid Services (CMS) Bundled Payment for Care Improvement (BPCI) initiative, which links payments for the multiple services patients receive during an episode of care. Organizations participating in the BPCI initiative enter into payment arrangements that include financial and performance accountability for episodes of care. The BPCI initiative provides a framework for episodes of care across multiple types of facilities and clinicians over periods of time (30-day, 60-day, and 90-day episodes).^1-5 Evidence that the use of these payment incentives reduces spending for episodes of care while maintaining or improving quality is accumulating. A recent study of BPCI and quality outcomes in joint replacement episodes found that nearly all the reduction in spending within BPCI hospitals was generated from the reduced use of institutional post-acute care, such as skilled nursing facilities (SNF), long-term care facilities, and inpatient rehabilitation facilities.¹

Our hospital, the Grant Medical Center, which is part of the OhioHealth system, had agreed to participate in the CMS BPCI–Advanced Model for major joint replacement of the lower extremity, with a start date of October 1, 2018. Prior to adopting this bundled payment and service delivery model for major joint replacement through the BPCI program, we implemented strategic interventions to improve the efficiency of care delivery and reduce post-acute utilization. Although the BPCI program applied only to Medicare patients, the interventions that were developed, implemented, and evaluated in this quality improvement project, which we describe in this article, were provided to all patients who underwent lower-extremity joint replacement, regardless of payer.

Gap Analysis

Prior to developing and implementing the intervention, a gap analysis was performed to determine differences between Grant Medical Center’s care pathway/processes and evidence-based best practice. A steering committee comprised of physician champions, rehabilitation services, senior leadership from the Bone and Joint Center, and care management was gathered. The gap analysis examined the care paths in the preoperative phase, index admission phase, and the post-acute phase of care. Findings of the gap analysis included an underutilized joint education class, overutilization of SNF placement, and lack of key resources to assess the needs of patients prior to surgery.

The Grant Bone and Joint Center offered a comprehensive joint education class in person, but also gave patients the option of utilizing an online learning source. While both were successful, staff believed the in-person class had a greater impact than the online version. Patients who attended the class completed a preoperative assessment by hand, which included a social assessment for identifying potential challenges prior to admission. However, because class attendance was low (< 10%), this assessment tool was not utilized until the patient’s admission in most cases. The gap analysis also identified that the educational content of the class lacked key points to encourage a home-going plan.

The baseline SNF utilization rate (using data from July 1, 2015–June 30, 2016) within the Medicare population was 39.5% (70/177), with an overall (all payers) rate of 22.9% (192/838). This SNF utilization rate was higher than the national benchmark, underscoring the need to focus on a preoperative “plan for home” message. In addition, review of Medicare fee-for-service data from 2014 to 2016 revealed that Grant Medical Center utilized 83 different SNFs over the course of approximately 2 years. In this context, staff saw an opportunity to develop stronger relationships with fewer SNF partners, as well as OhioHealth Home Care, in order to improve care by standardizing functional recovery in post-acute care management.

In sum, the gap analysis found that a lack of standardization, follow through, and engagement in daily multidisciplinary rounds often led to a plan for SNF discharge instead of home. As such, it was determined that the pilot program would target the preoperative and post-acute phases of care and that its primary endpoint would be the reduction of the SNF discharge rate among Medicare fee-for-service patients.

Literature Review

Targeting the SNF discharge rate as the endpoint was also supported by a recent study that showed that most of the reduction in spending for total joint replacement within BPCI hospitals was linked to reduced use of institutional post-acute care.¹ Other studies in the joint replacement literature have delineated the specific aspects of care redesign that allow hospitals to provide more efficient and effective care delivery during an episode of care.^6-8 A review of these and similar studies of joint replacement quality improvement interventions yielded a number of actionable findings:

• Engaging and educating patients and families is critical. Families and other caregivers must be identified preoperatively, actively engaged, and committed to helping the patient recover.
• Providers must build the expectation in patients that they will return home as soon as it is safe to do so. This includes working to restore physiologic function, managing pain with oral medication, and restoring the physical capability of adapting to a home environment.
• Relationships must be established with post-acute care providers who are able to demonstrate best practices and be willing partners on performance outcomes.
• Providers need to invest in personnel to coordinate care transitions initiated preoperatively that continue through the post-acute phase of care.
• Providers must promote processes that allow patients to more fully own their recovery through coaching and improved communication.

A total joint replacement initiative undertaken at another hospital within the OhioHealth system, Riverside Methodist Hospital, that incorporated these aspects of care redesign demonstrated a significant reduction in SNF utilization. That success informed the development of the initiative at Grant Medical Center.

Methods

Setting

This pilot project was conducted from July 2017 through July 2018 at the Grant Bone and Joint Center in the Grant Medical Center, an urban hospital in Columbus, Ohio. The Bone and Joint Center performs more than 7400 surgeries each year, of which 12% are total joint replacements. Grant Medical Center is a Level I Trauma Center that has received a fourth designation in Magnet Nursing status and has attained The Joint Commission Disease-Specific Care Certification for its total knee and hip arthroplasty, total shoulder, and hip fracture programs.

Intervention

The findings from the gap analysis were incorporated into a standardized preoperative care pathway at the Center. Standardization of the care pathway required developing relationships between office staff, schedulers, inpatient work teams, and preadmission testing, as well as physician group realignment with the larger organization.

During this time, the steering committee identified the need for a designated full-time pre-habilitation case manager to support patients undergoing hip and knee replacements at the Center. With the addition of a new role, prehab case manager, attention was directed to patient social assessment and communication. After the surgery was scheduled but prior to the preoperative education class, each patient received a screening phone call from the prehab case manager that included an initial social assessment. The electronic health record (EHR) was utilized to communicate the results of the assessment, including barriers to a home-going plan. The phone call allowed the case manager to reinforce the importance of class attendance for the patient and primary caregiver, and also allowed any specific concerns identified to be addressed and resolved prior to surgery.

A work group consisting of the prehab case manager, office staff, and the bone and joint leadership team focused on improving the core preoperative education content, same-day preadmission clearance, and class attendance. To support these efforts, the work group (1) created a scheduling document to align preadmission testing and the preoperative education class so they occurred on the same day, (2) improved prior authorization of the surgery to support the post-surgical care team, (3) clarified expectations and roles among office staff and care management staff to optimize the discharge process, and (4) engaged the physician team to encourage a culture change towards setting patient expectations to be discharged to home or a preferred SNF location. Regarding prior authorization communications, prior to the intervention, communication was insufficient, paper driven, and lacking in continuity. Utilizing the EHR, an EPIC platform, a designated documentation location was created, which increased communication among the office schedulers, preadmission testing, and surgery schedulers. The consistent location for recording prior authorization avoided canceled surgeries and claim denials due to missing pieces of information. In addition to these process changes, the surgical offices were geographically realigned to a new single location, a change that brought the staff together and in turn allowed for role clarification and team building and also allowed the staff to identify opportunities for improvement.

The core content of the education class was redesigned to support patients’ understanding of the procedure and what to expect during the hospital stay and discharge for home. Staff worked first to align all preadmission patient requirements with the content of the class. In pilot studies, patients were asked to provide feedback, and this feedback was incorporated into subsequent revisions. Staff developed multilingual handouts, including a surgery instruction sheet with a preoperative social assessment, in addition to creating opportunities for 1:1 education when it was medically or socially appropriate.

The work group brought the physicians in the care pathway together for a focused conversation and education regarding the need for including class attendance as part of their practice. They worked with the physicians’ support team to coordinate standardized follow-up care in the post-acute setting and encouraged the physicians to create a “home-going” culture and reset expectations for length of stay. Prior to the start of this project, the rehabilitation department began using the 6-Clicks Inpatient Basic Mobility Short Form, a standardized instrument comprised of short forms created from the Activity Measure for Post-Acute Care (AM-PAC) instrument. The AMPAC score is used to help establish the patient’s functional level; patients scoring 18 or higher have a higher probability of a successful return home (rather than an institutional discharge). Physical therapists at the Center adminster the 6-Clicks tool for each therapy patient daily, and document the AM-PAC score in the appropriate flowsheet in the EHR in a manner consistent with best practices.^9-11 The group utilized the AMPAC score to determine functional status upon discharge, offering guidance for the correct post-acute discharge plan.

The workgroup also established a relationship with the lead home health care service to develop a standard notification process to set volume and service expectations. Finally, they worked with the lead SNFs to explain the surgical procedure and set expectations for patient recovery at the facilities. These changes are summarized in the Figure.

Analysis

Descriptive statistics were used to describe patients and metrics in the baseline and performance periods. The difference in the proportion of patients discharged to a SNF in the baseline and performance periods was examined by a Z-test of proportion and change in relative risk. A Z-test of proportion was also used examine differences in the 90-day all-cause readmission rate and in the average length of stay between the 2 periods.

Results

Differences between Medicare fee-for-service patients in the baseline and performance periods are reported in Table 1. While age, sex, diagnoses, and surgical types were similar, AM-PAC scores and the proportion of patients married or living with someone were higher in the performance period. The AM-PAC score in Table 1 represents the last documented score prior to discharge.

The proportion of Medicare patients discharged to a SNF fell from 39.5% (70/177) in the baseline period to 17.7% (34/192) in the performance period (Table 2). The 21.9% difference was significant at the 0.05 level (Z = 4.6586, P = 0.0001). Medicare patients in the intervention period had nearly half (0.45) the risk (95% confidence interval, 0.314-0.639) of SNF utilization compared with patients in the baseline period. Using Fisher’s exact test and a 2-tailed test, this reduction was found to be significant (P < 0.0001).

Concomitantly, the 90-day all-cause readmission rate among Medicare patients rose from 2.8% (5/177) to 4.7% (9/192), but the difference in proportions was not statistically significant (Z = –0.9356, P = 0.3495). Similarly, the average length of stay for Medicare patients was 2.9 days in both the baseline and performance periods.

The intervention was associated with a statistically significant decrease in the SNF discharge rate following total joint replacement. The readmission rate and average length of stay were statistically unchanged. The lack of a statistically significant change in readmissions is important, as previous research has found that total joint replacement patients discharged to a SNF have higher odds of hospital readmission within 90 days than those discharged home.¹² Moreover, the readmission rate in the performance period (4.7%) was still substantially lower than the national estimate of 90-day readmission rates associated with total hip arthroplasty (7.7%) and total knee arthroplasty (9.7%).¹³ For patients, these quality improvements are associated with improved outcomes and lower costs of care.

These outcomes were achieved after a substantial effort at the facility level to onboard new staff; orient them and their colleagues in each step along the care pathway, from scheduling through post-acute care; and build trust among all team members. The critical difference was changing expectations for post-acute recovery and rehabilitation throughout both the new clinical coordination workflow and processes and the existing processes. Orientation of the clinical coordination role was necessary to establish relationships with inpatient team members who were not as intimately involved with the position and expectations. To accomplish this, competing priorities had to be addressed and resolved through standardization efforts developed and implemented by the multidisciplinary team. The team first reviewed reports of such efforts in the initial review of the BPCI literature.^1-5 Subsequent analyses of the most germane study³ and related research¹⁴ confirmed that a team-based approach to standardization could be successful. The former study used physician and affiliated care teams to build a care pathway that minimized variation in practices across the episode of care, and the latter used a multidisciplinary team approach to develop rapid recovery protocols. Subsequent research has validated the findings that hospital-based multidisciplinary teams have long been associated with improved patient safety, shorter length of stay, and fewer complications.¹⁵

Limitations

This quality improvement project was limited to a single facility. As such, adapting the improvements made to Grant Medical Center’s care pathway for implementation throughout the OhioHealth system will take time due to variation of care provided at each campus; scale-up efforts are ongoing. In the Grant facility, the project uncovered instances of unstandardized provider communication pathways, clinical staff workflows, and expectations for patients. Standardization in all 3 instances improved the patient experience. Additionally, data collection requirements for rigorous research and evaluation efforts that had to be done by hand during the project are now being integrated into the EHR.

The improvements described here, which were implemented in anticipation of adopting the CMS BPCI bundled payment model for joint replacement of the lower extremity, were provided to every patient regardless of payer. Patient outcomes varied across payer, as did preoperative education rates and other variables (Table 1). These differences are being tracked and analyzed following the Center’s entry into the CMS BPCI model on October 1, 2018.

Corresponding author: Gregg M. Gascon, PhD, CHDA, OhioHealth Group, 155 E. Broad Street, Suite 1700, Columbus, Ohio 43215; [email protected].

Financial disclosures: None.

From Grant Medical Center (Dr. Wasielewski, Dr. Polonia, Ms. Barca, Ms. Cebriak, Ms. Lucki), and OhioHealth Group (Mr. Rogers, Ms. St. John, Dr. Gascon), Columbus, OH.

Abstract

• Background: Organizations participating in the Centers for Medicare and Medicaid Services (CMS) Bundled Payment for Care Improvement (BPCI) initiative enter into payment arrangements that include financial and performance accountability for episodes of care. There is growing evidence that the use of these payment incentives reduces spending for episodes of care while maintaining or improving quality. A recent study of BPCI and quality outcomes in joint replacement episodes found that nearly all the reduction in spending within BPCI hospitals was generated from the reduced use of institutional post-acute care (eg, skilled nursing facilities [SNF], long-term care facilities, and inpatient rehabilitation facilities).
• Objective: To describe a pilot program designed to reduce the utilization of institutional post-acute care for total joint replacement surgical patients.
• Methods: A multidisciplinary intervention team optimized scheduling, preadmission testing, patient communication, and patient education along a total joint replacement care pathway.
• Results: Among Medicare patients, total discharges to a SNF fell from 39.5% (70/177) in the baseline period to 17.7% (34/192) in the performance period. The risk of SNF utilization among patients in the intervention period was nearly half (0.45; 95% confidence interval, 0.314-0.639) that of patients in the baseline period. Using Fisher’s exact test and a 2-tailed test, this reduction was found to be significant (P < 0.0001). The readmission rate was substantially lower than national norms.
• Conclusion: Optimizing patient care throughout the care pathway using the concerted efforts of a multidisciplinary team is possible given a common vision, shared goals, and clearly communicated expectations.

Keywords: arthroplasty; readmissions; Medicare; post-acute care; Bundled Payment for Care Improvement.

Quality improvement in health care is partially dependent upon processes that standardize episodes of care. This is especially true in the post–acute care setting, where efforts to increase patient engagement and care coordination can improve a patient’s recovery process. One framework for optimizing patient care across an episode of care is the Centers for Medicare and Medicaid Services (CMS) Bundled Payment for Care Improvement (BPCI) initiative, which links payments for the multiple services patients receive during an episode of care. Organizations participating in the BPCI initiative enter into payment arrangements that include financial and performance accountability for episodes of care. The BPCI initiative provides a framework for episodes of care across multiple types of facilities and clinicians over periods of time (30-day, 60-day, and 90-day episodes).^1-5 Evidence that the use of these payment incentives reduces spending for episodes of care while maintaining or improving quality is accumulating. A recent study of BPCI and quality outcomes in joint replacement episodes found that nearly all the reduction in spending within BPCI hospitals was generated from the reduced use of institutional post-acute care, such as skilled nursing facilities (SNF), long-term care facilities, and inpatient rehabilitation facilities.¹

Our hospital, the Grant Medical Center, which is part of the OhioHealth system, had agreed to participate in the CMS BPCI–Advanced Model for major joint replacement of the lower extremity, with a start date of October 1, 2018. Prior to adopting this bundled payment and service delivery model for major joint replacement through the BPCI program, we implemented strategic interventions to improve the efficiency of care delivery and reduce post-acute utilization. Although the BPCI program applied only to Medicare patients, the interventions that were developed, implemented, and evaluated in this quality improvement project, which we describe in this article, were provided to all patients who underwent lower-extremity joint replacement, regardless of payer.

Gap Analysis

Prior to developing and implementing the intervention, a gap analysis was performed to determine differences between Grant Medical Center’s care pathway/processes and evidence-based best practice. A steering committee comprised of physician champions, rehabilitation services, senior leadership from the Bone and Joint Center, and care management was gathered. The gap analysis examined the care paths in the preoperative phase, index admission phase, and the post-acute phase of care. Findings of the gap analysis included an underutilized joint education class, overutilization of SNF placement, and lack of key resources to assess the needs of patients prior to surgery.

The Grant Bone and Joint Center offered a comprehensive joint education class in person, but also gave patients the option of utilizing an online learning source. While both were successful, staff believed the in-person class had a greater impact than the online version. Patients who attended the class completed a preoperative assessment by hand, which included a social assessment for identifying potential challenges prior to admission. However, because class attendance was low (< 10%), this assessment tool was not utilized until the patient’s admission in most cases. The gap analysis also identified that the educational content of the class lacked key points to encourage a home-going plan.

The baseline SNF utilization rate (using data from July 1, 2015–June 30, 2016) within the Medicare population was 39.5% (70/177), with an overall (all payers) rate of 22.9% (192/838). This SNF utilization rate was higher than the national benchmark, underscoring the need to focus on a preoperative “plan for home” message. In addition, review of Medicare fee-for-service data from 2014 to 2016 revealed that Grant Medical Center utilized 83 different SNFs over the course of approximately 2 years. In this context, staff saw an opportunity to develop stronger relationships with fewer SNF partners, as well as OhioHealth Home Care, in order to improve care by standardizing functional recovery in post-acute care management.

In sum, the gap analysis found that a lack of standardization, follow through, and engagement in daily multidisciplinary rounds often led to a plan for SNF discharge instead of home. As such, it was determined that the pilot program would target the preoperative and post-acute phases of care and that its primary endpoint would be the reduction of the SNF discharge rate among Medicare fee-for-service patients.

