Federal Practitioner

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Older adults admitted to post-acute settings frequently have complex rehabilitation needs and multimorbidity, which predisposes them to pain management challenges.^1,2 The prevalence of pain in post-acute and long-term care is as high as 65%, and opioid use is common among this population with 1 in 7 residents receiving long-term opioids.^3,4

Opioids that do not adequately control pain represent a missed opportunity for deprescribing. There is limited evidence regarding efficacy of long-term opioid use (> 90 days) for improving pain and physical functioning.⁵ In addition, long-term opioid use carries significant risks, including overdose-related death, dependence, and increased emergency department visits.⁵ These risks are likely to be pronounced among veterans receiving post-acute care (PAC) who are older, have comorbid psychiatric disorders, are prescribed several centrally acting medications, and experience substance use disorder (SUD).⁶

Older adults are at increased risk for opioid toxicity because of reduced drug clearance and smaller therapeutic window.⁵ Centers for Disease Control and Prevention (CDC) guidelines recommend frequently assessing patients for benefit in terms of sustained improvement in pain as well as physical function.⁵ If pain and functional improvements are minimal, opioid use and nonopioid pain management strategies should be considered. Some patients will struggle with this approach. Directly asking patients about the effectiveness of opioids is challenging. Opioid users with chronic pain frequently report problems with opioids even as they describe them as indispensable for pain management.^7,8

Earlier studies have assessed patient perspectives regarding opioid difficulties as well as their helpfulness, which could introduce recall bias. Patient-level factors that contribute to a global sense of distress, in addition to the presence of painful physical conditions, also could contribute to patients requesting opioids without experiencing adequate pain relief. One study in veterans residing in PAC facilities found that individuals with depression, posttraumatic stress disorder (PTSD), and SUD were more likely to report pain and receive scheduled analgesics; this effect persisted in individuals with PTSD even after adjusting for demographic and functional status variables.⁹ The study looked only at analgesics as a class and did not examine opioids specifically. It is possible that distressed individuals, such as those with uncontrolled depression, PTSD, and SUD, might be more likely to report high pain levels and receive opioids with inadequate benefit and increased risk. Identifying the primary condition causing distress and targeting treatment to that condition (ie, depression) is preferable to escalating opioids in an attempt to treat pain in the context of nonresponse. Assessing an individual’s aggregate response to opioids rather than relying on a single self-report is a useful addition to current pain management strategies.

The goal of this study was to pilot a method of identifying opioid-nonresponsive pain using administrative data, measure its prevalence in a PAC population of veterans, and explore clinical and demographic correlates with particular attention to variates that could indicate high levels of psychological and physical distress. Identifying pain that is poorly responsive to opioids would give clinicians the opportunity to avoid or minimize opioid use and prioritize treatments that are likely to improve the resident’s pain, quality of life, and physical function while minimizing recall bias. We hypothesized that pain that responds poorly to opioids would be prevalent among veterans residing in a PAC unit. We considered that veterans with pain poorly responsive to opioids would be more likely to have factors that would place them at increased risk of adverse effects, such as comorbid psychiatric conditions, history of SUD, and multimorbidity, providing further rationale for clinical equipoise in that population.⁶

Methods

This was a small, retrospective cross-sectional study using administrative data and chart review. The study included veterans who were administered opioids while residing in a single US Department of Veterans Affairs (VA) community living center PAC (CLC-PAC) unit during at least 1 of 4 nonconsecutive, random days in 2016 and 2017. The study was approved by the institutional review board of the Ann Arbor VA Health System (#2017-1034) as part of a larger project involving models of care in vulnerable older veterans.

Inclusion criteria were the presence of at least moderate pain (≥ 4 on a 0 to 10 scale); receiving ≥ 2 opioids ordered as needed over the prespecified 24-hour observation period; and having ≥ 2 pre-and postopioid administration pain scores during the observation period. Veterans who did not meet these criteria were excluded. At the time of initial sample selection, we did not capture information related to coprescribed analgesics, including a standing order of opioids. To obtain the sample, we initially characterized all veterans on the 4 days residing in the CLC-PAC unit as those reporting at least moderate pain (≥ 4) and those who reported no or mild pain (< 4). The cut point of 4 of 10 is consistent with moderate pain based on earlier work showing higher likelihood of pain that interferes with physical function.¹⁰ We then restricted the sample to veterans who received ≥ 2 opioids ordered as needed for pain and had ≥ 2 pre- and postopioid administration numeric pain rating scores during the 24-hour observation period. This methodology was chosen to enrich our sample for those who received opioids regularly for ongoing pain. Opioids were defined as full µ-opioid receptor agonists and included hydrocodone, oxycodone, morphine, hydromorphone, fentanyl, tramadol, and methadone.