Literature Review

Targeting the SNF discharge rate as the endpoint was also supported by a recent study that showed that most of the reduction in spending for total joint replacement within BPCI hospitals was linked to reduced use of institutional post-acute care.¹ Other studies in the joint replacement literature have delineated the specific aspects of care redesign that allow hospitals to provide more efficient and effective care delivery during an episode of care.^6-8 A review of these and similar studies of joint replacement quality improvement interventions yielded a number of actionable findings:

• Engaging and educating patients and families is critical. Families and other caregivers must be identified preoperatively, actively engaged, and committed to helping the patient recover.
• Providers must build the expectation in patients that they will return home as soon as it is safe to do so. This includes working to restore physiologic function, managing pain with oral medication, and restoring the physical capability of adapting to a home environment.
• Relationships must be established with post-acute care providers who are able to demonstrate best practices and be willing partners on performance outcomes.
• Providers need to invest in personnel to coordinate care transitions initiated preoperatively that continue through the post-acute phase of care.
• Providers must promote processes that allow patients to more fully own their recovery through coaching and improved communication.

A total joint replacement initiative undertaken at another hospital within the OhioHealth system, Riverside Methodist Hospital, that incorporated these aspects of care redesign demonstrated a significant reduction in SNF utilization. That success informed the development of the initiative at Grant Medical Center.

Methods

Setting

This pilot project was conducted from July 2017 through July 2018 at the Grant Bone and Joint Center in the Grant Medical Center, an urban hospital in Columbus, Ohio. The Bone and Joint Center performs more than 7400 surgeries each year, of which 12% are total joint replacements. Grant Medical Center is a Level I Trauma Center that has received a fourth designation in Magnet Nursing status and has attained The Joint Commission Disease-Specific Care Certification for its total knee and hip arthroplasty, total shoulder, and hip fracture programs.

Intervention

The findings from the gap analysis were incorporated into a standardized preoperative care pathway at the Center. Standardization of the care pathway required developing relationships between office staff, schedulers, inpatient work teams, and preadmission testing, as well as physician group realignment with the larger organization.

During this time, the steering committee identified the need for a designated full-time pre-habilitation case manager to support patients undergoing hip and knee replacements at the Center. With the addition of a new role, prehab case manager, attention was directed to patient social assessment and communication. After the surgery was scheduled but prior to the preoperative education class, each patient received a screening phone call from the prehab case manager that included an initial social assessment. The electronic health record (EHR) was utilized to communicate the results of the assessment, including barriers to a home-going plan. The phone call allowed the case manager to reinforce the importance of class attendance for the patient and primary caregiver, and also allowed any specific concerns identified to be addressed and resolved prior to surgery.

A work group consisting of the prehab case manager, office staff, and the bone and joint leadership team focused on improving the core preoperative education content, same-day preadmission clearance, and class attendance. To support these efforts, the work group (1) created a scheduling document to align preadmission testing and the preoperative education class so they occurred on the same day, (2) improved prior authorization of the surgery to support the post-surgical care team, (3) clarified expectations and roles among office staff and care management staff to optimize the discharge process, and (4) engaged the physician team to encourage a culture change towards setting patient expectations to be discharged to home or a preferred SNF location. Regarding prior authorization communications, prior to the intervention, communication was insufficient, paper driven, and lacking in continuity. Utilizing the EHR, an EPIC platform, a designated documentation location was created, which increased communication among the office schedulers, preadmission testing, and surgery schedulers. The consistent location for recording prior authorization avoided canceled surgeries and claim denials due to missing pieces of information. In addition to these process changes, the surgical offices were geographically realigned to a new single location, a change that brought the staff together and in turn allowed for role clarification and team building and also allowed the staff to identify opportunities for improvement.

The core content of the education class was redesigned to support patients’ understanding of the procedure and what to expect during the hospital stay and discharge for home. Staff worked first to align all preadmission patient requirements with the content of the class. In pilot studies, patients were asked to provide feedback, and this feedback was incorporated into subsequent revisions. Staff developed multilingual handouts, including a surgery instruction sheet with a preoperative social assessment, in addition to creating opportunities for 1:1 education when it was medically or socially appropriate.

The work group brought the physicians in the care pathway together for a focused conversation and education regarding the need for including class attendance as part of their practice. They worked with the physicians’ support team to coordinate standardized follow-up care in the post-acute setting and encouraged the physicians to create a “home-going” culture and reset expectations for length of stay. Prior to the start of this project, the rehabilitation department began using the 6-Clicks Inpatient Basic Mobility Short Form, a standardized instrument comprised of short forms created from the Activity Measure for Post-Acute Care (AM-PAC) instrument. The AMPAC score is used to help establish the patient’s functional level; patients scoring 18 or higher have a higher probability of a successful return home (rather than an institutional discharge). Physical therapists at the Center adminster the 6-Clicks tool for each therapy patient daily, and document the AM-PAC score in the appropriate flowsheet in the EHR in a manner consistent with best practices.^9-11 The group utilized the AMPAC score to determine functional status upon discharge, offering guidance for the correct post-acute discharge plan.

The workgroup also established a relationship with the lead home health care service to develop a standard notification process to set volume and service expectations. Finally, they worked with the lead SNFs to explain the surgical procedure and set expectations for patient recovery at the facilities. These changes are summarized in the Figure.

Analysis

Descriptive statistics were used to describe patients and metrics in the baseline and performance periods. The difference in the proportion of patients discharged to a SNF in the baseline and performance periods was examined by a Z-test of proportion and change in relative risk. A Z-test of proportion was also used examine differences in the 90-day all-cause readmission rate and in the average length of stay between the 2 periods.

Results

Differences between Medicare fee-for-service patients in the baseline and performance periods are reported in Table 1. While age, sex, diagnoses, and surgical types were similar, AM-PAC scores and the proportion of patients married or living with someone were higher in the performance period. The AM-PAC score in Table 1 represents the last documented score prior to discharge.

The proportion of Medicare patients discharged to a SNF fell from 39.5% (70/177) in the baseline period to 17.7% (34/192) in the performance period (Table 2). The 21.9% difference was significant at the 0.05 level (Z = 4.6586, P = 0.0001). Medicare patients in the intervention period had nearly half (0.45) the risk (95% confidence interval, 0.314-0.639) of SNF utilization compared with patients in the baseline period. Using Fisher’s exact test and a 2-tailed test, this reduction was found to be significant (P < 0.0001).

Concomitantly, the 90-day all-cause readmission rate among Medicare patients rose from 2.8% (5/177) to 4.7% (9/192), but the difference in proportions was not statistically significant (Z = –0.9356, P = 0.3495). Similarly, the average length of stay for Medicare patients was 2.9 days in both the baseline and performance periods.

The intervention was associated with a statistically significant decrease in the SNF discharge rate following total joint replacement. The readmission rate and average length of stay were statistically unchanged. The lack of a statistically significant change in readmissions is important, as previous research has found that total joint replacement patients discharged to a SNF have higher odds of hospital readmission within 90 days than those discharged home.¹² Moreover, the readmission rate in the performance period (4.7%) was still substantially lower than the national estimate of 90-day readmission rates associated with total hip arthroplasty (7.7%) and total knee arthroplasty (9.7%).¹³ For patients, these quality improvements are associated with improved outcomes and lower costs of care.

These outcomes were achieved after a substantial effort at the facility level to onboard new staff; orient them and their colleagues in each step along the care pathway, from scheduling through post-acute care; and build trust among all team members. The critical difference was changing expectations for post-acute recovery and rehabilitation throughout both the new clinical coordination workflow and processes and the existing processes. Orientation of the clinical coordination role was necessary to establish relationships with inpatient team members who were not as intimately involved with the position and expectations. To accomplish this, competing priorities had to be addressed and resolved through standardization efforts developed and implemented by the multidisciplinary team. The team first reviewed reports of such efforts in the initial review of the BPCI literature.^1-5 Subsequent analyses of the most germane study³ and related research¹⁴ confirmed that a team-based approach to standardization could be successful. The former study used physician and affiliated care teams to build a care pathway that minimized variation in practices across the episode of care, and the latter used a multidisciplinary team approach to develop rapid recovery protocols. Subsequent research has validated the findings that hospital-based multidisciplinary teams have long been associated with improved patient safety, shorter length of stay, and fewer complications.¹⁵

Limitations

This quality improvement project was limited to a single facility. As such, adapting the improvements made to Grant Medical Center’s care pathway for implementation throughout the OhioHealth system will take time due to variation of care provided at each campus; scale-up efforts are ongoing. In the Grant facility, the project uncovered instances of unstandardized provider communication pathways, clinical staff workflows, and expectations for patients. Standardization in all 3 instances improved the patient experience. Additionally, data collection requirements for rigorous research and evaluation efforts that had to be done by hand during the project are now being integrated into the EHR.

The improvements described here, which were implemented in anticipation of adopting the CMS BPCI bundled payment model for joint replacement of the lower extremity, were provided to every patient regardless of payer. Patient outcomes varied across payer, as did preoperative education rates and other variables (Table 1). These differences are being tracked and analyzed following the Center’s entry into the CMS BPCI model on October 1, 2018.

Corresponding author: Gregg M. Gascon, PhD, CHDA, OhioHealth Group, 155 E. Broad Street, Suite 1700, Columbus, Ohio 43215; [email protected].

Financial disclosures: None.

From Grant Medical Center (Dr. Wasielewski, Dr. Polonia, Ms. Barca, Ms. Cebriak, Ms. Lucki), and OhioHealth Group (Mr. Rogers, Ms. St. John, Dr. Gascon), Columbus, OH.

Abstract

• Background: Organizations participating in the Centers for Medicare and Medicaid Services (CMS) Bundled Payment for Care Improvement (BPCI) initiative enter into payment arrangements that include financial and performance accountability for episodes of care. There is growing evidence that the use of these payment incentives reduces spending for episodes of care while maintaining or improving quality. A recent study of BPCI and quality outcomes in joint replacement episodes found that nearly all the reduction in spending within BPCI hospitals was generated from the reduced use of institutional post-acute care (eg, skilled nursing facilities [SNF], long-term care facilities, and inpatient rehabilitation facilities).
• Objective: To describe a pilot program designed to reduce the utilization of institutional post-acute care for total joint replacement surgical patients.
• Methods: A multidisciplinary intervention team optimized scheduling, preadmission testing, patient communication, and patient education along a total joint replacement care pathway.
• Results: Among Medicare patients, total discharges to a SNF fell from 39.5% (70/177) in the baseline period to 17.7% (34/192) in the performance period. The risk of SNF utilization among patients in the intervention period was nearly half (0.45; 95% confidence interval, 0.314-0.639) that of patients in the baseline period. Using Fisher’s exact test and a 2-tailed test, this reduction was found to be significant (P < 0.0001). The readmission rate was substantially lower than national norms.
• Conclusion: Optimizing patient care throughout the care pathway using the concerted efforts of a multidisciplinary team is possible given a common vision, shared goals, and clearly communicated expectations.

Keywords: arthroplasty; readmissions; Medicare; post-acute care; Bundled Payment for Care Improvement.

Quality improvement in health care is partially dependent upon processes that standardize episodes of care. This is especially true in the post–acute care setting, where efforts to increase patient engagement and care coordination can improve a patient’s recovery process. One framework for optimizing patient care across an episode of care is the Centers for Medicare and Medicaid Services (CMS) Bundled Payment for Care Improvement (BPCI) initiative, which links payments for the multiple services patients receive during an episode of care. Organizations participating in the BPCI initiative enter into payment arrangements that include financial and performance accountability for episodes of care. The BPCI initiative provides a framework for episodes of care across multiple types of facilities and clinicians over periods of time (30-day, 60-day, and 90-day episodes).^1-5 Evidence that the use of these payment incentives reduces spending for episodes of care while maintaining or improving quality is accumulating. A recent study of BPCI and quality outcomes in joint replacement episodes found that nearly all the reduction in spending within BPCI hospitals was generated from the reduced use of institutional post-acute care, such as skilled nursing facilities (SNF), long-term care facilities, and inpatient rehabilitation facilities.¹

Our hospital, the Grant Medical Center, which is part of the OhioHealth system, had agreed to participate in the CMS BPCI–Advanced Model for major joint replacement of the lower extremity, with a start date of October 1, 2018. Prior to adopting this bundled payment and service delivery model for major joint replacement through the BPCI program, we implemented strategic interventions to improve the efficiency of care delivery and reduce post-acute utilization. Although the BPCI program applied only to Medicare patients, the interventions that were developed, implemented, and evaluated in this quality improvement project, which we describe in this article, were provided to all patients who underwent lower-extremity joint replacement, regardless of payer.

Gap Analysis

Prior to developing and implementing the intervention, a gap analysis was performed to determine differences between Grant Medical Center’s care pathway/processes and evidence-based best practice. A steering committee comprised of physician champions, rehabilitation services, senior leadership from the Bone and Joint Center, and care management was gathered. The gap analysis examined the care paths in the preoperative phase, index admission phase, and the post-acute phase of care. Findings of the gap analysis included an underutilized joint education class, overutilization of SNF placement, and lack of key resources to assess the needs of patients prior to surgery.

The Grant Bone and Joint Center offered a comprehensive joint education class in person, but also gave patients the option of utilizing an online learning source. While both were successful, staff believed the in-person class had a greater impact than the online version. Patients who attended the class completed a preoperative assessment by hand, which included a social assessment for identifying potential challenges prior to admission. However, because class attendance was low (< 10%), this assessment tool was not utilized until the patient’s admission in most cases. The gap analysis also identified that the educational content of the class lacked key points to encourage a home-going plan.

The baseline SNF utilization rate (using data from July 1, 2015–June 30, 2016) within the Medicare population was 39.5% (70/177), with an overall (all payers) rate of 22.9% (192/838). This SNF utilization rate was higher than the national benchmark, underscoring the need to focus on a preoperative “plan for home” message. In addition, review of Medicare fee-for-service data from 2014 to 2016 revealed that Grant Medical Center utilized 83 different SNFs over the course of approximately 2 years. In this context, staff saw an opportunity to develop stronger relationships with fewer SNF partners, as well as OhioHealth Home Care, in order to improve care by standardizing functional recovery in post-acute care management.

In sum, the gap analysis found that a lack of standardization, follow through, and engagement in daily multidisciplinary rounds often led to a plan for SNF discharge instead of home. As such, it was determined that the pilot program would target the preoperative and post-acute phases of care and that its primary endpoint would be the reduction of the SNF discharge rate among Medicare fee-for-service patients.

Literature Review

Targeting the SNF discharge rate as the endpoint was also supported by a recent study that showed that most of the reduction in spending for total joint replacement within BPCI hospitals was linked to reduced use of institutional post-acute care.¹ Other studies in the joint replacement literature have delineated the specific aspects of care redesign that allow hospitals to provide more efficient and effective care delivery during an episode of care.^6-8 A review of these and similar studies of joint replacement quality improvement interventions yielded a number of actionable findings:

• Engaging and educating patients and families is critical. Families and other caregivers must be identified preoperatively, actively engaged, and committed to helping the patient recover.
• Providers must build the expectation in patients that they will return home as soon as it is safe to do so. This includes working to restore physiologic function, managing pain with oral medication, and restoring the physical capability of adapting to a home environment.
• Relationships must be established with post-acute care providers who are able to demonstrate best practices and be willing partners on performance outcomes.
• Providers need to invest in personnel to coordinate care transitions initiated preoperatively that continue through the post-acute phase of care.
• Providers must promote processes that allow patients to more fully own their recovery through coaching and improved communication.

A total joint replacement initiative undertaken at another hospital within the OhioHealth system, Riverside Methodist Hospital, that incorporated these aspects of care redesign demonstrated a significant reduction in SNF utilization. That success informed the development of the initiative at Grant Medical Center.

Methods

Setting

This pilot project was conducted from July 2017 through July 2018 at the Grant Bone and Joint Center in the Grant Medical Center, an urban hospital in Columbus, Ohio. The Bone and Joint Center performs more than 7400 surgeries each year, of which 12% are total joint replacements. Grant Medical Center is a Level I Trauma Center that has received a fourth designation in Magnet Nursing status and has attained The Joint Commission Disease-Specific Care Certification for its total knee and hip arthroplasty, total shoulder, and hip fracture programs.

Intervention

The findings from the gap analysis were incorporated into a standardized preoperative care pathway at the Center. Standardization of the care pathway required developing relationships between office staff, schedulers, inpatient work teams, and preadmission testing, as well as physician group realignment with the larger organization.

During this time, the steering committee identified the need for a designated full-time pre-habilitation case manager to support patients undergoing hip and knee replacements at the Center. With the addition of a new role, prehab case manager, attention was directed to patient social assessment and communication. After the surgery was scheduled but prior to the preoperative education class, each patient received a screening phone call from the prehab case manager that included an initial social assessment. The electronic health record (EHR) was utilized to communicate the results of the assessment, including barriers to a home-going plan. The phone call allowed the case manager to reinforce the importance of class attendance for the patient and primary caregiver, and also allowed any specific concerns identified to be addressed and resolved prior to surgery.

A work group consisting of the prehab case manager, office staff, and the bone and joint leadership team focused on improving the core preoperative education content, same-day preadmission clearance, and class attendance. To support these efforts, the work group (1) created a scheduling document to align preadmission testing and the preoperative education class so they occurred on the same day, (2) improved prior authorization of the surgery to support the post-surgical care team, (3) clarified expectations and roles among office staff and care management staff to optimize the discharge process, and (4) engaged the physician team to encourage a culture change towards setting patient expectations to be discharged to home or a preferred SNF location. Regarding prior authorization communications, prior to the intervention, communication was insufficient, paper driven, and lacking in continuity. Utilizing the EHR, an EPIC platform, a designated documentation location was created, which increased communication among the office schedulers, preadmission testing, and surgery schedulers. The consistent location for recording prior authorization avoided canceled surgeries and claim denials due to missing pieces of information. In addition to these process changes, the surgical offices were geographically realigned to a new single location, a change that brought the staff together and in turn allowed for role clarification and team building and also allowed the staff to identify opportunities for improvement.

The core content of the education class was redesigned to support patients’ understanding of the procedure and what to expect during the hospital stay and discharge for home. Staff worked first to align all preadmission patient requirements with the content of the class. In pilot studies, patients were asked to provide feedback, and this feedback was incorporated into subsequent revisions. Staff developed multilingual handouts, including a surgery instruction sheet with a preoperative social assessment, in addition to creating opportunities for 1:1 education when it was medically or socially appropriate.

The work group brought the physicians in the care pathway together for a focused conversation and education regarding the need for including class attendance as part of their practice. They worked with the physicians’ support team to coordinate standardized follow-up care in the post-acute setting and encouraged the physicians to create a “home-going” culture and reset expectations for length of stay. Prior to the start of this project, the rehabilitation department began using the 6-Clicks Inpatient Basic Mobility Short Form, a standardized instrument comprised of short forms created from the Activity Measure for Post-Acute Care (AM-PAC) instrument. The AMPAC score is used to help establish the patient’s functional level; patients scoring 18 or higher have a higher probability of a successful return home (rather than an institutional discharge). Physical therapists at the Center adminster the 6-Clicks tool for each therapy patient daily, and document the AM-PAC score in the appropriate flowsheet in the EHR in a manner consistent with best practices.^9-11 The group utilized the AMPAC score to determine functional status upon discharge, offering guidance for the correct post-acute discharge plan.

The workgroup also established a relationship with the lead home health care service to develop a standard notification process to set volume and service expectations. Finally, they worked with the lead SNFs to explain the surgical procedure and set expectations for patient recovery at the facilities. These changes are summarized in the Figure.

Analysis

Descriptive statistics were used to describe patients and metrics in the baseline and performance periods. The difference in the proportion of patients discharged to a SNF in the baseline and performance periods was examined by a Z-test of proportion and change in relative risk. A Z-test of proportion was also used examine differences in the 90-day all-cause readmission rate and in the average length of stay between the 2 periods.

Results

Differences between Medicare fee-for-service patients in the baseline and performance periods are reported in Table 1. While age, sex, diagnoses, and surgical types were similar, AM-PAC scores and the proportion of patients married or living with someone were higher in the performance period. The AM-PAC score in Table 1 represents the last documented score prior to discharge.

The proportion of Medicare patients discharged to a SNF fell from 39.5% (70/177) in the baseline period to 17.7% (34/192) in the performance period (Table 2). The 21.9% difference was significant at the 0.05 level (Z = 4.6586, P = 0.0001). Medicare patients in the intervention period had nearly half (0.45) the risk (95% confidence interval, 0.314-0.639) of SNF utilization compared with patients in the baseline period. Using Fisher’s exact test and a 2-tailed test, this reduction was found to be significant (P < 0.0001).

Concomitantly, the 90-day all-cause readmission rate among Medicare patients rose from 2.8% (5/177) to 4.7% (9/192), but the difference in proportions was not statistically significant (Z = –0.9356, P = 0.3495). Similarly, the average length of stay for Medicare patients was 2.9 days in both the baseline and performance periods.

The intervention was associated with a statistically significant decrease in the SNF discharge rate following total joint replacement. The readmission rate and average length of stay were statistically unchanged. The lack of a statistically significant change in readmissions is important, as previous research has found that total joint replacement patients discharged to a SNF have higher odds of hospital readmission within 90 days than those discharged home.¹² Moreover, the readmission rate in the performance period (4.7%) was still substantially lower than the national estimate of 90-day readmission rates associated with total hip arthroplasty (7.7%) and total knee arthroplasty (9.7%).¹³ For patients, these quality improvements are associated with improved outcomes and lower costs of care.

These outcomes were achieved after a substantial effort at the facility level to onboard new staff; orient them and their colleagues in each step along the care pathway, from scheduling through post-acute care; and build trust among all team members. The critical difference was changing expectations for post-acute recovery and rehabilitation throughout both the new clinical coordination workflow and processes and the existing processes. Orientation of the clinical coordination role was necessary to establish relationships with inpatient team members who were not as intimately involved with the position and expectations. To accomplish this, competing priorities had to be addressed and resolved through standardization efforts developed and implemented by the multidisciplinary team. The team first reviewed reports of such efforts in the initial review of the BPCI literature.^1-5 Subsequent analyses of the most germane study³ and related research¹⁴ confirmed that a team-based approach to standardization could be successful. The former study used physician and affiliated care teams to build a care pathway that minimized variation in practices across the episode of care, and the latter used a multidisciplinary team approach to develop rapid recovery protocols. Subsequent research has validated the findings that hospital-based multidisciplinary teams have long been associated with improved patient safety, shorter length of stay, and fewer complications.¹⁵

Limitations

This quality improvement project was limited to a single facility. As such, adapting the improvements made to Grant Medical Center’s care pathway for implementation throughout the OhioHealth system will take time due to variation of care provided at each campus; scale-up efforts are ongoing. In the Grant facility, the project uncovered instances of unstandardized provider communication pathways, clinical staff workflows, and expectations for patients. Standardization in all 3 instances improved the patient experience. Additionally, data collection requirements for rigorous research and evaluation efforts that had to be done by hand during the project are now being integrated into the EHR.

The improvements described here, which were implemented in anticipation of adopting the CMS BPCI bundled payment model for joint replacement of the lower extremity, were provided to every patient regardless of payer. Patient outcomes varied across payer, as did preoperative education rates and other variables (Table 1). These differences are being tracked and analyzed following the Center’s entry into the CMS BPCI model on October 1, 2018.

Corresponding author: Gregg M. Gascon, PhD, CHDA, OhioHealth Group, 155 E. Broad Street, Suite 1700, Columbus, Ohio 43215; [email protected].

Financial disclosures: None.

Study Overview

Objective. To evaluate the association of number of steps taken per day and stepping intensity with all-cause mortality in older women.

Design. This was a prospective cohort study of US women participating in the Women’s Health Study (WHS). Participants wore an accelerometer device (ActiGraph GT3X+, ActiGraph Corp, Pensacola, FL) on the hip during waking hours for 7 consecutive days between 2011 and 2015. The accelerator data were collected at 30 Hz and aggregated into 60-second, time-stamped epochs. Data from participants who were adherent with wearing devices (defined as ≥ 10 hours/day of wear on ≥ 4 days) were used in an analysis that was conducted between 2018 and 2019. The exposure variables were defined as steps taken per day and measures of stepping intensity (ie, peak 1-minute cadence; peak 30-minute cadence; maximum 5-minute cadence; and time spent at a stepping rate of ≥ 40 steps/minute, reflecting purposeful steps).

Setting and participants. In total, 18,289 women participated in this study. Of these, 17,708 wore and returned their accelerometer devices, and data were downloaded successfully from 17,466 devices. Compliant wearers of the device (≥ 10 hours/day of wear on ≥4 days) included 16,741 participants (96% compliance rate of all downloaded device data).

Main outcome measure. All-cause mortality as ascertained through the National Death Index or confirmed by medical records and death certificates.

Main results. In this cohort of 16,741 women, average age at baseline was 72.0 ± 5.7 years (range, 62 to 101 years) and the mean step count was 5499 per day (median, 5094 steps/day) during the 7-day data capture period between 2011 and 2015. Not taking steps (0 steps/minute) accounted for 51.4% of the recorded time, incidental steps (1 to 39 steps/minute) accounted for 45.5%, and purposeful steps (≥ 40 steps/minute) accounted for 3.1%. The mean follow-up period was 4.3 years; during this time, 504 participants died. The median steps per day across quartiles were 2718 (lowest), 4363, 5905, and 8442 (highest). The corresponding quartile hazard ratios (HRs) associated with mortality adjusted for confounders were 1.00 (reference; lowest quartile), 0.59 (95% confidence interval [CI], 0.47-0.75), 0.54 (95% CI, 0.41-0.72), and 0.42 (95% CI, 0.30-0.60; highest quartile), respectively (P < 0.01). A higher mean step count per day, up to approximately 7500 steps/day, corresponded with progressive and steady decline in mortality HRs using spline analyses. Similar results were observed using sensitivity analyses that minimized reverse causation bias. While the adjusted analysis of measures of stepping intensity showed an inverse association with mortality rates, these associations were no longer significant after accounting for steps per day. Specifically, adjusted HRs comparing highest to lowest quartile were 0.87 (95% CI, 0.68-1.11) for peak 1-minute cadence; 0.86 (95% CI, 0.65-1.13) for peak 30-minute cadence; 0.80 (95% CI, 0.62-1.05) for maximum 5-minute cadence; and 1.27 (95% CI, 0.96-1.68) for time spent at a stepping rate of ≥ 40 steps/minute.

Conclusion. Older women who took approximately 4400 steps per day had lower all-cause mortality rates during a follow-up period of 4.3 years compared to those who took approximately 2700 steps each day. Progressive reduction in mortality rates was associated with increased steps per day before leveling at about 7500 steps/day. Stepping intensity, when accounting for number of steps taken per day, was not associated with reduction in mortality rates in older women.

Commentary

The health and mortality benefits of exercise are well recognized. The 2018 Department of Health and Human Services Physical Activity Guidelines (DHHS-PAG) recommend that adults should do at least 150 to 300 minutes of moderate-intensity aerobic physical activity per week, or 75 to 150 minutes of vigorous-intensity aerobic physical activity per week, in addition to doing muscle-strengthening activities on 2 or more days a week.¹ Importantly, the guidelines emphasize that moving more and sitting less benefit nearly everyone, and note that measures of steps as a metric of ambulation can further promote translation of research into public health recommendations for exercise interventions. Despite this recognition, there is limited information centering on the number of daily steps (step volume) and the intensity of stepping that are needed to achieve optimal health outcomes in older adults. The study reported by Lee and colleagues adds new knowledge regarding the relationship between step volume and intensity and mortality in older women.

To date, only a handful of studies conducted outside of the United States have investigated the association between mortality and objectively measured step volume as determined by pedometer or accelerometer.^2-4 While these studies observed that higher step counts are associated with lower mortality rates during follow-up periods of 5 to 10 years, their sample sizes were smaller and the study populations were different from those included in the study reported by Lee and colleagues. For example, the cohort from the United Kingdom included only men,² and the participants in the Australian study were considerably younger, with a mean age of 59 years.⁴ In the current study, the largest of its kind thus far, it was observed that older women in the United States who take about 4400 steps a day have a lower mortality rate compared to those who take about 2700 steps a day. Moreover, the benefit of increased step volume on mortality progressively increases until plateauing at about 7500 steps per day. On the other hand, stepping intensity does not appear to lower mortality when step volume is accounted for. These results are important in that they add novel evidence that in older women, a patient population that tends to be sedentary, increased step volume (steps per day) but not stepping intensity (how quickly steps are taken) is associated with a reduction in mortality. Thus, these findings help to better characterize steps as a metric of ambulation in sedentary older adults per DHHS-PAG and add to the evidence necessary to translate this line of research into public health recommendations and programs.

While the health benefit of regular physical activity is well known and has been brought to the foreground with DDHA-PAG, only a small percentage of older adults engage in the recommended amounts and types of exercises. In other words, finding motivation to exercise is hard. Thus, identifying practical methods to facilitate behavioral change that increase and sustain physical activity in sedentary older adults would be essential to promoting health in this population. The use of wearable technologies such as fitness trackers and smartphone apps, devices that are now widely used, has shown promise for measuring and encouraging physical activity. The study by Lee and colleagues adds to this notion and further highlights the potential significance of step volume and mortality benefits in older women. Thus, future research in fitness technology should aim to integrate behavior change techniques (such as goal setting, feedback rewards, and action planning) and physical activity levels in order to improve health outcomes in older adults.⁵

In this study, the large sample size (> 16,000 participants), high compliance rate of accelerometer use (96% compliance rate), and reliable and continuous data capture (a built-in device feature) provide a large and complete dataset. This dataset, a major strength of the study, allowed the investigators to adequately control for potential confounders of physical activity, such as history of smoking, alcohol use, diet, and self-rated health, and therefore statistically minimize biases that are common in observational studies. However, some limitations inherent to the observational design are noted in this study. For instance, the observed association between step volume and mortality is correlational rather than causal, and a one-time assessment of steps taken over 7 consecutive days (ie, exposure) may not accurately reflect step volume and intensity of study participants over the span of 4.3 years of follow-up. Also, participants of WHS are predominately white, have higher socioeconomic status, and are more physically active than a national sample in the United States; therefore, caution should be exercised when making inferences to the general population.

Applications for Clinical Practice

Increased steps taken each day, up to about 7500 steps per day, is associated with lower mortality in older women. This finding can help inform the discussion when clinicians offer physical activity recommendations to older sedentary patients.

—Fred Ko, MD

Study Overview

Objective. To evaluate the association of number of steps taken per day and stepping intensity with all-cause mortality in older women.

Design. This was a prospective cohort study of US women participating in the Women’s Health Study (WHS). Participants wore an accelerometer device (ActiGraph GT3X+, ActiGraph Corp, Pensacola, FL) on the hip during waking hours for 7 consecutive days between 2011 and 2015. The accelerator data were collected at 30 Hz and aggregated into 60-second, time-stamped epochs. Data from participants who were adherent with wearing devices (defined as ≥ 10 hours/day of wear on ≥ 4 days) were used in an analysis that was conducted between 2018 and 2019. The exposure variables were defined as steps taken per day and measures of stepping intensity (ie, peak 1-minute cadence; peak 30-minute cadence; maximum 5-minute cadence; and time spent at a stepping rate of ≥ 40 steps/minute, reflecting purposeful steps).

Setting and participants. In total, 18,289 women participated in this study. Of these, 17,708 wore and returned their accelerometer devices, and data were downloaded successfully from 17,466 devices. Compliant wearers of the device (≥ 10 hours/day of wear on ≥4 days) included 16,741 participants (96% compliance rate of all downloaded device data).

Main outcome measure. All-cause mortality as ascertained through the National Death Index or confirmed by medical records and death certificates.

Main results. In this cohort of 16,741 women, average age at baseline was 72.0 ± 5.7 years (range, 62 to 101 years) and the mean step count was 5499 per day (median, 5094 steps/day) during the 7-day data capture period between 2011 and 2015. Not taking steps (0 steps/minute) accounted for 51.4% of the recorded time, incidental steps (1 to 39 steps/minute) accounted for 45.5%, and purposeful steps (≥ 40 steps/minute) accounted for 3.1%. The mean follow-up period was 4.3 years; during this time, 504 participants died. The median steps per day across quartiles were 2718 (lowest), 4363, 5905, and 8442 (highest). The corresponding quartile hazard ratios (HRs) associated with mortality adjusted for confounders were 1.00 (reference; lowest quartile), 0.59 (95% confidence interval [CI], 0.47-0.75), 0.54 (95% CI, 0.41-0.72), and 0.42 (95% CI, 0.30-0.60; highest quartile), respectively (P < 0.01). A higher mean step count per day, up to approximately 7500 steps/day, corresponded with progressive and steady decline in mortality HRs using spline analyses. Similar results were observed using sensitivity analyses that minimized reverse causation bias. While the adjusted analysis of measures of stepping intensity showed an inverse association with mortality rates, these associations were no longer significant after accounting for steps per day. Specifically, adjusted HRs comparing highest to lowest quartile were 0.87 (95% CI, 0.68-1.11) for peak 1-minute cadence; 0.86 (95% CI, 0.65-1.13) for peak 30-minute cadence; 0.80 (95% CI, 0.62-1.05) for maximum 5-minute cadence; and 1.27 (95% CI, 0.96-1.68) for time spent at a stepping rate of ≥ 40 steps/minute.

Conclusion. Older women who took approximately 4400 steps per day had lower all-cause mortality rates during a follow-up period of 4.3 years compared to those who took approximately 2700 steps each day. Progressive reduction in mortality rates was associated with increased steps per day before leveling at about 7500 steps/day. Stepping intensity, when accounting for number of steps taken per day, was not associated with reduction in mortality rates in older women.

Commentary

The health and mortality benefits of exercise are well recognized. The 2018 Department of Health and Human Services Physical Activity Guidelines (DHHS-PAG) recommend that adults should do at least 150 to 300 minutes of moderate-intensity aerobic physical activity per week, or 75 to 150 minutes of vigorous-intensity aerobic physical activity per week, in addition to doing muscle-strengthening activities on 2 or more days a week.¹ Importantly, the guidelines emphasize that moving more and sitting less benefit nearly everyone, and note that measures of steps as a metric of ambulation can further promote translation of research into public health recommendations for exercise interventions. Despite this recognition, there is limited information centering on the number of daily steps (step volume) and the intensity of stepping that are needed to achieve optimal health outcomes in older adults. The study reported by Lee and colleagues adds new knowledge regarding the relationship between step volume and intensity and mortality in older women.

To date, only a handful of studies conducted outside of the United States have investigated the association between mortality and objectively measured step volume as determined by pedometer or accelerometer.^2-4 While these studies observed that higher step counts are associated with lower mortality rates during follow-up periods of 5 to 10 years, their sample sizes were smaller and the study populations were different from those included in the study reported by Lee and colleagues. For example, the cohort from the United Kingdom included only men,² and the participants in the Australian study were considerably younger, with a mean age of 59 years.⁴ In the current study, the largest of its kind thus far, it was observed that older women in the United States who take about 4400 steps a day have a lower mortality rate compared to those who take about 2700 steps a day. Moreover, the benefit of increased step volume on mortality progressively increases until plateauing at about 7500 steps per day. On the other hand, stepping intensity does not appear to lower mortality when step volume is accounted for. These results are important in that they add novel evidence that in older women, a patient population that tends to be sedentary, increased step volume (steps per day) but not stepping intensity (how quickly steps are taken) is associated with a reduction in mortality. Thus, these findings help to better characterize steps as a metric of ambulation in sedentary older adults per DHHS-PAG and add to the evidence necessary to translate this line of research into public health recommendations and programs.