Outcome of Interest

The primary outcome of interest was an individual’s response to as-needed opioids, which we defined as change in the pain score after opioid administration. The pre-opioid pain score was the score that immediately preceded administration of an as-needed opioid. The postopioid administration pain score was the first score after opioid administration if obtained within 3 hours of administration. Scores collected > 3 hours after opioid administration were excluded because they no longer accurately reflected the impact of the opioid due to the short half-lives. Observations were excluded if an opioid was administered without a recorded pain score; this occurred once for 6 individuals. Observations also were excluded if an opioid was administered but the data were captured on the following day (outside of the 24-hour window); this occurred once for 3 individuals.

We calculated a ∆ score by subtracting the postopioid pain rating score from the pre-opioid score. Individual ∆ scores were then averaged over the 24-hour period (range, 2-5 opioid doses). For example, if an individual reported a pre-opioid pain score of 10, and a postopioid pain score of 2, the ∆ was recorded as 8. If the individual’s next pre-opioid score was 10, and post-opioid score was 6, the ∆ was recorded as 4. ∆ scores over the 24-hour period were averaged together to determine that individual’s response to as-needed opioids. In the previous example, the mean ∆ score is 6. Lower mean ∆ scores reflect decreased responsiveness to opioids’ analgesic effect.

Demographic and clinical data were obtained from electronic health record review using a standardized assessment form. These data included information about medical and psychiatric comorbidities, specialist consultations, and CLC-PAC unit admission indications and diagnoses. Medications of interest were categorized as antidepressants, antipsychotics, benzodiazepines, muscle relaxants, hypnotics, stimulants, antiepileptic drugs/mood stabilizers (including gabapentin and pregabalin), and all adjuvant analgesics. Adjuvant analgesics were defined as medications administered for pain as documented by chart notes or those ordered as needed for pain, and analyzed as a composite variable. Antidepressants with analgesic properties (serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants) were considered adjuvant analgesics. Psychiatric information collected included presence of mood, anxiety, and psychotic disorders, and PTSD. SUD information was collected separately from other psychiatric disorders.

Analyses

The study population was described using tabulations for categorical data and means and standard deviations for continuous data. Responsiveness to opioids was analyzed as a continuous variable. Those with higher mean ∆ scores were considered to have pain relatively more responsive to opioids, while lower mean ∆ scores indicated pain less responsive to opioids. We constructed linear regression models controlling for average pre-opioid pain rating scores to explore associations between opioid responsiveness and variables of interest. All analyses were completed using Stata version 15. This study was not adequately powered to detect differences across the spectrum of opioid responsiveness, although the authors have reported differences in this article.

Results

Over the 4-day observational period there were 146 resident-days. Of these, 88 (60.3%) reported at least 1 pain score of ≥ 4. Of those, 61 (41.8%) received ≥ 1 as-needed opioid for pain. We identified 46 resident-days meeting study criteria of ≥ 2 pre- and postanalgesic scores. We identified 41 unique individuals (Figure 1). Two individuals were admitted to the CLC-PAC unit on 2 of the 4 observation days, and 1 individual was admitted to the CLC-PAC unit on 3 of the 4 observation days. For individuals admitted several days, we included data only from the initial observation day.

Response to opioids varied greatly in this sample. The mean (SD) ∆ pain score was 3.4 (1.6) and ranged from 0.5 to 6.3. Using linear regression, we found no relationship between admission indication, medical comorbidities (including active cancer), and opioid responsiveness (Table).

A poorer response to opioids was associated with a significantly higher as-needed opioid dosage (β = −0.02; 95% CI, −0.04 to −0.01; P = .002) as well as a trend toward higher total opioid dosage (β = −0.005; 95% CI, −0.01 to 0.0003; P = .06) (Figure 4). Thirty-eight (92.7%) participants received nonopioid adjuvant analgesics for pain. More than half (56.1%) received antidepressants or gabapentinoids (51.2%), although we did not assess whether they were prescribed for pain or another indication. We did not identify a relationship between any specific psychoactive drug class and opioid responsiveness in this sample.

Discussion

This exploratory study used readily available administrative data in a CLC-PAC unit to assess responsiveness to opioids via a numeric mean ∆ score, with higher values indicating more pain relief in response to opioids. We then constructed linear regression models to characterize the relationship between the mean ∆ score and factors known to be associated with difficult-to-control pain and psychosocial distress. As expected, opioid responsiveness was highly variable among residents; some residents experienced essentially no reduction in pain, on average, despite receiving opioids. Psychiatric comorbidity, higher dosage in OMEs, and the presence of a pain service consult significantly correlated with poorer response to opioids. To our knowledge, this is the first study to quantify opioid responsiveness and describe the relationship with clinical correlates in the understudied PAC population.

Earlier research has demonstrated a relationship between the presence of psychiatric disorders and increased likelihood of receiving any analgesics among veterans residing in PAC.⁹ Our study adds to the literature by quantifying opioid response using readily available administrative data and examining associations with psychiatric diagnoses. These findings highlight the possibility that attempting to treat high levels of pain by escalating the opioid dosage in patients with a comorbid psychiatric diagnosis should be re-addressed, particularly if there is no meaningful pain reduction at lower opioid dosages. Our sample had a variety of admission diagnoses and medical comorbidities, however, we did not identify a relationship with opioid responsiveness, including an active cancer diagnosis. Although SUDs were highly prevalent in our sample, there was no relationship with opioid responsiveness. This suggests that lack of response to opioids is not merely a matter of drug tolerance or an indication of drug-seeking behavior.

Factors Impacting Response

Many factors could affect whether an individual obtains an adequate analgesic response to opioids or other pain medications, including variations in genes encoding opioid receptors and hepatic enzymes involved in drug metabolism and an individual’s opioid exposure history.¹³ The phenomenon of requiring more drug to produce the same relief after repeated exposures (ie, tolerance) is well known.¹⁴ Opioid-induced hyperalgesia is a phenomenon whereby a patient’s overall pain increases while receiving opioids, but each opioid dose might be perceived as beneficial.¹⁵ Increasingly, psychosocial distress is an important factor in opioid response. Adverse selection is the process culminating in those with psychosocial distress and/or SUDs being prescribed more opioids for longer durations.¹⁶ Our data suggests that this process could play a role in PAC settings. In addition, exaggerating pain to obtain additional opioids for nonmedical purposes, such as euphoria or relaxation, also is possible.¹⁷

When clinically assessing an individual whose pain is not well controlled despite escalating opioid dosages, prescribers must consider which of these factors likely is predominant. However, the first step of determining who has a poor opioid response is not straightforward. Directly asking patients is challenging; many individuals perceive opioids to be helpful while simultaneously reporting inadequately controlled pain.^7,8 The primary value of this study is the possibility of providing prescribers a quick, simple method of assessing a patient’s response to opioids. Using this method, individuals who are responding poorly to opioids, including those who might exaggerate pain for secondary gain, could be identified. Health care professionals could consider revisiting pain management strategies, assess for the presence of OUD, or evaluate other contributors to inadequately controlled pain. Although we only collected data regarding response to opioids in this study, any pain medication administered as needed (ie, nonsteroidal anti-inflammatory drugs, acetaminophen) could be analyzed using this methodology, allowing identification of other helpful pain management strategies. We began the validation process with extensive chart review, but further validation is required before this method can be applied to routine clinical practice.

Patients who report uncontrolled pain despite receiving opioids are a clinically challenging population. The traditional strategy has been to escalate opioids, which is recommended by the World Health Organization stepladder approach for patients with cancer pain and limited life expectancy.¹⁸ Applying this approach to a general population of patients with chronic pain is ineffective and dangerous.¹⁹ The CDC and the VA/US Department of Defense (VA/DoD) guidelines both recommend carefully reassessing risks and benefits at total daily dosages > 50 OME and avoid increasing dosages to > 90 OME daily in most circumstances.^5,20 Our finding that participants taking higher dosages of opioids were not more likely to have better control over their pain supports this recommendation.