While the health benefit of regular physical activity is well known and has been brought to the foreground with DDHA-PAG, only a small percentage of older adults engage in the recommended amounts and types of exercises. In other words, finding motivation to exercise is hard. Thus, identifying practical methods to facilitate behavioral change that increase and sustain physical activity in sedentary older adults would be essential to promoting health in this population. The use of wearable technologies such as fitness trackers and smartphone apps, devices that are now widely used, has shown promise for measuring and encouraging physical activity. The study by Lee and colleagues adds to this notion and further highlights the potential significance of step volume and mortality benefits in older women. Thus, future research in fitness technology should aim to integrate behavior change techniques (such as goal setting, feedback rewards, and action planning) and physical activity levels in order to improve health outcomes in older adults.⁵

In this study, the large sample size (> 16,000 participants), high compliance rate of accelerometer use (96% compliance rate), and reliable and continuous data capture (a built-in device feature) provide a large and complete dataset. This dataset, a major strength of the study, allowed the investigators to adequately control for potential confounders of physical activity, such as history of smoking, alcohol use, diet, and self-rated health, and therefore statistically minimize biases that are common in observational studies. However, some limitations inherent to the observational design are noted in this study. For instance, the observed association between step volume and mortality is correlational rather than causal, and a one-time assessment of steps taken over 7 consecutive days (ie, exposure) may not accurately reflect step volume and intensity of study participants over the span of 4.3 years of follow-up. Also, participants of WHS are predominately white, have higher socioeconomic status, and are more physically active than a national sample in the United States; therefore, caution should be exercised when making inferences to the general population.

Applications for Clinical Practice

Increased steps taken each day, up to about 7500 steps per day, is associated with lower mortality in older women. This finding can help inform the discussion when clinicians offer physical activity recommendations to older sedentary patients.

—Fred Ko, MD

Study Overview

Objective. To evaluate the association of number of steps taken per day and stepping intensity with all-cause mortality in older women.

Design. This was a prospective cohort study of US women participating in the Women’s Health Study (WHS). Participants wore an accelerometer device (ActiGraph GT3X+, ActiGraph Corp, Pensacola, FL) on the hip during waking hours for 7 consecutive days between 2011 and 2015. The accelerator data were collected at 30 Hz and aggregated into 60-second, time-stamped epochs. Data from participants who were adherent with wearing devices (defined as ≥ 10 hours/day of wear on ≥ 4 days) were used in an analysis that was conducted between 2018 and 2019. The exposure variables were defined as steps taken per day and measures of stepping intensity (ie, peak 1-minute cadence; peak 30-minute cadence; maximum 5-minute cadence; and time spent at a stepping rate of ≥ 40 steps/minute, reflecting purposeful steps).

Setting and participants. In total, 18,289 women participated in this study. Of these, 17,708 wore and returned their accelerometer devices, and data were downloaded successfully from 17,466 devices. Compliant wearers of the device (≥ 10 hours/day of wear on ≥4 days) included 16,741 participants (96% compliance rate of all downloaded device data).

Main outcome measure. All-cause mortality as ascertained through the National Death Index or confirmed by medical records and death certificates.

Main results. In this cohort of 16,741 women, average age at baseline was 72.0 ± 5.7 years (range, 62 to 101 years) and the mean step count was 5499 per day (median, 5094 steps/day) during the 7-day data capture period between 2011 and 2015. Not taking steps (0 steps/minute) accounted for 51.4% of the recorded time, incidental steps (1 to 39 steps/minute) accounted for 45.5%, and purposeful steps (≥ 40 steps/minute) accounted for 3.1%. The mean follow-up period was 4.3 years; during this time, 504 participants died. The median steps per day across quartiles were 2718 (lowest), 4363, 5905, and 8442 (highest). The corresponding quartile hazard ratios (HRs) associated with mortality adjusted for confounders were 1.00 (reference; lowest quartile), 0.59 (95% confidence interval [CI], 0.47-0.75), 0.54 (95% CI, 0.41-0.72), and 0.42 (95% CI, 0.30-0.60; highest quartile), respectively (P < 0.01). A higher mean step count per day, up to approximately 7500 steps/day, corresponded with progressive and steady decline in mortality HRs using spline analyses. Similar results were observed using sensitivity analyses that minimized reverse causation bias. While the adjusted analysis of measures of stepping intensity showed an inverse association with mortality rates, these associations were no longer significant after accounting for steps per day. Specifically, adjusted HRs comparing highest to lowest quartile were 0.87 (95% CI, 0.68-1.11) for peak 1-minute cadence; 0.86 (95% CI, 0.65-1.13) for peak 30-minute cadence; 0.80 (95% CI, 0.62-1.05) for maximum 5-minute cadence; and 1.27 (95% CI, 0.96-1.68) for time spent at a stepping rate of ≥ 40 steps/minute.

Conclusion. Older women who took approximately 4400 steps per day had lower all-cause mortality rates during a follow-up period of 4.3 years compared to those who took approximately 2700 steps each day. Progressive reduction in mortality rates was associated with increased steps per day before leveling at about 7500 steps/day. Stepping intensity, when accounting for number of steps taken per day, was not associated with reduction in mortality rates in older women.

Commentary

The health and mortality benefits of exercise are well recognized. The 2018 Department of Health and Human Services Physical Activity Guidelines (DHHS-PAG) recommend that adults should do at least 150 to 300 minutes of moderate-intensity aerobic physical activity per week, or 75 to 150 minutes of vigorous-intensity aerobic physical activity per week, in addition to doing muscle-strengthening activities on 2 or more days a week.¹ Importantly, the guidelines emphasize that moving more and sitting less benefit nearly everyone, and note that measures of steps as a metric of ambulation can further promote translation of research into public health recommendations for exercise interventions. Despite this recognition, there is limited information centering on the number of daily steps (step volume) and the intensity of stepping that are needed to achieve optimal health outcomes in older adults. The study reported by Lee and colleagues adds new knowledge regarding the relationship between step volume and intensity and mortality in older women.

To date, only a handful of studies conducted outside of the United States have investigated the association between mortality and objectively measured step volume as determined by pedometer or accelerometer.^2-4 While these studies observed that higher step counts are associated with lower mortality rates during follow-up periods of 5 to 10 years, their sample sizes were smaller and the study populations were different from those included in the study reported by Lee and colleagues. For example, the cohort from the United Kingdom included only men,² and the participants in the Australian study were considerably younger, with a mean age of 59 years.⁴ In the current study, the largest of its kind thus far, it was observed that older women in the United States who take about 4400 steps a day have a lower mortality rate compared to those who take about 2700 steps a day. Moreover, the benefit of increased step volume on mortality progressively increases until plateauing at about 7500 steps per day. On the other hand, stepping intensity does not appear to lower mortality when step volume is accounted for. These results are important in that they add novel evidence that in older women, a patient population that tends to be sedentary, increased step volume (steps per day) but not stepping intensity (how quickly steps are taken) is associated with a reduction in mortality. Thus, these findings help to better characterize steps as a metric of ambulation in sedentary older adults per DHHS-PAG and add to the evidence necessary to translate this line of research into public health recommendations and programs.

While the health benefit of regular physical activity is well known and has been brought to the foreground with DDHA-PAG, only a small percentage of older adults engage in the recommended amounts and types of exercises. In other words, finding motivation to exercise is hard. Thus, identifying practical methods to facilitate behavioral change that increase and sustain physical activity in sedentary older adults would be essential to promoting health in this population. The use of wearable technologies such as fitness trackers and smartphone apps, devices that are now widely used, has shown promise for measuring and encouraging physical activity. The study by Lee and colleagues adds to this notion and further highlights the potential significance of step volume and mortality benefits in older women. Thus, future research in fitness technology should aim to integrate behavior change techniques (such as goal setting, feedback rewards, and action planning) and physical activity levels in order to improve health outcomes in older adults.⁵

In this study, the large sample size (> 16,000 participants), high compliance rate of accelerometer use (96% compliance rate), and reliable and continuous data capture (a built-in device feature) provide a large and complete dataset. This dataset, a major strength of the study, allowed the investigators to adequately control for potential confounders of physical activity, such as history of smoking, alcohol use, diet, and self-rated health, and therefore statistically minimize biases that are common in observational studies. However, some limitations inherent to the observational design are noted in this study. For instance, the observed association between step volume and mortality is correlational rather than causal, and a one-time assessment of steps taken over 7 consecutive days (ie, exposure) may not accurately reflect step volume and intensity of study participants over the span of 4.3 years of follow-up. Also, participants of WHS are predominately white, have higher socioeconomic status, and are more physically active than a national sample in the United States; therefore, caution should be exercised when making inferences to the general population.

Applications for Clinical Practice

Increased steps taken each day, up to about 7500 steps per day, is associated with lower mortality in older women. This finding can help inform the discussion when clinicians offer physical activity recommendations to older sedentary patients.

—Fred Ko, MD

Study Overview

Objective. To compare the efficacy and safety of lenalidomide in combination with rituximab (known as the R² regimen) to rituximab plus placebo in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL).

Design. Phase 3, multicenter, international, placebo controlled randomized trial.

Setting and participants. 358 patients with rituximab-sensitive relapsed or refractory grade 1-3a follicular lymphoma or MZL.

Intervention. Patients were randomly assigned 1:1 to receive lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5.

Main outcome measures. The primary endpoint was progression-free survival (PFS) as determined by independent radiology reviewers using intent-to-treat analysis. Secondary end points included overall response rate, complete response rate, duration of response, overall survival, event-free survival, and time to next anti-lymphoma therapy. Time to next chemotherapy treatment and histologic transformation were exploratory endpoints. Responses were assessed by participating investigators and independent reviewers. Computed tomography or magnetic resonance imaging was used to obtain tumor measurements. Positron emission tomography was not used. Complete remissions were confirmed by bone marrow biopsy, as bone marrow involvement is exceedingly common in these lymphomas. Gastrointestinal endoscopy was performed to obtain disease status if there was involvement by lymphoma initially.

Improvement in primary and secondary endpoints as well as extrapolatory endpoints were reported in the R² group. Primary efficacy analyses were conducted in the intention-to-treat population primary endpoint of PFS at 1-sided α = 0.025 level.

Main results. PFS was significantly improved for patients treated with the R² regimen compared to those who recieved placebo plus rituximab, with a hazard ratio of 0.46 (95% confidence interval [CI], 0.34-0.62; P < 0.001). Median duration of PFS in the R² group was 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months) in the rituximab/placebo group. Overall response in the R² group was 78% (95% CI, 71%-83%) versus 53% (95% CI, 46%-61%; P < 0.0001) in the rituximab/placebo group, with 34% (95% CI, 27%-41%) versus 18% (95% CI, 13%-25%) of patients achieving complete remission (P = 0.001). There were 15 deaths in the R² group versus 26 deaths in the rituximab/placebo group. Overall survival data is not mature yet.

Conclusion. The R² regimen was superior to rituximab and placebo in relapsed or recurrent follicular lymphomas. The regimen’s safety profile was acceptable, with higher events of usual and expected but manageable toxicities in the R² regimen compared to rituximab/placebo.

Commentary

Nearly half of non-Hodgkins lymphomas (NHLs) diagnosed in the United States are classified as indolent B-cell lymphomas.¹ Follicular lymphomas constitute about 50% of all indolent NHLs, while MZLs comprise less than 15%.¹ These slowly progressive B-cell lymphomas are currently considered treatable but have very low cure rates. Cure is primarily limited to early stage I/II disease and may be possible in less than half of patients by applying involved-field radiation therapy with curative intent.

More than two thirds of indolent lymphomas present in advanced stages (III-IV). Despite an advanced stage at presentation, initial chemoimmunotherapy can induce complete remission in nearly 60% of patients. Unfortunately, nearly all patients relapse over the next 10 years.² The wait-and-watch approach is a common strategy, and most patients are administered initial therapy or subsequent lines of therapy if they are symptomatic.² As such, for the majority of these patients, the goal of therapy is to minimize toxicities, preserve quality of life, treat symptoms, and achieve a long PFS without an attempt to cure. Following each line of therapy, patients often revert to watchful surveillance, sometimes for more than a decade. With additional subsequent lines of therapy, lymphoma tends to get more refractory to treatment.

A median survival of nearly 2 decades has been achieved in advanced follicular lymphomas^2,3 and MZL.⁴ However, wide variation in overall response, duration of response, and survival is reported based on the individual risk profile.

The drug of interest in the present study by Leonard and colleagues, lenalidomide, has immunomodulatory properties and antiproliferative effects, possibly related to its binding of the E3 ligase protein cereblon and subsequent ubiquitination of the transcription factors Aiolos and Ikaros.⁵ The benefits of combination lenalidomide/rituximab against follicular lymphoma in preclinical settings have been attributed to mechanisms mediated by tumor-infiltrating lymphocytes, natural killer cells, monocytes, and antibody-dependent cell-mediated toxicity.⁵ The combination has now been studied in first-line and subsequent lines of therapy for follicular lymphoma and MZL.⁶

RELEVANCE, a phase 3 trial, compared the R² regimen in the upfront setting in advanced follicular lymphoma with rituximab and chemotherapy combination (including CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVP [cyclophosphamide, vincristine, prednisone], and bendamustine).⁷ Efficacy outcomes were similar between the comparators and R² was noninferior. MAGNIFY, a phase 3b trial involving rituximab-sensitive and rituximab-refractory patients with previously treated follicular lymphoma and MZL, demonstrated an overall response rate of 73%, complete response rate of 45%, and median PFS of 36 months in patients who received the R² regimen and who entered a plan to receive maintenance with rituximab.⁸

The AUGMENT trial was conducted at 97 centers in the United States and 14 Asian and European countries; it enrolled 358 patients, 82% of whom had a follicular lymphoma, between February 13, 2014 and January 26, 2017. The study was well conducted. The R² regimen was compared to the often used second-line therapy of rituximab alone, and 1:1 randomization was done with stratification factors of prior rituximab use, marginal versus follicular histology, and time lapse of less than or greater than 2 years since last therapy. A limitation of this study is that it selected individuals with a better prognosis, as the study patients were not rituximab refractory and 57% had received only a single prior therapy.

As observed in other R² regimen trials in follicular or marginal zone lymphomas, the most common adverse reactions (occurring in at least 20% of patients) were neutropenia, fatigue, and constipation. These were manageable with dose adjustments and interruptions, and, in the opinion of authors, did not take away from the overall benefits seen.

The authors acknowledge that a limitation of this study was a lower assessment of median PFS in both arms by investigators than by independent reviewers. The independent review committee assessed PFS for R² at 39.4 months, whereas investigators assessed it at 25.4 months. The median PFS benefit remained at 14.1 months by both methods of assessment. This may highlight the differences of radiographic measurements in a central setting versus at individual centers.

Histologic transformation to a higher-grade aggressive lymphoma occurred in 2 patients in the R² arm and 10 patients in the placebo/rituximab arm. After transformation, 1 patient in the R² arm and 6 in the placebo plus rituximab arm died. A plausible mechanism for this variation has not been provided. If confirmed across a wider population, this may be one of the most significant benefits of the R² regimen.

Applications for Clinical Practice

Therapy for relapsed and refractory indolent B-cell lymphomas continues to evolve. While chemotherapy remains an effective option, immunomodulation using non-chemotherapeutic intervention has emerged as an attractive strategy. The AUGMENT trial further solidifies adoption of the non-chemotherapy doublet option of rituximab/lenalidomide based on the premise of immunomodulation. Both the agents have been commercially available for more than a decade and are being used for other indications beyond the study population for this trial.

Based on the AUGMENT and MAGNIFY trials, lenalidomide combined with rituximab was approved by the Food and Drug Administration for use in relapsed and refractory follicular or marginal zone lymphomas soon after the AUGMENT study results were published. The recommended lenalidomide dose for both lymphomas is 20 mg once daily orally on days 1 to 21 of repeated 28-day cycles for up to 12 cycles.

The evidence from this trial has yielded what is likely to be a practice changing regimen, with R² replacing single-agent rituximab for treating follicular lymphoma in the second line or beyond. The response rates and PFS periods were slightly lower in MZL. R² offers advantages associated with a chemotherapy-free regimen and improved PFS. Also, in the AUGEMENT trial the secondary and exploratory endpoints of time to next therapy, overall response rates, and overall survival rates were improved in patients treated with R².

Practitioners may choose lenalidomide plus rituximab over rituximab alone based on the AUGMENT study. When considering this regimen, several points should be kept in mind. A very careful selection of patients would be prudent, considering that the study’s follow-up of less than 4 years is short for a disease with long overall survival rates. The study was not powered to compare overall survival benefit. Also, practitioners are reminded to limit the use of lenalidomide to a maximum of 12 months, with planned interruptions and 8 doses of rituximab, replicating the trial schema. Additionally, as per the clinical trial design, the regimen is not intended for rituximab-refractory patients. Patients with MZL constituted only 18% of the study, and conclusions of superiority in this subgroup were not statistically significant. Lenalidomide is not approved for other indolent B cell lymphoproliferative malignancies, such as small lymphocytic lymphoma and chronic lymphocytic leukemia. The conclusion of the published study abstract suggests acceptable use in recurrent indolent lymphomas, but no such conclusion can be made due to lack of inclusion of all indolent lymphoma subtypes in this study.

Longer-term use of lenalidomide has been associated with a marginally increased risk of secondary hematologic malignancies in patients with multiple myeloma who were prescribed lenalidomide maintenance therapy for up to 2 years following high-dose chemotherapy and autologous hematopoietic stem cell transplant.⁹ Interestingly, in the AUGMENT study and other trials using lenalidomide/rituximab, no significant increase in secondary hematologic malignancies has been reported. The absence of prior myeloablative chemotherapy and a shorter duration of use (1 year) in this group of patients may be factors in why no additional risk of secondary hematologic malignancies was observed. Longer-term follow-up may be needed to evaluate this risk.

In the R² arm of this study, 55% patients experienced grades 3 and 4 neutropenia. With a median age of presentation for both follicular lymphoma and MZL of over 60 years, oncologists should remain aware of this potentially fatal complication, especially in the frail, the elderly, and previously treated individuals who may have a high risk of myelosuppression. Clinicians should be prepared to rapidly adopt strategies of dose interruption, dose reduction, and growth factor use, as implemented in the trial. Of note, despite the high rates of severe neutropenia, only 3% of the participants experienced febrile neutropenia, and 71% patients in R² group and 61% in rituximab group completed planned protocol therapy. Growth factor use was high at 36% in the R² group, which may have been responsible for a lower incidence of febrile neutropenia.

Increased toxicities of tumor flare, rash, and constipation were observed in the R² arm. Patients with greater than grade 1 neuropathy were excluded. For those at risk of thromboembolism, prophylactic anticoagulation or antiplatelet therapy was recommended in the trial. Lenalidomide dose was reduced to 10 mg for those with creatinine clearance of 30 to 59 mL/min.

The cost-effectiveness of lenalidomide/rituximab combination has not been fully studied against a sequential approach of using rituximab and lenalidomide for a limited number of cycles. The cost of a Revlimid 10-mg pill may be over $700.¹⁰ Costs associated with supportive care due to additional toxicities have not been quantified. For those with cost concerns or lack of insurance coverage, the R² regimen may be cost prohibitive without financial assistance from charities.

Indolent NHL remains mostly incurable. The R² approach is still not a curative one, and resources should be directed to investigate a cure for this population. Whenever feasible, participation in a clinical trial should be encouraged. Parameters have not been reported based on prognostic groups, and the study did not identify any biomarkers that may correlate with improved outcome. Perhaps a biomarker-based trial design may be most suitable in explaining the heterogeneity in follicular and marginal zone lymphomas.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To compare the efficacy and safety of lenalidomide in combination with rituximab (known as the R² regimen) to rituximab plus placebo in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL).

Design. Phase 3, multicenter, international, placebo controlled randomized trial.

Setting and participants. 358 patients with rituximab-sensitive relapsed or refractory grade 1-3a follicular lymphoma or MZL.

Intervention. Patients were randomly assigned 1:1 to receive lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5.

Main outcome measures. The primary endpoint was progression-free survival (PFS) as determined by independent radiology reviewers using intent-to-treat analysis. Secondary end points included overall response rate, complete response rate, duration of response, overall survival, event-free survival, and time to next anti-lymphoma therapy. Time to next chemotherapy treatment and histologic transformation were exploratory endpoints. Responses were assessed by participating investigators and independent reviewers. Computed tomography or magnetic resonance imaging was used to obtain tumor measurements. Positron emission tomography was not used. Complete remissions were confirmed by bone marrow biopsy, as bone marrow involvement is exceedingly common in these lymphomas. Gastrointestinal endoscopy was performed to obtain disease status if there was involvement by lymphoma initially.

Improvement in primary and secondary endpoints as well as extrapolatory endpoints were reported in the R² group. Primary efficacy analyses were conducted in the intention-to-treat population primary endpoint of PFS at 1-sided α = 0.025 level.

Main results. PFS was significantly improved for patients treated with the R² regimen compared to those who recieved placebo plus rituximab, with a hazard ratio of 0.46 (95% confidence interval [CI], 0.34-0.62; P < 0.001). Median duration of PFS in the R² group was 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months) in the rituximab/placebo group. Overall response in the R² group was 78% (95% CI, 71%-83%) versus 53% (95% CI, 46%-61%; P < 0.0001) in the rituximab/placebo group, with 34% (95% CI, 27%-41%) versus 18% (95% CI, 13%-25%) of patients achieving complete remission (P = 0.001). There were 15 deaths in the R² group versus 26 deaths in the rituximab/placebo group. Overall survival data is not mature yet.

Conclusion. The R² regimen was superior to rituximab and placebo in relapsed or recurrent follicular lymphomas. The regimen’s safety profile was acceptable, with higher events of usual and expected but manageable toxicities in the R² regimen compared to rituximab/placebo.

Commentary

Nearly half of non-Hodgkins lymphomas (NHLs) diagnosed in the United States are classified as indolent B-cell lymphomas.¹ Follicular lymphomas constitute about 50% of all indolent NHLs, while MZLs comprise less than 15%.¹ These slowly progressive B-cell lymphomas are currently considered treatable but have very low cure rates. Cure is primarily limited to early stage I/II disease and may be possible in less than half of patients by applying involved-field radiation therapy with curative intent.

More than two thirds of indolent lymphomas present in advanced stages (III-IV). Despite an advanced stage at presentation, initial chemoimmunotherapy can induce complete remission in nearly 60% of patients. Unfortunately, nearly all patients relapse over the next 10 years.² The wait-and-watch approach is a common strategy, and most patients are administered initial therapy or subsequent lines of therapy if they are symptomatic.² As such, for the majority of these patients, the goal of therapy is to minimize toxicities, preserve quality of life, treat symptoms, and achieve a long PFS without an attempt to cure. Following each line of therapy, patients often revert to watchful surveillance, sometimes for more than a decade. With additional subsequent lines of therapy, lymphoma tends to get more refractory to treatment.

A median survival of nearly 2 decades has been achieved in advanced follicular lymphomas^2,3 and MZL.⁴ However, wide variation in overall response, duration of response, and survival is reported based on the individual risk profile.

The drug of interest in the present study by Leonard and colleagues, lenalidomide, has immunomodulatory properties and antiproliferative effects, possibly related to its binding of the E3 ligase protein cereblon and subsequent ubiquitination of the transcription factors Aiolos and Ikaros.⁵ The benefits of combination lenalidomide/rituximab against follicular lymphoma in preclinical settings have been attributed to mechanisms mediated by tumor-infiltrating lymphocytes, natural killer cells, monocytes, and antibody-dependent cell-mediated toxicity.⁵ The combination has now been studied in first-line and subsequent lines of therapy for follicular lymphoma and MZL.⁶

RELEVANCE, a phase 3 trial, compared the R² regimen in the upfront setting in advanced follicular lymphoma with rituximab and chemotherapy combination (including CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVP [cyclophosphamide, vincristine, prednisone], and bendamustine).⁷ Efficacy outcomes were similar between the comparators and R² was noninferior. MAGNIFY, a phase 3b trial involving rituximab-sensitive and rituximab-refractory patients with previously treated follicular lymphoma and MZL, demonstrated an overall response rate of 73%, complete response rate of 45%, and median PFS of 36 months in patients who received the R² regimen and who entered a plan to receive maintenance with rituximab.⁸

The AUGMENT trial was conducted at 97 centers in the United States and 14 Asian and European countries; it enrolled 358 patients, 82% of whom had a follicular lymphoma, between February 13, 2014 and January 26, 2017. The study was well conducted. The R² regimen was compared to the often used second-line therapy of rituximab alone, and 1:1 randomization was done with stratification factors of prior rituximab use, marginal versus follicular histology, and time lapse of less than or greater than 2 years since last therapy. A limitation of this study is that it selected individuals with a better prognosis, as the study patients were not rituximab refractory and 57% had received only a single prior therapy.

As observed in other R² regimen trials in follicular or marginal zone lymphomas, the most common adverse reactions (occurring in at least 20% of patients) were neutropenia, fatigue, and constipation. These were manageable with dose adjustments and interruptions, and, in the opinion of authors, did not take away from the overall benefits seen.

The authors acknowledge that a limitation of this study was a lower assessment of median PFS in both arms by investigators than by independent reviewers. The independent review committee assessed PFS for R² at 39.4 months, whereas investigators assessed it at 25.4 months. The median PFS benefit remained at 14.1 months by both methods of assessment. This may highlight the differences of radiographic measurements in a central setting versus at individual centers.

Histologic transformation to a higher-grade aggressive lymphoma occurred in 2 patients in the R² arm and 10 patients in the placebo/rituximab arm. After transformation, 1 patient in the R² arm and 6 in the placebo plus rituximab arm died. A plausible mechanism for this variation has not been provided. If confirmed across a wider population, this may be one of the most significant benefits of the R² regimen.

Applications for Clinical Practice

Therapy for relapsed and refractory indolent B-cell lymphomas continues to evolve. While chemotherapy remains an effective option, immunomodulation using non-chemotherapeutic intervention has emerged as an attractive strategy. The AUGMENT trial further solidifies adoption of the non-chemotherapy doublet option of rituximab/lenalidomide based on the premise of immunomodulation. Both the agents have been commercially available for more than a decade and are being used for other indications beyond the study population for this trial.

Based on the AUGMENT and MAGNIFY trials, lenalidomide combined with rituximab was approved by the Food and Drug Administration for use in relapsed and refractory follicular or marginal zone lymphomas soon after the AUGMENT study results were published. The recommended lenalidomide dose for both lymphomas is 20 mg once daily orally on days 1 to 21 of repeated 28-day cycles for up to 12 cycles.

The evidence from this trial has yielded what is likely to be a practice changing regimen, with R² replacing single-agent rituximab for treating follicular lymphoma in the second line or beyond. The response rates and PFS periods were slightly lower in MZL. R² offers advantages associated with a chemotherapy-free regimen and improved PFS. Also, in the AUGEMENT trial the secondary and exploratory endpoints of time to next therapy, overall response rates, and overall survival rates were improved in patients treated with R².

Practitioners may choose lenalidomide plus rituximab over rituximab alone based on the AUGMENT study. When considering this regimen, several points should be kept in mind. A very careful selection of patients would be prudent, considering that the study’s follow-up of less than 4 years is short for a disease with long overall survival rates. The study was not powered to compare overall survival benefit. Also, practitioners are reminded to limit the use of lenalidomide to a maximum of 12 months, with planned interruptions and 8 doses of rituximab, replicating the trial schema. Additionally, as per the clinical trial design, the regimen is not intended for rituximab-refractory patients. Patients with MZL constituted only 18% of the study, and conclusions of superiority in this subgroup were not statistically significant. Lenalidomide is not approved for other indolent B cell lymphoproliferative malignancies, such as small lymphocytic lymphoma and chronic lymphocytic leukemia. The conclusion of the published study abstract suggests acceptable use in recurrent indolent lymphomas, but no such conclusion can be made due to lack of inclusion of all indolent lymphoma subtypes in this study.

Longer-term use of lenalidomide has been associated with a marginally increased risk of secondary hematologic malignancies in patients with multiple myeloma who were prescribed lenalidomide maintenance therapy for up to 2 years following high-dose chemotherapy and autologous hematopoietic stem cell transplant.⁹ Interestingly, in the AUGMENT study and other trials using lenalidomide/rituximab, no significant increase in secondary hematologic malignancies has been reported. The absence of prior myeloablative chemotherapy and a shorter duration of use (1 year) in this group of patients may be factors in why no additional risk of secondary hematologic malignancies was observed. Longer-term follow-up may be needed to evaluate this risk.

In the R² arm of this study, 55% patients experienced grades 3 and 4 neutropenia. With a median age of presentation for both follicular lymphoma and MZL of over 60 years, oncologists should remain aware of this potentially fatal complication, especially in the frail, the elderly, and previously treated individuals who may have a high risk of myelosuppression. Clinicians should be prepared to rapidly adopt strategies of dose interruption, dose reduction, and growth factor use, as implemented in the trial. Of note, despite the high rates of severe neutropenia, only 3% of the participants experienced febrile neutropenia, and 71% patients in R² group and 61% in rituximab group completed planned protocol therapy. Growth factor use was high at 36% in the R² group, which may have been responsible for a lower incidence of febrile neutropenia.

Increased toxicities of tumor flare, rash, and constipation were observed in the R² arm. Patients with greater than grade 1 neuropathy were excluded. For those at risk of thromboembolism, prophylactic anticoagulation or antiplatelet therapy was recommended in the trial. Lenalidomide dose was reduced to 10 mg for those with creatinine clearance of 30 to 59 mL/min.

The cost-effectiveness of lenalidomide/rituximab combination has not been fully studied against a sequential approach of using rituximab and lenalidomide for a limited number of cycles. The cost of a Revlimid 10-mg pill may be over $700.¹⁰ Costs associated with supportive care due to additional toxicities have not been quantified. For those with cost concerns or lack of insurance coverage, the R² regimen may be cost prohibitive without financial assistance from charities.

Indolent NHL remains mostly incurable. The R² approach is still not a curative one, and resources should be directed to investigate a cure for this population. Whenever feasible, participation in a clinical trial should be encouraged. Parameters have not been reported based on prognostic groups, and the study did not identify any biomarkers that may correlate with improved outcome. Perhaps a biomarker-based trial design may be most suitable in explaining the heterogeneity in follicular and marginal zone lymphomas.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

Study Overview

Objective. To compare the efficacy and safety of lenalidomide in combination with rituximab (known as the R² regimen) to rituximab plus placebo in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL).

Design. Phase 3, multicenter, international, placebo controlled randomized trial.

Setting and participants. 358 patients with rituximab-sensitive relapsed or refractory grade 1-3a follicular lymphoma or MZL.

Intervention. Patients were randomly assigned 1:1 to receive lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5.

Main outcome measures. The primary endpoint was progression-free survival (PFS) as determined by independent radiology reviewers using intent-to-treat analysis. Secondary end points included overall response rate, complete response rate, duration of response, overall survival, event-free survival, and time to next anti-lymphoma therapy. Time to next chemotherapy treatment and histologic transformation were exploratory endpoints. Responses were assessed by participating investigators and independent reviewers. Computed tomography or magnetic resonance imaging was used to obtain tumor measurements. Positron emission tomography was not used. Complete remissions were confirmed by bone marrow biopsy, as bone marrow involvement is exceedingly common in these lymphomas. Gastrointestinal endoscopy was performed to obtain disease status if there was involvement by lymphoma initially.

Improvement in primary and secondary endpoints as well as extrapolatory endpoints were reported in the R² group. Primary efficacy analyses were conducted in the intention-to-treat population primary endpoint of PFS at 1-sided α = 0.025 level.

Main results. PFS was significantly improved for patients treated with the R² regimen compared to those who recieved placebo plus rituximab, with a hazard ratio of 0.46 (95% confidence interval [CI], 0.34-0.62; P < 0.001). Median duration of PFS in the R² group was 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months) in the rituximab/placebo group. Overall response in the R² group was 78% (95% CI, 71%-83%) versus 53% (95% CI, 46%-61%; P < 0.0001) in the rituximab/placebo group, with 34% (95% CI, 27%-41%) versus 18% (95% CI, 13%-25%) of patients achieving complete remission (P = 0.001). There were 15 deaths in the R² group versus 26 deaths in the rituximab/placebo group. Overall survival data is not mature yet.

Conclusion. The R² regimen was superior to rituximab and placebo in relapsed or recurrent follicular lymphomas. The regimen’s safety profile was acceptable, with higher events of usual and expected but manageable toxicities in the R² regimen compared to rituximab/placebo.

Commentary

Nearly half of non-Hodgkins lymphomas (NHLs) diagnosed in the United States are classified as indolent B-cell lymphomas.¹ Follicular lymphomas constitute about 50% of all indolent NHLs, while MZLs comprise less than 15%.¹ These slowly progressive B-cell lymphomas are currently considered treatable but have very low cure rates. Cure is primarily limited to early stage I/II disease and may be possible in less than half of patients by applying involved-field radiation therapy with curative intent.

More than two thirds of indolent lymphomas present in advanced stages (III-IV). Despite an advanced stage at presentation, initial chemoimmunotherapy can induce complete remission in nearly 60% of patients. Unfortunately, nearly all patients relapse over the next 10 years.² The wait-and-watch approach is a common strategy, and most patients are administered initial therapy or subsequent lines of therapy if they are symptomatic.² As such, for the majority of these patients, the goal of therapy is to minimize toxicities, preserve quality of life, treat symptoms, and achieve a long PFS without an attempt to cure. Following each line of therapy, patients often revert to watchful surveillance, sometimes for more than a decade. With additional subsequent lines of therapy, lymphoma tends to get more refractory to treatment.

A median survival of nearly 2 decades has been achieved in advanced follicular lymphomas^2,3 and MZL.⁴ However, wide variation in overall response, duration of response, and survival is reported based on the individual risk profile.

The drug of interest in the present study by Leonard and colleagues, lenalidomide, has immunomodulatory properties and antiproliferative effects, possibly related to its binding of the E3 ligase protein cereblon and subsequent ubiquitination of the transcription factors Aiolos and Ikaros.⁵ The benefits of combination lenalidomide/rituximab against follicular lymphoma in preclinical settings have been attributed to mechanisms mediated by tumor-infiltrating lymphocytes, natural killer cells, monocytes, and antibody-dependent cell-mediated toxicity.⁵ The combination has now been studied in first-line and subsequent lines of therapy for follicular lymphoma and MZL.⁶

RELEVANCE, a phase 3 trial, compared the R² regimen in the upfront setting in advanced follicular lymphoma with rituximab and chemotherapy combination (including CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVP [cyclophosphamide, vincristine, prednisone], and bendamustine).⁷ Efficacy outcomes were similar between the comparators and R² was noninferior. MAGNIFY, a phase 3b trial involving rituximab-sensitive and rituximab-refractory patients with previously treated follicular lymphoma and MZL, demonstrated an overall response rate of 73%, complete response rate of 45%, and median PFS of 36 months in patients who received the R² regimen and who entered a plan to receive maintenance with rituximab.⁸

The AUGMENT trial was conducted at 97 centers in the United States and 14 Asian and European countries; it enrolled 358 patients, 82% of whom had a follicular lymphoma, between February 13, 2014 and January 26, 2017. The study was well conducted. The R² regimen was compared to the often used second-line therapy of rituximab alone, and 1:1 randomization was done with stratification factors of prior rituximab use, marginal versus follicular histology, and time lapse of less than or greater than 2 years since last therapy. A limitation of this study is that it selected individuals with a better prognosis, as the study patients were not rituximab refractory and 57% had received only a single prior therapy.

As observed in other R² regimen trials in follicular or marginal zone lymphomas, the most common adverse reactions (occurring in at least 20% of patients) were neutropenia, fatigue, and constipation. These were manageable with dose adjustments and interruptions, and, in the opinion of authors, did not take away from the overall benefits seen.

The authors acknowledge that a limitation of this study was a lower assessment of median PFS in both arms by investigators than by independent reviewers. The independent review committee assessed PFS for R² at 39.4 months, whereas investigators assessed it at 25.4 months. The median PFS benefit remained at 14.1 months by both methods of assessment. This may highlight the differences of radiographic measurements in a central setting versus at individual centers.