Limitations

This study has several limitations, the most significant is its small sample size because of the exploratory nature of the project. Results are based on a small pilot sample enriched to include individuals with at least moderate pain who receive opioids frequently at 1 VA CLC-PAC unit; therefore, the results might not be representative of all veterans or a more general population. Our small sample size limits power to detect small differences. Data collected should be used to inform formal power calculations before subsequent larger studies to select adequate sample size. Validation studies, including samples from the same population using different dates, which reproduce findings are an important step. Moreover, we only had data on a single dimension of pain (intensity/severity), as measured by the pain scale, which nursing staff used to make a real-time clinical decision of whether to administer an as-needed opioid. Future studies should consider using pain measures that provide multidimensional assessment (ie, severity, functional interference) and/or were developed specifically for veterans, such as the Defense and Veterans Pain Rating Scale.²¹

Our study was cross-sectional in nature and addressed a single 24-hour period of data per participant. The years of data collection (2016 and 2017) followed a decline in overall opioid prescribing that has continued, likely influenced by CDC and VA/DoD guidelines.²² It is unclear whether our observations are an accurate reflection of individuals’ response over time or whether prescribing practices in PAC have shifted.

We did not consider the type of pain being treated or explore clinicians’ reasons for prescribing opioids, therefore limiting our ability to know whether opioids were indicated. Information regarding OUD and other SUDs was limited to what was documented in the chart during the CLC-PAC unit admission. We did not have information on length of exposure to opioids. It is possible that opioid tolerance could play a role in reducing opioid responsiveness. However, simple tolerance would not be expected to explain robust correlations with psychiatric comorbidities. Also, simple tolerance would be expected to be overcome with higher opioid dosages, whereas our study demonstrates less responsiveness. These data suggests that some individuals’ pain might be poorly opioid responsive, and psychiatric factors could increase this risk. We used a novel data source in combination with chart review; to our knowledge, barcode medication administration data have not been used in this manner previously. Future work needs to validate this method, using larger sample sizes and several clinical sites. Finally, we used regression models that controlled for average pre-opioid pain rating scores, which is only 1 covariate important for examining effects. Larger studies with adequate power should control for multiple covariates known to be associated with pain and opioid response.

Conclusions

Opioid responsiveness is important clinically yet challenging to assess. This pilot study identifies a way of classifying pain as relatively opioid nonresponsive using administrative data but requires further validation before considering scaling for more general use. The possibility that a substantial percentage of residents in a CLC-PAC unit could be receiving increasing dosages of opioids without adequate benefit justifies the need for more research and underscores the need for prescribers to assess individuals frequently for ongoing benefit of opioids regardless of diagnosis or mechanism of pain.

Acknowledgments

The authors thank Andrzej Galecki, Corey Powell, and the University of Michigan Consulting for Statistics, Computing and Analytics Research Center for assistance with statistical analysis.

Older adults admitted to post-acute settings frequently have complex rehabilitation needs and multimorbidity, which predisposes them to pain management challenges.^1,2 The prevalence of pain in post-acute and long-term care is as high as 65%, and opioid use is common among this population with 1 in 7 residents receiving long-term opioids.^3,4

Opioids that do not adequately control pain represent a missed opportunity for deprescribing. There is limited evidence regarding efficacy of long-term opioid use (> 90 days) for improving pain and physical functioning.⁵ In addition, long-term opioid use carries significant risks, including overdose-related death, dependence, and increased emergency department visits.⁵ These risks are likely to be pronounced among veterans receiving post-acute care (PAC) who are older, have comorbid psychiatric disorders, are prescribed several centrally acting medications, and experience substance use disorder (SUD).⁶

Older adults are at increased risk for opioid toxicity because of reduced drug clearance and smaller therapeutic window.⁵ Centers for Disease Control and Prevention (CDC) guidelines recommend frequently assessing patients for benefit in terms of sustained improvement in pain as well as physical function.⁵ If pain and functional improvements are minimal, opioid use and nonopioid pain management strategies should be considered. Some patients will struggle with this approach. Directly asking patients about the effectiveness of opioids is challenging. Opioid users with chronic pain frequently report problems with opioids even as they describe them as indispensable for pain management.^7,8

Earlier studies have assessed patient perspectives regarding opioid difficulties as well as their helpfulness, which could introduce recall bias. Patient-level factors that contribute to a global sense of distress, in addition to the presence of painful physical conditions, also could contribute to patients requesting opioids without experiencing adequate pain relief. One study in veterans residing in PAC facilities found that individuals with depression, posttraumatic stress disorder (PTSD), and SUD were more likely to report pain and receive scheduled analgesics; this effect persisted in individuals with PTSD even after adjusting for demographic and functional status variables.⁹ The study looked only at analgesics as a class and did not examine opioids specifically. It is possible that distressed individuals, such as those with uncontrolled depression, PTSD, and SUD, might be more likely to report high pain levels and receive opioids with inadequate benefit and increased risk. Identifying the primary condition causing distress and targeting treatment to that condition (ie, depression) is preferable to escalating opioids in an attempt to treat pain in the context of nonresponse. Assessing an individual’s aggregate response to opioids rather than relying on a single self-report is a useful addition to current pain management strategies.

The goal of this study was to pilot a method of identifying opioid-nonresponsive pain using administrative data, measure its prevalence in a PAC population of veterans, and explore clinical and demographic correlates with particular attention to variates that could indicate high levels of psychological and physical distress. Identifying pain that is poorly responsive to opioids would give clinicians the opportunity to avoid or minimize opioid use and prioritize treatments that are likely to improve the resident’s pain, quality of life, and physical function while minimizing recall bias. We hypothesized that pain that responds poorly to opioids would be prevalent among veterans residing in a PAC unit. We considered that veterans with pain poorly responsive to opioids would be more likely to have factors that would place them at increased risk of adverse effects, such as comorbid psychiatric conditions, history of SUD, and multimorbidity, providing further rationale for clinical equipoise in that population.⁶

Methods

This was a small, retrospective cross-sectional study using administrative data and chart review. The study included veterans who were administered opioids while residing in a single US Department of Veterans Affairs (VA) community living center PAC (CLC-PAC) unit during at least 1 of 4 nonconsecutive, random days in 2016 and 2017. The study was approved by the institutional review board of the Ann Arbor VA Health System (#2017-1034) as part of a larger project involving models of care in vulnerable older veterans.

Inclusion criteria were the presence of at least moderate pain (≥ 4 on a 0 to 10 scale); receiving ≥ 2 opioids ordered as needed over the prespecified 24-hour observation period; and having ≥ 2 pre-and postopioid administration pain scores during the observation period. Veterans who did not meet these criteria were excluded. At the time of initial sample selection, we did not capture information related to coprescribed analgesics, including a standing order of opioids. To obtain the sample, we initially characterized all veterans on the 4 days residing in the CLC-PAC unit as those reporting at least moderate pain (≥ 4) and those who reported no or mild pain (< 4). The cut point of 4 of 10 is consistent with moderate pain based on earlier work showing higher likelihood of pain that interferes with physical function.¹⁰ We then restricted the sample to veterans who received ≥ 2 opioids ordered as needed for pain and had ≥ 2 pre- and postopioid administration numeric pain rating scores during the 24-hour observation period. This methodology was chosen to enrich our sample for those who received opioids regularly for ongoing pain. Opioids were defined as full µ-opioid receptor agonists and included hydrocodone, oxycodone, morphine, hydromorphone, fentanyl, tramadol, and methadone.

Outcome of Interest

The primary outcome of interest was an individual’s response to as-needed opioids, which we defined as change in the pain score after opioid administration. The pre-opioid pain score was the score that immediately preceded administration of an as-needed opioid. The postopioid administration pain score was the first score after opioid administration if obtained within 3 hours of administration. Scores collected > 3 hours after opioid administration were excluded because they no longer accurately reflected the impact of the opioid due to the short half-lives. Observations were excluded if an opioid was administered without a recorded pain score; this occurred once for 6 individuals. Observations also were excluded if an opioid was administered but the data were captured on the following day (outside of the 24-hour window); this occurred once for 3 individuals.