Histologic transformation to a higher-grade aggressive lymphoma occurred in 2 patients in the R² arm and 10 patients in the placebo/rituximab arm. After transformation, 1 patient in the R² arm and 6 in the placebo plus rituximab arm died. A plausible mechanism for this variation has not been provided. If confirmed across a wider population, this may be one of the most significant benefits of the R² regimen.

Applications for Clinical Practice

Therapy for relapsed and refractory indolent B-cell lymphomas continues to evolve. While chemotherapy remains an effective option, immunomodulation using non-chemotherapeutic intervention has emerged as an attractive strategy. The AUGMENT trial further solidifies adoption of the non-chemotherapy doublet option of rituximab/lenalidomide based on the premise of immunomodulation. Both the agents have been commercially available for more than a decade and are being used for other indications beyond the study population for this trial.

Based on the AUGMENT and MAGNIFY trials, lenalidomide combined with rituximab was approved by the Food and Drug Administration for use in relapsed and refractory follicular or marginal zone lymphomas soon after the AUGMENT study results were published. The recommended lenalidomide dose for both lymphomas is 20 mg once daily orally on days 1 to 21 of repeated 28-day cycles for up to 12 cycles.

The evidence from this trial has yielded what is likely to be a practice changing regimen, with R² replacing single-agent rituximab for treating follicular lymphoma in the second line or beyond. The response rates and PFS periods were slightly lower in MZL. R² offers advantages associated with a chemotherapy-free regimen and improved PFS. Also, in the AUGEMENT trial the secondary and exploratory endpoints of time to next therapy, overall response rates, and overall survival rates were improved in patients treated with R².

Practitioners may choose lenalidomide plus rituximab over rituximab alone based on the AUGMENT study. When considering this regimen, several points should be kept in mind. A very careful selection of patients would be prudent, considering that the study’s follow-up of less than 4 years is short for a disease with long overall survival rates. The study was not powered to compare overall survival benefit. Also, practitioners are reminded to limit the use of lenalidomide to a maximum of 12 months, with planned interruptions and 8 doses of rituximab, replicating the trial schema. Additionally, as per the clinical trial design, the regimen is not intended for rituximab-refractory patients. Patients with MZL constituted only 18% of the study, and conclusions of superiority in this subgroup were not statistically significant. Lenalidomide is not approved for other indolent B cell lymphoproliferative malignancies, such as small lymphocytic lymphoma and chronic lymphocytic leukemia. The conclusion of the published study abstract suggests acceptable use in recurrent indolent lymphomas, but no such conclusion can be made due to lack of inclusion of all indolent lymphoma subtypes in this study.

Longer-term use of lenalidomide has been associated with a marginally increased risk of secondary hematologic malignancies in patients with multiple myeloma who were prescribed lenalidomide maintenance therapy for up to 2 years following high-dose chemotherapy and autologous hematopoietic stem cell transplant.⁹ Interestingly, in the AUGMENT study and other trials using lenalidomide/rituximab, no significant increase in secondary hematologic malignancies has been reported. The absence of prior myeloablative chemotherapy and a shorter duration of use (1 year) in this group of patients may be factors in why no additional risk of secondary hematologic malignancies was observed. Longer-term follow-up may be needed to evaluate this risk.

In the R² arm of this study, 55% patients experienced grades 3 and 4 neutropenia. With a median age of presentation for both follicular lymphoma and MZL of over 60 years, oncologists should remain aware of this potentially fatal complication, especially in the frail, the elderly, and previously treated individuals who may have a high risk of myelosuppression. Clinicians should be prepared to rapidly adopt strategies of dose interruption, dose reduction, and growth factor use, as implemented in the trial. Of note, despite the high rates of severe neutropenia, only 3% of the participants experienced febrile neutropenia, and 71% patients in R² group and 61% in rituximab group completed planned protocol therapy. Growth factor use was high at 36% in the R² group, which may have been responsible for a lower incidence of febrile neutropenia.

Increased toxicities of tumor flare, rash, and constipation were observed in the R² arm. Patients with greater than grade 1 neuropathy were excluded. For those at risk of thromboembolism, prophylactic anticoagulation or antiplatelet therapy was recommended in the trial. Lenalidomide dose was reduced to 10 mg for those with creatinine clearance of 30 to 59 mL/min.

The cost-effectiveness of lenalidomide/rituximab combination has not been fully studied against a sequential approach of using rituximab and lenalidomide for a limited number of cycles. The cost of a Revlimid 10-mg pill may be over $700.¹⁰ Costs associated with supportive care due to additional toxicities have not been quantified. For those with cost concerns or lack of insurance coverage, the R² regimen may be cost prohibitive without financial assistance from charities.

Indolent NHL remains mostly incurable. The R² approach is still not a curative one, and resources should be directed to investigate a cure for this population. Whenever feasible, participation in a clinical trial should be encouraged. Parameters have not been reported based on prognostic groups, and the study did not identify any biomarkers that may correlate with improved outcome. Perhaps a biomarker-based trial design may be most suitable in explaining the heterogeneity in follicular and marginal zone lymphomas.

—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS

SAN DIEGO – Mental health professionals can lower the risk of legal exposure from patients filing malpractice suits through proper assessment and proper documentation, a psychiatrist said at the annual Psych Congress.

“You don’t have to have a perfect performance, but you do have to gather relevant data. And you’ll be judged on whether you took reasonable precautions once you identified the risk,” said Phillip J. Resnick, MD, professor of psychiatry at Case Western Reserve University, Cleveland.

Research suggests that 35% of malpractice claims involve incorrect treatment and 19% involve medication problems. More than half of all U.S. physicians reportedly have been sued, and psychiatrists are named in lawsuits less often than other medical specialists.

What’s “reasonable” in terms of assessment and precautions? In the past, courts may have held to a community standard: Did you provide the usual care that others in your region would provide? This approach allowed physicians to avoid responsibility if “you could prove that the majority of [local] doctors do what you did,” Dr. Resnick said, even if they’re “sloppy and bad.”

A newer, “reasonably prudent practitioner” standard expects medical professionals to do the right thing no matter where they live. “You have to do what a prudent practitioner would do whether others in your community are doing it or not,” said Dr. Resnick, who has consulted on numerous well-known cases, including that of Jeffrey Dahmer, Susan Smith, Timothy McVey, and Theodore Kaczynski.

Psychiatrists can be vulnerable legally if they refuse to respond to concerns from family members, Dr. Resnick said. The best approach is to listen. “You don’t need permission to listen – only to release information. You can always listen.”

Dr. Resnick is a former president of the American Academy of Psychiatry and the Law. He has no disclosures.

SAN DIEGO – Mental health professionals can lower the risk of legal exposure from patients filing malpractice suits through proper assessment and proper documentation, a psychiatrist said at the annual Psych Congress.

“You don’t have to have a perfect performance, but you do have to gather relevant data. And you’ll be judged on whether you took reasonable precautions once you identified the risk,” said Phillip J. Resnick, MD, professor of psychiatry at Case Western Reserve University, Cleveland.

Research suggests that 35% of malpractice claims involve incorrect treatment and 19% involve medication problems. More than half of all U.S. physicians reportedly have been sued, and psychiatrists are named in lawsuits less often than other medical specialists.

What’s “reasonable” in terms of assessment and precautions? In the past, courts may have held to a community standard: Did you provide the usual care that others in your region would provide? This approach allowed physicians to avoid responsibility if “you could prove that the majority of [local] doctors do what you did,” Dr. Resnick said, even if they’re “sloppy and bad.”

A newer, “reasonably prudent practitioner” standard expects medical professionals to do the right thing no matter where they live. “You have to do what a prudent practitioner would do whether others in your community are doing it or not,” said Dr. Resnick, who has consulted on numerous well-known cases, including that of Jeffrey Dahmer, Susan Smith, Timothy McVey, and Theodore Kaczynski.

Psychiatrists can be vulnerable legally if they refuse to respond to concerns from family members, Dr. Resnick said. The best approach is to listen. “You don’t need permission to listen – only to release information. You can always listen.”

Dr. Resnick is a former president of the American Academy of Psychiatry and the Law. He has no disclosures.

SAN DIEGO – Mental health professionals can lower the risk of legal exposure from patients filing malpractice suits through proper assessment and proper documentation, a psychiatrist said at the annual Psych Congress.

“You don’t have to have a perfect performance, but you do have to gather relevant data. And you’ll be judged on whether you took reasonable precautions once you identified the risk,” said Phillip J. Resnick, MD, professor of psychiatry at Case Western Reserve University, Cleveland.

Research suggests that 35% of malpractice claims involve incorrect treatment and 19% involve medication problems. More than half of all U.S. physicians reportedly have been sued, and psychiatrists are named in lawsuits less often than other medical specialists.

What’s “reasonable” in terms of assessment and precautions? In the past, courts may have held to a community standard: Did you provide the usual care that others in your region would provide? This approach allowed physicians to avoid responsibility if “you could prove that the majority of [local] doctors do what you did,” Dr. Resnick said, even if they’re “sloppy and bad.”

A newer, “reasonably prudent practitioner” standard expects medical professionals to do the right thing no matter where they live. “You have to do what a prudent practitioner would do whether others in your community are doing it or not,” said Dr. Resnick, who has consulted on numerous well-known cases, including that of Jeffrey Dahmer, Susan Smith, Timothy McVey, and Theodore Kaczynski.

Psychiatrists can be vulnerable legally if they refuse to respond to concerns from family members, Dr. Resnick said. The best approach is to listen. “You don’t need permission to listen – only to release information. You can always listen.”

Dr. Resnick is a former president of the American Academy of Psychiatry and the Law. He has no disclosures.

WASHINGTON – The top existential threats to health today are climate change and overpopulation, but third in this list is antimicrobial resistance, according to Helen Boucher, MD, of Tufts Medical Center, Boston. In her talk at an annual scientific meeting on infectious diseases, however, she focused on the last, presenting the hottest developments in the clinical science of treating and identifying disease-causing agents.

In particular, she discussed two of the most important developments in the area of rapid diagnostics: cell-free microbial DNA in plasma and the use of next-generation gene sequencing for determining disease etiology.

Using a meta-genomics test, cell-free microbial DNA can be identified in plasma from more than 1,000 relevant bacteria, DNA viruses, fungi, and parasites. Though importantly, RNA viruses are not detectable using this technology, she added. Although current sampling is of plasma, this might expand to the ability to use urine in the future. She discussed its particular use in sepsis, as outlined in a paper in Nature Microbiology (2019;4[4]:663-74). The researchers examined 350 suspected sepsis patients and they found a 93% sensitivity, compared with reference standards, using this new test. The main issue with the test was a high incidence of false positives.

Another test Dr. Boucher discussed was the use of meta-genomic next-generation sequencing. She referred to a 2019 paper in the New England Journal of Medicine, which discussed the use of clinical meta-genomic next-generation sequencing of cerebrospinal fluid for the diagnosis of meningitis and encephalitis (2019;380[27]:2327-40). Next-generation sequencing identified 13% of patients positive who were missed using standard screening. However, a number of patients were not diagnosed using the new test, showing that this technique was an improvement over current methods, but not 100% successful.

Dr. Boucher stressed the need for “diagnostic stewardship” to identify the correct microbial agent causing disease, allowing for the use of appropriate treatment rather than shotgun approaches to prevent the development of antibiotic resistance. This practice requires collaboration between the clinical laboratory, pharmacists, and infectious disease specialists.

Dr. Boucher then switched to the area of therapeutics, focusing on the introduction of new antibiotics and other innovations in disease treatment methodologies, especially in the field of transplant ID.

“We have new drugs. That is the good news,” with the goals of the 10 x ’20 initiative to develop 10 new systemic antibiotics by 2020, having “been met and then some,” said Dr. Boucher.

“We now have 13 new drugs, systemically available antibiotics, available by August 2019,” she added, discussing several of the new drugs.

In addition, she pointed out several studies that have indicated that shorter courses of antibiotics are better than longer, and that, in many cases, oral therapy is better than intravenous.

In the burgeoning area of transplant ID studies, Dr. Boucher discussed new research showing that vaccinations in transplanted patients can be advised in several instances, though may require higher dosing, and how the use of hepatitis C virus–positive organs for transplant is showing good results and increasing the availability of organs for transplant.

Dr. Boucher has served on data review committees for Actelion and Medtronix and has served as a consultant/advisor for Cerexa, Durata Therapeutics, Merck (adjudication committee), Rib-X, and Wyeth/Pfizer (data safety monitoring committee).

[email protected]

WASHINGTON – The top existential threats to health today are climate change and overpopulation, but third in this list is antimicrobial resistance, according to Helen Boucher, MD, of Tufts Medical Center, Boston. In her talk at an annual scientific meeting on infectious diseases, however, she focused on the last, presenting the hottest developments in the clinical science of treating and identifying disease-causing agents.

In particular, she discussed two of the most important developments in the area of rapid diagnostics: cell-free microbial DNA in plasma and the use of next-generation gene sequencing for determining disease etiology.

Using a meta-genomics test, cell-free microbial DNA can be identified in plasma from more than 1,000 relevant bacteria, DNA viruses, fungi, and parasites. Though importantly, RNA viruses are not detectable using this technology, she added. Although current sampling is of plasma, this might expand to the ability to use urine in the future. She discussed its particular use in sepsis, as outlined in a paper in Nature Microbiology (2019;4[4]:663-74). The researchers examined 350 suspected sepsis patients and they found a 93% sensitivity, compared with reference standards, using this new test. The main issue with the test was a high incidence of false positives.

Another test Dr. Boucher discussed was the use of meta-genomic next-generation sequencing. She referred to a 2019 paper in the New England Journal of Medicine, which discussed the use of clinical meta-genomic next-generation sequencing of cerebrospinal fluid for the diagnosis of meningitis and encephalitis (2019;380[27]:2327-40). Next-generation sequencing identified 13% of patients positive who were missed using standard screening. However, a number of patients were not diagnosed using the new test, showing that this technique was an improvement over current methods, but not 100% successful.

Dr. Boucher stressed the need for “diagnostic stewardship” to identify the correct microbial agent causing disease, allowing for the use of appropriate treatment rather than shotgun approaches to prevent the development of antibiotic resistance. This practice requires collaboration between the clinical laboratory, pharmacists, and infectious disease specialists.

Dr. Boucher then switched to the area of therapeutics, focusing on the introduction of new antibiotics and other innovations in disease treatment methodologies, especially in the field of transplant ID.

“We have new drugs. That is the good news,” with the goals of the 10 x ’20 initiative to develop 10 new systemic antibiotics by 2020, having “been met and then some,” said Dr. Boucher.

“We now have 13 new drugs, systemically available antibiotics, available by August 2019,” she added, discussing several of the new drugs.

In addition, she pointed out several studies that have indicated that shorter courses of antibiotics are better than longer, and that, in many cases, oral therapy is better than intravenous.

In the burgeoning area of transplant ID studies, Dr. Boucher discussed new research showing that vaccinations in transplanted patients can be advised in several instances, though may require higher dosing, and how the use of hepatitis C virus–positive organs for transplant is showing good results and increasing the availability of organs for transplant.

Dr. Boucher has served on data review committees for Actelion and Medtronix and has served as a consultant/advisor for Cerexa, Durata Therapeutics, Merck (adjudication committee), Rib-X, and Wyeth/Pfizer (data safety monitoring committee).

[email protected]

WASHINGTON – The top existential threats to health today are climate change and overpopulation, but third in this list is antimicrobial resistance, according to Helen Boucher, MD, of Tufts Medical Center, Boston. In her talk at an annual scientific meeting on infectious diseases, however, she focused on the last, presenting the hottest developments in the clinical science of treating and identifying disease-causing agents.

In particular, she discussed two of the most important developments in the area of rapid diagnostics: cell-free microbial DNA in plasma and the use of next-generation gene sequencing for determining disease etiology.

Using a meta-genomics test, cell-free microbial DNA can be identified in plasma from more than 1,000 relevant bacteria, DNA viruses, fungi, and parasites. Though importantly, RNA viruses are not detectable using this technology, she added. Although current sampling is of plasma, this might expand to the ability to use urine in the future. She discussed its particular use in sepsis, as outlined in a paper in Nature Microbiology (2019;4[4]:663-74). The researchers examined 350 suspected sepsis patients and they found a 93% sensitivity, compared with reference standards, using this new test. The main issue with the test was a high incidence of false positives.

Another test Dr. Boucher discussed was the use of meta-genomic next-generation sequencing. She referred to a 2019 paper in the New England Journal of Medicine, which discussed the use of clinical meta-genomic next-generation sequencing of cerebrospinal fluid for the diagnosis of meningitis and encephalitis (2019;380[27]:2327-40). Next-generation sequencing identified 13% of patients positive who were missed using standard screening. However, a number of patients were not diagnosed using the new test, showing that this technique was an improvement over current methods, but not 100% successful.

Dr. Boucher stressed the need for “diagnostic stewardship” to identify the correct microbial agent causing disease, allowing for the use of appropriate treatment rather than shotgun approaches to prevent the development of antibiotic resistance. This practice requires collaboration between the clinical laboratory, pharmacists, and infectious disease specialists.

Dr. Boucher then switched to the area of therapeutics, focusing on the introduction of new antibiotics and other innovations in disease treatment methodologies, especially in the field of transplant ID.

“We have new drugs. That is the good news,” with the goals of the 10 x ’20 initiative to develop 10 new systemic antibiotics by 2020, having “been met and then some,” said Dr. Boucher.

“We now have 13 new drugs, systemically available antibiotics, available by August 2019,” she added, discussing several of the new drugs.

In addition, she pointed out several studies that have indicated that shorter courses of antibiotics are better than longer, and that, in many cases, oral therapy is better than intravenous.

In the burgeoning area of transplant ID studies, Dr. Boucher discussed new research showing that vaccinations in transplanted patients can be advised in several instances, though may require higher dosing, and how the use of hepatitis C virus–positive organs for transplant is showing good results and increasing the availability of organs for transplant.