We calculated a ∆ score by subtracting the postopioid pain rating score from the pre-opioid score. Individual ∆ scores were then averaged over the 24-hour period (range, 2-5 opioid doses). For example, if an individual reported a pre-opioid pain score of 10, and a postopioid pain score of 2, the ∆ was recorded as 8. If the individual’s next pre-opioid score was 10, and post-opioid score was 6, the ∆ was recorded as 4. ∆ scores over the 24-hour period were averaged together to determine that individual’s response to as-needed opioids. In the previous example, the mean ∆ score is 6. Lower mean ∆ scores reflect decreased responsiveness to opioids’ analgesic effect.

Demographic and clinical data were obtained from electronic health record review using a standardized assessment form. These data included information about medical and psychiatric comorbidities, specialist consultations, and CLC-PAC unit admission indications and diagnoses. Medications of interest were categorized as antidepressants, antipsychotics, benzodiazepines, muscle relaxants, hypnotics, stimulants, antiepileptic drugs/mood stabilizers (including gabapentin and pregabalin), and all adjuvant analgesics. Adjuvant analgesics were defined as medications administered for pain as documented by chart notes or those ordered as needed for pain, and analyzed as a composite variable. Antidepressants with analgesic properties (serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants) were considered adjuvant analgesics. Psychiatric information collected included presence of mood, anxiety, and psychotic disorders, and PTSD. SUD information was collected separately from other psychiatric disorders.

Analyses

The study population was described using tabulations for categorical data and means and standard deviations for continuous data. Responsiveness to opioids was analyzed as a continuous variable. Those with higher mean ∆ scores were considered to have pain relatively more responsive to opioids, while lower mean ∆ scores indicated pain less responsive to opioids. We constructed linear regression models controlling for average pre-opioid pain rating scores to explore associations between opioid responsiveness and variables of interest. All analyses were completed using Stata version 15. This study was not adequately powered to detect differences across the spectrum of opioid responsiveness, although the authors have reported differences in this article.

Results

Over the 4-day observational period there were 146 resident-days. Of these, 88 (60.3%) reported at least 1 pain score of ≥ 4. Of those, 61 (41.8%) received ≥ 1 as-needed opioid for pain. We identified 46 resident-days meeting study criteria of ≥ 2 pre- and postanalgesic scores. We identified 41 unique individuals (Figure 1). Two individuals were admitted to the CLC-PAC unit on 2 of the 4 observation days, and 1 individual was admitted to the CLC-PAC unit on 3 of the 4 observation days. For individuals admitted several days, we included data only from the initial observation day.

Response to opioids varied greatly in this sample. The mean (SD) ∆ pain score was 3.4 (1.6) and ranged from 0.5 to 6.3. Using linear regression, we found no relationship between admission indication, medical comorbidities (including active cancer), and opioid responsiveness (Table).

A poorer response to opioids was associated with a significantly higher as-needed opioid dosage (β = −0.02; 95% CI, −0.04 to −0.01; P = .002) as well as a trend toward higher total opioid dosage (β = −0.005; 95% CI, −0.01 to 0.0003; P = .06) (Figure 4). Thirty-eight (92.7%) participants received nonopioid adjuvant analgesics for pain. More than half (56.1%) received antidepressants or gabapentinoids (51.2%), although we did not assess whether they were prescribed for pain or another indication. We did not identify a relationship between any specific psychoactive drug class and opioid responsiveness in this sample.

Discussion

This exploratory study used readily available administrative data in a CLC-PAC unit to assess responsiveness to opioids via a numeric mean ∆ score, with higher values indicating more pain relief in response to opioids. We then constructed linear regression models to characterize the relationship between the mean ∆ score and factors known to be associated with difficult-to-control pain and psychosocial distress. As expected, opioid responsiveness was highly variable among residents; some residents experienced essentially no reduction in pain, on average, despite receiving opioids. Psychiatric comorbidity, higher dosage in OMEs, and the presence of a pain service consult significantly correlated with poorer response to opioids. To our knowledge, this is the first study to quantify opioid responsiveness and describe the relationship with clinical correlates in the understudied PAC population.