Dr. Boucher has served on data review committees for Actelion and Medtronix and has served as a consultant/advisor for Cerexa, Durata Therapeutics, Merck (adjudication committee), Rib-X, and Wyeth/Pfizer (data safety monitoring committee).

[email protected]

Stray radiation exposure could be responsible for up to 28% of the contralateral breast cancer that occurs years after radiotherapy of the primary tumor.

The risk is highest among women initially treated when younger than 40 years, who had at lest 5 years’ lapse between the first and second occurrences, and had a higher genetic risk score, Gordon P. Watt, PhD, and colleagues reported in JAMA Network Open.

“These findings may support clinical decision making related to radiation treatment, particularly among women for whom other modalities may be considered,” wrote Dr. Watt of Memorial Sloan Kettering Cancer Center, New York, and coauthors. “For example, young women with a high [genetic risk] may consider partial-breast radiation therapy, rather than whole-breast radiation therapy when appropriate, opt for radiation therapy techniques that reduce integral dose (e.g., proton beam), or decide for non–radiation therapy–based locoregional management (e.g., mastectomy). These findings may be especially important in younger women with medially located breast cancers, where the scatter dose to the contralateral breast is likely to be higher.”

The investigators enrolled women who received a diagnosis for a first invasive local or regional breast cancer when they were younger than 55 years in a case-control study to investigate whether the NHEJ genetic risk score (GRS) could predict a woman’s risk of developing contralateral breast cancer after irradiation of a primary breast cancer. The risk score comprises 93 single nucleotide polymorphisms (SNPs) located in or near the seven genes in the NHEJ pathway, including DCLRE1C, LIG4, NHEJ1, PRKDC, XRCC4, XRCC5, and XRCC6. Dr. Watts’ team investigated risks associated with 69 of the SNPs.

The study comprised 3,732 women who were recruited from 2000 to 2012, with primary diagnosis occurring from 1985 to 2008. Of these, 1,521 had contralateral breast cancer; the remainder had unilateral disease and were used as controls.

At first diagnosis, they were aged a median of 46 years, although age ranged from 23 to 54 years. Most of the primary tumors (84%) were ductal. Among the recurrences, 9% were in situ, 63% local, 23% regional, and 2% distant. Stage was unknown on the remainder. Among these recurrent tumors, 54% were estrogen receptor positive and 24% were progesterone receptor positive, with unknown status on the remainder.

For women aged younger than 40 years at the time of the primary tumor, and at least 5 years out from treatment, radiation increased the risk of contralateral disease by 70%. But there was no significant risk to younger women with less than 5 years’ latency, or to women diagnosed at 40 years or older regardless of the time since treatment.

Age played a similar role when considering location-specific stray radiation dose. The risk was doubled in younger women who were exposed to at least 1 Gy and at least 5 years out from treatment, but there was no significantly increased risk to women older at first diagnosis.

Nor were the individual SNPs associated with increased risk. “The NHEJ GRS was approximately normally distributed and was dichotomized at the overall median for analysis; the median (range) GRS in the case group was 75 alleles and the median GRS in the control group was 74 alleles,” the investigators wrote.

But when examined by total GRS score, differences emerged.

“In the high NHEJ GRS group, among women who received the first diagnosis when they were younger than 40 years with a latency of 5 years or more, a stray radiation dose of 1.0 Gy or more was associated with threefold greater contralateral breast cancer risk, compared with no radiation exposure. In contrast, for women with an NHEJ GRS of 74 alleles or fewer in the same age and latency group, there was no association between radiation dose and contralateral breast cancer,” they wrote.

Again, there was no increased risk for women aged older than 40 years at first diagnosis.

“Based on these results, after a latency of 5 years or longer among women who received their first breast cancer diagnosis when they were younger than 40 years with a high NHEJ GRS, the population-attributable risk fraction of contralateral breast cancer attributable to stray radiation exposure to the contralateral breast was 28%. The corresponding population attributable risk fraction among women who received their first diagnosis when they were younger than 40 years after a latency of 5 years or more with a low NHEJ GRS was 18%,” the investigators wrote.

Five of the seven NHEJ pathway genes appeared to be driving these increased risks: LIG4, NHEJ1, XRCC4, XRCC5, and XRCC6. The expression quantitative trait loci (eQTLs) in each gene were always associated with a single direction of association; all risk alleles in XRCC4 were associated with decreased expression and all risk alleles in LIG4 were associated with increased expression.

“The consistent association of multiple NHEJ GRS risk alleles with eQTLs in a single direction suggests that the NHEJ GRS may be capturing the effect of SNP alleles on the transcription of one or more genes in the NHEJ pathway. This supports the hypothesis that the variation in this pathway may alter double-stranded DNA damage response, thereby increasing the risk of tumor development. However, the results from [the Genotype-Tissue Expression database] are drawn from multiple tissues that may not be appropriate proxies for breast tissue and the impact of genetic variation in the overall NHEJ pathway is likely to be complex,” the investigators wrote.

Dr. Watt had no financial disclosures. The research was funded by the National Cancer Institute.

SOURCE: Watt GP et al. JAMA Netw Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.12259.

Stray radiation exposure could be responsible for up to 28% of the contralateral breast cancer that occurs years after radiotherapy of the primary tumor.

The risk is highest among women initially treated when younger than 40 years, who had at lest 5 years’ lapse between the first and second occurrences, and had a higher genetic risk score, Gordon P. Watt, PhD, and colleagues reported in JAMA Network Open.

“These findings may support clinical decision making related to radiation treatment, particularly among women for whom other modalities may be considered,” wrote Dr. Watt of Memorial Sloan Kettering Cancer Center, New York, and coauthors. “For example, young women with a high [genetic risk] may consider partial-breast radiation therapy, rather than whole-breast radiation therapy when appropriate, opt for radiation therapy techniques that reduce integral dose (e.g., proton beam), or decide for non–radiation therapy–based locoregional management (e.g., mastectomy). These findings may be especially important in younger women with medially located breast cancers, where the scatter dose to the contralateral breast is likely to be higher.”

The investigators enrolled women who received a diagnosis for a first invasive local or regional breast cancer when they were younger than 55 years in a case-control study to investigate whether the NHEJ genetic risk score (GRS) could predict a woman’s risk of developing contralateral breast cancer after irradiation of a primary breast cancer. The risk score comprises 93 single nucleotide polymorphisms (SNPs) located in or near the seven genes in the NHEJ pathway, including DCLRE1C, LIG4, NHEJ1, PRKDC, XRCC4, XRCC5, and XRCC6. Dr. Watts’ team investigated risks associated with 69 of the SNPs.

The study comprised 3,732 women who were recruited from 2000 to 2012, with primary diagnosis occurring from 1985 to 2008. Of these, 1,521 had contralateral breast cancer; the remainder had unilateral disease and were used as controls.

At first diagnosis, they were aged a median of 46 years, although age ranged from 23 to 54 years. Most of the primary tumors (84%) were ductal. Among the recurrences, 9% were in situ, 63% local, 23% regional, and 2% distant. Stage was unknown on the remainder. Among these recurrent tumors, 54% were estrogen receptor positive and 24% were progesterone receptor positive, with unknown status on the remainder.

For women aged younger than 40 years at the time of the primary tumor, and at least 5 years out from treatment, radiation increased the risk of contralateral disease by 70%. But there was no significant risk to younger women with less than 5 years’ latency, or to women diagnosed at 40 years or older regardless of the time since treatment.

Age played a similar role when considering location-specific stray radiation dose. The risk was doubled in younger women who were exposed to at least 1 Gy and at least 5 years out from treatment, but there was no significantly increased risk to women older at first diagnosis.

Nor were the individual SNPs associated with increased risk. “The NHEJ GRS was approximately normally distributed and was dichotomized at the overall median for analysis; the median (range) GRS in the case group was 75 alleles and the median GRS in the control group was 74 alleles,” the investigators wrote.

But when examined by total GRS score, differences emerged.

“In the high NHEJ GRS group, among women who received the first diagnosis when they were younger than 40 years with a latency of 5 years or more, a stray radiation dose of 1.0 Gy or more was associated with threefold greater contralateral breast cancer risk, compared with no radiation exposure. In contrast, for women with an NHEJ GRS of 74 alleles or fewer in the same age and latency group, there was no association between radiation dose and contralateral breast cancer,” they wrote.

Again, there was no increased risk for women aged older than 40 years at first diagnosis.

“Based on these results, after a latency of 5 years or longer among women who received their first breast cancer diagnosis when they were younger than 40 years with a high NHEJ GRS, the population-attributable risk fraction of contralateral breast cancer attributable to stray radiation exposure to the contralateral breast was 28%. The corresponding population attributable risk fraction among women who received their first diagnosis when they were younger than 40 years after a latency of 5 years or more with a low NHEJ GRS was 18%,” the investigators wrote.

Five of the seven NHEJ pathway genes appeared to be driving these increased risks: LIG4, NHEJ1, XRCC4, XRCC5, and XRCC6. The expression quantitative trait loci (eQTLs) in each gene were always associated with a single direction of association; all risk alleles in XRCC4 were associated with decreased expression and all risk alleles in LIG4 were associated with increased expression.

“The consistent association of multiple NHEJ GRS risk alleles with eQTLs in a single direction suggests that the NHEJ GRS may be capturing the effect of SNP alleles on the transcription of one or more genes in the NHEJ pathway. This supports the hypothesis that the variation in this pathway may alter double-stranded DNA damage response, thereby increasing the risk of tumor development. However, the results from [the Genotype-Tissue Expression database] are drawn from multiple tissues that may not be appropriate proxies for breast tissue and the impact of genetic variation in the overall NHEJ pathway is likely to be complex,” the investigators wrote.

Dr. Watt had no financial disclosures. The research was funded by the National Cancer Institute.

SOURCE: Watt GP et al. JAMA Netw Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.12259.

Stray radiation exposure could be responsible for up to 28% of the contralateral breast cancer that occurs years after radiotherapy of the primary tumor.

The risk is highest among women initially treated when younger than 40 years, who had at lest 5 years’ lapse between the first and second occurrences, and had a higher genetic risk score, Gordon P. Watt, PhD, and colleagues reported in JAMA Network Open.

“These findings may support clinical decision making related to radiation treatment, particularly among women for whom other modalities may be considered,” wrote Dr. Watt of Memorial Sloan Kettering Cancer Center, New York, and coauthors. “For example, young women with a high [genetic risk] may consider partial-breast radiation therapy, rather than whole-breast radiation therapy when appropriate, opt for radiation therapy techniques that reduce integral dose (e.g., proton beam), or decide for non–radiation therapy–based locoregional management (e.g., mastectomy). These findings may be especially important in younger women with medially located breast cancers, where the scatter dose to the contralateral breast is likely to be higher.”

The investigators enrolled women who received a diagnosis for a first invasive local or regional breast cancer when they were younger than 55 years in a case-control study to investigate whether the NHEJ genetic risk score (GRS) could predict a woman’s risk of developing contralateral breast cancer after irradiation of a primary breast cancer. The risk score comprises 93 single nucleotide polymorphisms (SNPs) located in or near the seven genes in the NHEJ pathway, including DCLRE1C, LIG4, NHEJ1, PRKDC, XRCC4, XRCC5, and XRCC6. Dr. Watts’ team investigated risks associated with 69 of the SNPs.

The study comprised 3,732 women who were recruited from 2000 to 2012, with primary diagnosis occurring from 1985 to 2008. Of these, 1,521 had contralateral breast cancer; the remainder had unilateral disease and were used as controls.

At first diagnosis, they were aged a median of 46 years, although age ranged from 23 to 54 years. Most of the primary tumors (84%) were ductal. Among the recurrences, 9% were in situ, 63% local, 23% regional, and 2% distant. Stage was unknown on the remainder. Among these recurrent tumors, 54% were estrogen receptor positive and 24% were progesterone receptor positive, with unknown status on the remainder.

For women aged younger than 40 years at the time of the primary tumor, and at least 5 years out from treatment, radiation increased the risk of contralateral disease by 70%. But there was no significant risk to younger women with less than 5 years’ latency, or to women diagnosed at 40 years or older regardless of the time since treatment.

Age played a similar role when considering location-specific stray radiation dose. The risk was doubled in younger women who were exposed to at least 1 Gy and at least 5 years out from treatment, but there was no significantly increased risk to women older at first diagnosis.

Nor were the individual SNPs associated with increased risk. “The NHEJ GRS was approximately normally distributed and was dichotomized at the overall median for analysis; the median (range) GRS in the case group was 75 alleles and the median GRS in the control group was 74 alleles,” the investigators wrote.

But when examined by total GRS score, differences emerged.

“In the high NHEJ GRS group, among women who received the first diagnosis when they were younger than 40 years with a latency of 5 years or more, a stray radiation dose of 1.0 Gy or more was associated with threefold greater contralateral breast cancer risk, compared with no radiation exposure. In contrast, for women with an NHEJ GRS of 74 alleles or fewer in the same age and latency group, there was no association between radiation dose and contralateral breast cancer,” they wrote.

Again, there was no increased risk for women aged older than 40 years at first diagnosis.

“Based on these results, after a latency of 5 years or longer among women who received their first breast cancer diagnosis when they were younger than 40 years with a high NHEJ GRS, the population-attributable risk fraction of contralateral breast cancer attributable to stray radiation exposure to the contralateral breast was 28%. The corresponding population attributable risk fraction among women who received their first diagnosis when they were younger than 40 years after a latency of 5 years or more with a low NHEJ GRS was 18%,” the investigators wrote.

Five of the seven NHEJ pathway genes appeared to be driving these increased risks: LIG4, NHEJ1, XRCC4, XRCC5, and XRCC6. The expression quantitative trait loci (eQTLs) in each gene were always associated with a single direction of association; all risk alleles in XRCC4 were associated with decreased expression and all risk alleles in LIG4 were associated with increased expression.

“The consistent association of multiple NHEJ GRS risk alleles with eQTLs in a single direction suggests that the NHEJ GRS may be capturing the effect of SNP alleles on the transcription of one or more genes in the NHEJ pathway. This supports the hypothesis that the variation in this pathway may alter double-stranded DNA damage response, thereby increasing the risk of tumor development. However, the results from [the Genotype-Tissue Expression database] are drawn from multiple tissues that may not be appropriate proxies for breast tissue and the impact of genetic variation in the overall NHEJ pathway is likely to be complex,” the investigators wrote.

Dr. Watt had no financial disclosures. The research was funded by the National Cancer Institute.

SOURCE: Watt GP et al. JAMA Netw Open. 2019 Sep 27. doi: 10.1001/jamanetworkopen.2019.12259.

SAN DIEGO – Substance use disorders rarely ride alone, a psychiatrist told colleagues, and it’s crucial to treat the accompanying mental illness that is almost always present.

“If you’re really depressed and you’re smoking marijuana, the smoking could have made it worse, but you were probably depressed before,” said Timothy E. Wilens, MD, of Harvard Medical School and Massachusetts General Hospital, both in Boston. Dr. Wilens spoke at the annual Psych Congress.

He pointed to numbers supporting the link between substance use and mental illness. He also offered several tips about treating substance use disorder (SUD).

In ADHD, consider the big picture. If a person has both ADHD and SUD, treat both if the level of substance abuse is lower. But focus on the SUD in more severe cases, he said, and realize that “most likely your treatment for ADHD isn’t going to work as well.”

Be prepared to give high doses. “When you’re using stimulants in people with use disorders, you have to use high doses. You have to be brave,” he said. The same goes for the anxiolytic buspirone (Buspar) in patients with depression and SUD.

Consider N-acetyl cysteine in cannabis use disorder. N-acetyl cysteine, a nutraceutical used as an asthma medication, has shown promise in trials as a treatment for cannabis use disorder, Dr. Wilens said. It helps patients avoid the temptation to smoke. “They won’t say they’ve lost all their cravings, but you’ll hear, ‘I just didn’t need to do it; I’m not smoking as much.’ If you hear that from your patients, you know it’s working. It’s a subtle effect, but it can help.”

Scamming’ drugs shouldn’t be your main worry. Substance use research suggests that users of pharmaceutical drugs for nonmedical uses rarely get them directly from practitioners (7%), but instead mainly get them through friends, Dr. Wilens said. “If you work with this population and treat ADHD or anxiety, you’re paranoid that everyone coming in wants to scam medicines. Be more concerned about oversupplying them with immediate-release medications and not [taking] them to task about keeping the medication safely stored.”

Interventions such as Alcoholics Anonymous are as “effective as any other treatment for substance abuse, and it’s not costly,” Dr. Wilens said. He added that the Rational Recovery program, an alternative to Alcoholics Anonymous, also seems to work well. The approaches to ending substance use differ in that Alcoholics Anonymous’s orientation is spiritual and Rational Recovery’s is cognitive.

Dr. Wilens reported various disclosures, including consulting relationships with Ironshore Pharmaceuticals, KemPharm, and Neurovance/Otsuka.

SAN DIEGO – Substance use disorders rarely ride alone, a psychiatrist told colleagues, and it’s crucial to treat the accompanying mental illness that is almost always present.

“If you’re really depressed and you’re smoking marijuana, the smoking could have made it worse, but you were probably depressed before,” said Timothy E. Wilens, MD, of Harvard Medical School and Massachusetts General Hospital, both in Boston. Dr. Wilens spoke at the annual Psych Congress.

He pointed to numbers supporting the link between substance use and mental illness. He also offered several tips about treating substance use disorder (SUD).

In ADHD, consider the big picture. If a person has both ADHD and SUD, treat both if the level of substance abuse is lower. But focus on the SUD in more severe cases, he said, and realize that “most likely your treatment for ADHD isn’t going to work as well.”

Be prepared to give high doses. “When you’re using stimulants in people with use disorders, you have to use high doses. You have to be brave,” he said. The same goes for the anxiolytic buspirone (Buspar) in patients with depression and SUD.