Earlier research has demonstrated a relationship between the presence of psychiatric disorders and increased likelihood of receiving any analgesics among veterans residing in PAC.⁹ Our study adds to the literature by quantifying opioid response using readily available administrative data and examining associations with psychiatric diagnoses. These findings highlight the possibility that attempting to treat high levels of pain by escalating the opioid dosage in patients with a comorbid psychiatric diagnosis should be re-addressed, particularly if there is no meaningful pain reduction at lower opioid dosages. Our sample had a variety of admission diagnoses and medical comorbidities, however, we did not identify a relationship with opioid responsiveness, including an active cancer diagnosis. Although SUDs were highly prevalent in our sample, there was no relationship with opioid responsiveness. This suggests that lack of response to opioids is not merely a matter of drug tolerance or an indication of drug-seeking behavior.

Factors Impacting Response

Many factors could affect whether an individual obtains an adequate analgesic response to opioids or other pain medications, including variations in genes encoding opioid receptors and hepatic enzymes involved in drug metabolism and an individual’s opioid exposure history.¹³ The phenomenon of requiring more drug to produce the same relief after repeated exposures (ie, tolerance) is well known.¹⁴ Opioid-induced hyperalgesia is a phenomenon whereby a patient’s overall pain increases while receiving opioids, but each opioid dose might be perceived as beneficial.¹⁵ Increasingly, psychosocial distress is an important factor in opioid response. Adverse selection is the process culminating in those with psychosocial distress and/or SUDs being prescribed more opioids for longer durations.¹⁶ Our data suggests that this process could play a role in PAC settings. In addition, exaggerating pain to obtain additional opioids for nonmedical purposes, such as euphoria or relaxation, also is possible.¹⁷

When clinically assessing an individual whose pain is not well controlled despite escalating opioid dosages, prescribers must consider which of these factors likely is predominant. However, the first step of determining who has a poor opioid response is not straightforward. Directly asking patients is challenging; many individuals perceive opioids to be helpful while simultaneously reporting inadequately controlled pain.^7,8 The primary value of this study is the possibility of providing prescribers a quick, simple method of assessing a patient’s response to opioids. Using this method, individuals who are responding poorly to opioids, including those who might exaggerate pain for secondary gain, could be identified. Health care professionals could consider revisiting pain management strategies, assess for the presence of OUD, or evaluate other contributors to inadequately controlled pain. Although we only collected data regarding response to opioids in this study, any pain medication administered as needed (ie, nonsteroidal anti-inflammatory drugs, acetaminophen) could be analyzed using this methodology, allowing identification of other helpful pain management strategies. We began the validation process with extensive chart review, but further validation is required before this method can be applied to routine clinical practice.

Patients who report uncontrolled pain despite receiving opioids are a clinically challenging population. The traditional strategy has been to escalate opioids, which is recommended by the World Health Organization stepladder approach for patients with cancer pain and limited life expectancy.¹⁸ Applying this approach to a general population of patients with chronic pain is ineffective and dangerous.¹⁹ The CDC and the VA/US Department of Defense (VA/DoD) guidelines both recommend carefully reassessing risks and benefits at total daily dosages > 50 OME and avoid increasing dosages to > 90 OME daily in most circumstances.^5,20 Our finding that participants taking higher dosages of opioids were not more likely to have better control over their pain supports this recommendation.

Limitations

This study has several limitations, the most significant is its small sample size because of the exploratory nature of the project. Results are based on a small pilot sample enriched to include individuals with at least moderate pain who receive opioids frequently at 1 VA CLC-PAC unit; therefore, the results might not be representative of all veterans or a more general population. Our small sample size limits power to detect small differences. Data collected should be used to inform formal power calculations before subsequent larger studies to select adequate sample size. Validation studies, including samples from the same population using different dates, which reproduce findings are an important step. Moreover, we only had data on a single dimension of pain (intensity/severity), as measured by the pain scale, which nursing staff used to make a real-time clinical decision of whether to administer an as-needed opioid. Future studies should consider using pain measures that provide multidimensional assessment (ie, severity, functional interference) and/or were developed specifically for veterans, such as the Defense and Veterans Pain Rating Scale.²¹

Our study was cross-sectional in nature and addressed a single 24-hour period of data per participant. The years of data collection (2016 and 2017) followed a decline in overall opioid prescribing that has continued, likely influenced by CDC and VA/DoD guidelines.²² It is unclear whether our observations are an accurate reflection of individuals’ response over time or whether prescribing practices in PAC have shifted.