Consider N-acetyl cysteine in cannabis use disorder. N-acetyl cysteine, a nutraceutical used as an asthma medication, has shown promise in trials as a treatment for cannabis use disorder, Dr. Wilens said. It helps patients avoid the temptation to smoke. “They won’t say they’ve lost all their cravings, but you’ll hear, ‘I just didn’t need to do it; I’m not smoking as much.’ If you hear that from your patients, you know it’s working. It’s a subtle effect, but it can help.”

Scamming’ drugs shouldn’t be your main worry. Substance use research suggests that users of pharmaceutical drugs for nonmedical uses rarely get them directly from practitioners (7%), but instead mainly get them through friends, Dr. Wilens said. “If you work with this population and treat ADHD or anxiety, you’re paranoid that everyone coming in wants to scam medicines. Be more concerned about oversupplying them with immediate-release medications and not [taking] them to task about keeping the medication safely stored.”

Interventions such as Alcoholics Anonymous are as “effective as any other treatment for substance abuse, and it’s not costly,” Dr. Wilens said. He added that the Rational Recovery program, an alternative to Alcoholics Anonymous, also seems to work well. The approaches to ending substance use differ in that Alcoholics Anonymous’s orientation is spiritual and Rational Recovery’s is cognitive.

Dr. Wilens reported various disclosures, including consulting relationships with Ironshore Pharmaceuticals, KemPharm, and Neurovance/Otsuka.

SAN DIEGO – Substance use disorders rarely ride alone, a psychiatrist told colleagues, and it’s crucial to treat the accompanying mental illness that is almost always present.

“If you’re really depressed and you’re smoking marijuana, the smoking could have made it worse, but you were probably depressed before,” said Timothy E. Wilens, MD, of Harvard Medical School and Massachusetts General Hospital, both in Boston. Dr. Wilens spoke at the annual Psych Congress.

He pointed to numbers supporting the link between substance use and mental illness. He also offered several tips about treating substance use disorder (SUD).

In ADHD, consider the big picture. If a person has both ADHD and SUD, treat both if the level of substance abuse is lower. But focus on the SUD in more severe cases, he said, and realize that “most likely your treatment for ADHD isn’t going to work as well.”

Be prepared to give high doses. “When you’re using stimulants in people with use disorders, you have to use high doses. You have to be brave,” he said. The same goes for the anxiolytic buspirone (Buspar) in patients with depression and SUD.

Consider N-acetyl cysteine in cannabis use disorder. N-acetyl cysteine, a nutraceutical used as an asthma medication, has shown promise in trials as a treatment for cannabis use disorder, Dr. Wilens said. It helps patients avoid the temptation to smoke. “They won’t say they’ve lost all their cravings, but you’ll hear, ‘I just didn’t need to do it; I’m not smoking as much.’ If you hear that from your patients, you know it’s working. It’s a subtle effect, but it can help.”

Scamming’ drugs shouldn’t be your main worry. Substance use research suggests that users of pharmaceutical drugs for nonmedical uses rarely get them directly from practitioners (7%), but instead mainly get them through friends, Dr. Wilens said. “If you work with this population and treat ADHD or anxiety, you’re paranoid that everyone coming in wants to scam medicines. Be more concerned about oversupplying them with immediate-release medications and not [taking] them to task about keeping the medication safely stored.”

Interventions such as Alcoholics Anonymous are as “effective as any other treatment for substance abuse, and it’s not costly,” Dr. Wilens said. He added that the Rational Recovery program, an alternative to Alcoholics Anonymous, also seems to work well. The approaches to ending substance use differ in that Alcoholics Anonymous’s orientation is spiritual and Rational Recovery’s is cognitive.

Dr. Wilens reported various disclosures, including consulting relationships with Ironshore Pharmaceuticals, KemPharm, and Neurovance/Otsuka.

It with sadness that I read the new Department of Defense report documenting an increasing number of suicides in the military. And also, cynicism about the proposed remedies.

According the DoD report, the rate of suicide among active-duty military increased from 18.5 per 100,000 service members in 2013 to 24.8 suicides per service members in 2018.

For context, I was in the Army for a career and at the office of the Army surgeon general from 2005 to 2010. That was when the suicide rate began to rise from the normal 10 per 100,000 soldiers per year to almost double that rate.

I led conferences within the Army Medical Command aimed at reducing suicides. Later, when the problem escalated, I participated in a variety of efforts to lower it. I went to Iraq to consult.

There was a Department of the Army task force on suicide prevention. Later, a DoD task force.

Numerous recommendations were made. If I remember right, the Army task force had almost 200 recommendations. They ranged from tightening accession standards, to providing more mental health care. The issues of shaming and blaming commanders also were a key topic of discussion.

Resiliency training was big. At some point, there were more than 200 resilience programs in the DoD. There were no data (to my knowledge) showing that they work.

An emphasis was the message: “It is a sign of strength to ask for help.”

For a while, the suicide rate flattened among active-duty soldiers, although the rate continued to climb among National Guard and reservists.

The solutions were similar to those proposed in this article. The leaders in the Army and DoD were not shy about asking for help. The Army Study to Assess Risk and Resilience in Servicemembers (STARRS) program was created to examine risk factors for suicide.

The STARRS program had data to show us what we already knew. The majority of suicides are in young, enlisted men with access to firearms. Often, but not always, they had a history of suicide ideation or attempts.

The trigger was usually, but not always, precipitated by a humiliating event, such as breaking up with a partner, driving while intoxicated, or getting in trouble at work.

Now, almost 10 years into retirement from the military, I feel sorry for my former colleagues. They have tried everything they can think of.

One solution, which is out of the control of military mental health workers, is to limit access to guns. Consistently, about two-thirds of suicides in the military are by gunshot.

So, as we continue to look for ways to bring an end to these losses, we must not blame the military. After all, they have tried all they can think of. However, I can think of one factor we can blame: the all-too-easy access to firearms.

Dr. Ritchie is chair of psychiatry at Medstar Washington Hospital Center and professor of psychiatry at Georgetown University, Washington.

It with sadness that I read the new Department of Defense report documenting an increasing number of suicides in the military. And also, cynicism about the proposed remedies.

According the DoD report, the rate of suicide among active-duty military increased from 18.5 per 100,000 service members in 2013 to 24.8 suicides per service members in 2018.

For context, I was in the Army for a career and at the office of the Army surgeon general from 2005 to 2010. That was when the suicide rate began to rise from the normal 10 per 100,000 soldiers per year to almost double that rate.

I led conferences within the Army Medical Command aimed at reducing suicides. Later, when the problem escalated, I participated in a variety of efforts to lower it. I went to Iraq to consult.

There was a Department of the Army task force on suicide prevention. Later, a DoD task force.

Numerous recommendations were made. If I remember right, the Army task force had almost 200 recommendations. They ranged from tightening accession standards, to providing more mental health care. The issues of shaming and blaming commanders also were a key topic of discussion.

Resiliency training was big. At some point, there were more than 200 resilience programs in the DoD. There were no data (to my knowledge) showing that they work.

An emphasis was the message: “It is a sign of strength to ask for help.”

For a while, the suicide rate flattened among active-duty soldiers, although the rate continued to climb among National Guard and reservists.

The solutions were similar to those proposed in this article. The leaders in the Army and DoD were not shy about asking for help. The Army Study to Assess Risk and Resilience in Servicemembers (STARRS) program was created to examine risk factors for suicide.

The STARRS program had data to show us what we already knew. The majority of suicides are in young, enlisted men with access to firearms. Often, but not always, they had a history of suicide ideation or attempts.

The trigger was usually, but not always, precipitated by a humiliating event, such as breaking up with a partner, driving while intoxicated, or getting in trouble at work.

Now, almost 10 years into retirement from the military, I feel sorry for my former colleagues. They have tried everything they can think of.

One solution, which is out of the control of military mental health workers, is to limit access to guns. Consistently, about two-thirds of suicides in the military are by gunshot.

So, as we continue to look for ways to bring an end to these losses, we must not blame the military. After all, they have tried all they can think of. However, I can think of one factor we can blame: the all-too-easy access to firearms.

Dr. Ritchie is chair of psychiatry at Medstar Washington Hospital Center and professor of psychiatry at Georgetown University, Washington.

It with sadness that I read the new Department of Defense report documenting an increasing number of suicides in the military. And also, cynicism about the proposed remedies.

According the DoD report, the rate of suicide among active-duty military increased from 18.5 per 100,000 service members in 2013 to 24.8 suicides per service members in 2018.

For context, I was in the Army for a career and at the office of the Army surgeon general from 2005 to 2010. That was when the suicide rate began to rise from the normal 10 per 100,000 soldiers per year to almost double that rate.

I led conferences within the Army Medical Command aimed at reducing suicides. Later, when the problem escalated, I participated in a variety of efforts to lower it. I went to Iraq to consult.

There was a Department of the Army task force on suicide prevention. Later, a DoD task force.

Numerous recommendations were made. If I remember right, the Army task force had almost 200 recommendations. They ranged from tightening accession standards, to providing more mental health care. The issues of shaming and blaming commanders also were a key topic of discussion.

Resiliency training was big. At some point, there were more than 200 resilience programs in the DoD. There were no data (to my knowledge) showing that they work.

An emphasis was the message: “It is a sign of strength to ask for help.”

For a while, the suicide rate flattened among active-duty soldiers, although the rate continued to climb among National Guard and reservists.

The solutions were similar to those proposed in this article. The leaders in the Army and DoD were not shy about asking for help. The Army Study to Assess Risk and Resilience in Servicemembers (STARRS) program was created to examine risk factors for suicide.

The STARRS program had data to show us what we already knew. The majority of suicides are in young, enlisted men with access to firearms. Often, but not always, they had a history of suicide ideation or attempts.

The trigger was usually, but not always, precipitated by a humiliating event, such as breaking up with a partner, driving while intoxicated, or getting in trouble at work.

Now, almost 10 years into retirement from the military, I feel sorry for my former colleagues. They have tried everything they can think of.

One solution, which is out of the control of military mental health workers, is to limit access to guns. Consistently, about two-thirds of suicides in the military are by gunshot.

So, as we continue to look for ways to bring an end to these losses, we must not blame the military. After all, they have tried all they can think of. However, I can think of one factor we can blame: the all-too-easy access to firearms.

Dr. Ritchie is chair of psychiatry at Medstar Washington Hospital Center and professor of psychiatry at Georgetown University, Washington.

The Food and Drug Administration has approved trifarotene cream 0.005% for the treatment of acne vulgaris. The product is manufactured by Galderma under the brand name Aklief.

Olivier Le Moal/Getty Images

The approval was based on data from a pair of phase 3, randomized trials including 2,420 patients aged 9 years and older. The trials evaluated the effectiveness of the cream in a once-daily topical dose for facial and truncal acne at 12 weeks. Patients showed a significant reduction in the number of inflammatory lesions as early as 2 weeks on the face (including forehead cheeks, nose, and chin) and as early as 4 weeks on the trunk (including back, chest, and shoulders), compared with a control cream. The most common treatment-emergent adverse events were pain, dryness, discoloration, or rash at the site of application. Some patients also reported sunburn.

The complete study findings were published in the June issue of the Journal of the American Academy of Dermatology.

The studies, funded by Galderma, “showed that once-daily trifarotene cream appears effective and safe, with manageable local tolerability, for the treatment for facial and truncal acne,” wrote lead author Jerry Tan, MD, of the University of Western Ontario, London, and colleagues. “The studies provide substantial evidence to support use of this new topical retinoid in facial and truncal acne,” the researchers wrote.

Trifarotene is designed to target the retinoic acid receptor gamma, the most common retinoic acid receptor in the skin, and is the first new retinoid to be approved by the FDA in approximately 2 decades, according to a press release from Galderma.

The product is expected to be available in the United States in November 2019 in a 45-g pump.

The Food and Drug Administration has approved trifarotene cream 0.005% for the treatment of acne vulgaris. The product is manufactured by Galderma under the brand name Aklief.

Olivier Le Moal/Getty Images

The approval was based on data from a pair of phase 3, randomized trials including 2,420 patients aged 9 years and older. The trials evaluated the effectiveness of the cream in a once-daily topical dose for facial and truncal acne at 12 weeks. Patients showed a significant reduction in the number of inflammatory lesions as early as 2 weeks on the face (including forehead cheeks, nose, and chin) and as early as 4 weeks on the trunk (including back, chest, and shoulders), compared with a control cream. The most common treatment-emergent adverse events were pain, dryness, discoloration, or rash at the site of application. Some patients also reported sunburn.

The complete study findings were published in the June issue of the Journal of the American Academy of Dermatology.

The studies, funded by Galderma, “showed that once-daily trifarotene cream appears effective and safe, with manageable local tolerability, for the treatment for facial and truncal acne,” wrote lead author Jerry Tan, MD, of the University of Western Ontario, London, and colleagues. “The studies provide substantial evidence to support use of this new topical retinoid in facial and truncal acne,” the researchers wrote.

Trifarotene is designed to target the retinoic acid receptor gamma, the most common retinoic acid receptor in the skin, and is the first new retinoid to be approved by the FDA in approximately 2 decades, according to a press release from Galderma.

The product is expected to be available in the United States in November 2019 in a 45-g pump.

The Food and Drug Administration has approved trifarotene cream 0.005% for the treatment of acne vulgaris. The product is manufactured by Galderma under the brand name Aklief.

Olivier Le Moal/Getty Images

The approval was based on data from a pair of phase 3, randomized trials including 2,420 patients aged 9 years and older. The trials evaluated the effectiveness of the cream in a once-daily topical dose for facial and truncal acne at 12 weeks. Patients showed a significant reduction in the number of inflammatory lesions as early as 2 weeks on the face (including forehead cheeks, nose, and chin) and as early as 4 weeks on the trunk (including back, chest, and shoulders), compared with a control cream. The most common treatment-emergent adverse events were pain, dryness, discoloration, or rash at the site of application. Some patients also reported sunburn.

The complete study findings were published in the June issue of the Journal of the American Academy of Dermatology.

The studies, funded by Galderma, “showed that once-daily trifarotene cream appears effective and safe, with manageable local tolerability, for the treatment for facial and truncal acne,” wrote lead author Jerry Tan, MD, of the University of Western Ontario, London, and colleagues. “The studies provide substantial evidence to support use of this new topical retinoid in facial and truncal acne,” the researchers wrote.

Trifarotene is designed to target the retinoic acid receptor gamma, the most common retinoic acid receptor in the skin, and is the first new retinoid to be approved by the FDA in approximately 2 decades, according to a press release from Galderma.

The product is expected to be available in the United States in November 2019 in a 45-g pump.

SAN DIEGO – A relatively new treatment approach called good psychiatric management (GPM) is available for patients with borderline personality disorder.

It’s a solid option for “environments where people may not have many resources and might not be able to deliver treatments that are more resource intensive, like dialectical behavioral therapy,” the standard intervention, said James Jenkins, MD, a psychiatrist affiliated with Massachusetts General Hospital, Boston, in a video interview at the annual Psych Congress.

“GPM is a treatment, not a psychotherapy, that’s maybe a little bit more easily adaptable to a variety of different contexts and situations,” he said.

It’s an atheoretical, pragmatic approach that focuses on helping people establish a life outside of therapy. Clinicians actively engage with patients, encouraging them to start working and building successful relationships with other people. The model emphasizes the value of educating people about the condition and giving them hope. Typically, patients participate in GPM once each week (Curr Opin Psychol. 2018 Jun;21:127-31).

Vidyard Video

For most people, it works just as well as dialectical behavioral therapy, and when it doesn’t, patients can transition to that or another more intensive approach. Training is less intensive and sometimes free. GPM is offered at McLean Hospital in Boston, where the intervention originated. McLean also is Dr. Jenkins’s former institution.

Dr. Jenkins reported that he had no disclosures.

[email protected]

SAN DIEGO – A relatively new treatment approach called good psychiatric management (GPM) is available for patients with borderline personality disorder.

It’s a solid option for “environments where people may not have many resources and might not be able to deliver treatments that are more resource intensive, like dialectical behavioral therapy,” the standard intervention, said James Jenkins, MD, a psychiatrist affiliated with Massachusetts General Hospital, Boston, in a video interview at the annual Psych Congress.

“GPM is a treatment, not a psychotherapy, that’s maybe a little bit more easily adaptable to a variety of different contexts and situations,” he said.

It’s an atheoretical, pragmatic approach that focuses on helping people establish a life outside of therapy. Clinicians actively engage with patients, encouraging them to start working and building successful relationships with other people. The model emphasizes the value of educating people about the condition and giving them hope. Typically, patients participate in GPM once each week (Curr Opin Psychol. 2018 Jun;21:127-31).

Vidyard Video

For most people, it works just as well as dialectical behavioral therapy, and when it doesn’t, patients can transition to that or another more intensive approach. Training is less intensive and sometimes free. GPM is offered at McLean Hospital in Boston, where the intervention originated. McLean also is Dr. Jenkins’s former institution.

Dr. Jenkins reported that he had no disclosures.

[email protected]

SAN DIEGO – A relatively new treatment approach called good psychiatric management (GPM) is available for patients with borderline personality disorder.

It’s a solid option for “environments where people may not have many resources and might not be able to deliver treatments that are more resource intensive, like dialectical behavioral therapy,” the standard intervention, said James Jenkins, MD, a psychiatrist affiliated with Massachusetts General Hospital, Boston, in a video interview at the annual Psych Congress.

“GPM is a treatment, not a psychotherapy, that’s maybe a little bit more easily adaptable to a variety of different contexts and situations,” he said.

It’s an atheoretical, pragmatic approach that focuses on helping people establish a life outside of therapy. Clinicians actively engage with patients, encouraging them to start working and building successful relationships with other people. The model emphasizes the value of educating people about the condition and giving them hope. Typically, patients participate in GPM once each week (Curr Opin Psychol. 2018 Jun;21:127-31).

Vidyard Video

For most people, it works just as well as dialectical behavioral therapy, and when it doesn’t, patients can transition to that or another more intensive approach. Training is less intensive and sometimes free. GPM is offered at McLean Hospital in Boston, where the intervention originated. McLean also is Dr. Jenkins’s former institution.

Dr. Jenkins reported that he had no disclosures.

[email protected]