We did not consider the type of pain being treated or explore clinicians’ reasons for prescribing opioids, therefore limiting our ability to know whether opioids were indicated. Information regarding OUD and other SUDs was limited to what was documented in the chart during the CLC-PAC unit admission. We did not have information on length of exposure to opioids. It is possible that opioid tolerance could play a role in reducing opioid responsiveness. However, simple tolerance would not be expected to explain robust correlations with psychiatric comorbidities. Also, simple tolerance would be expected to be overcome with higher opioid dosages, whereas our study demonstrates less responsiveness. These data suggests that some individuals’ pain might be poorly opioid responsive, and psychiatric factors could increase this risk. We used a novel data source in combination with chart review; to our knowledge, barcode medication administration data have not been used in this manner previously. Future work needs to validate this method, using larger sample sizes and several clinical sites. Finally, we used regression models that controlled for average pre-opioid pain rating scores, which is only 1 covariate important for examining effects. Larger studies with adequate power should control for multiple covariates known to be associated with pain and opioid response.

Conclusions

Opioid responsiveness is important clinically yet challenging to assess. This pilot study identifies a way of classifying pain as relatively opioid nonresponsive using administrative data but requires further validation before considering scaling for more general use. The possibility that a substantial percentage of residents in a CLC-PAC unit could be receiving increasing dosages of opioids without adequate benefit justifies the need for more research and underscores the need for prescribers to assess individuals frequently for ongoing benefit of opioids regardless of diagnosis or mechanism of pain.

Acknowledgments

The authors thank Andrzej Galecki, Corey Powell, and the University of Michigan Consulting for Statistics, Computing and Analytics Research Center for assistance with statistical analysis.

Older adults admitted to post-acute settings frequently have complex rehabilitation needs and multimorbidity, which predisposes them to pain management challenges.^1,2 The prevalence of pain in post-acute and long-term care is as high as 65%, and opioid use is common among this population with 1 in 7 residents receiving long-term opioids.^3,4

Opioids that do not adequately control pain represent a missed opportunity for deprescribing. There is limited evidence regarding efficacy of long-term opioid use (> 90 days) for improving pain and physical functioning.⁵ In addition, long-term opioid use carries significant risks, including overdose-related death, dependence, and increased emergency department visits.⁵ These risks are likely to be pronounced among veterans receiving post-acute care (PAC) who are older, have comorbid psychiatric disorders, are prescribed several centrally acting medications, and experience substance use disorder (SUD).⁶

Older adults are at increased risk for opioid toxicity because of reduced drug clearance and smaller therapeutic window.⁵ Centers for Disease Control and Prevention (CDC) guidelines recommend frequently assessing patients for benefit in terms of sustained improvement in pain as well as physical function.⁵ If pain and functional improvements are minimal, opioid use and nonopioid pain management strategies should be considered. Some patients will struggle with this approach. Directly asking patients about the effectiveness of opioids is challenging. Opioid users with chronic pain frequently report problems with opioids even as they describe them as indispensable for pain management.^7,8

Earlier studies have assessed patient perspectives regarding opioid difficulties as well as their helpfulness, which could introduce recall bias. Patient-level factors that contribute to a global sense of distress, in addition to the presence of painful physical conditions, also could contribute to patients requesting opioids without experiencing adequate pain relief. One study in veterans residing in PAC facilities found that individuals with depression, posttraumatic stress disorder (PTSD), and SUD were more likely to report pain and receive scheduled analgesics; this effect persisted in individuals with PTSD even after adjusting for demographic and functional status variables.⁹ The study looked only at analgesics as a class and did not examine opioids specifically. It is possible that distressed individuals, such as those with uncontrolled depression, PTSD, and SUD, might be more likely to report high pain levels and receive opioids with inadequate benefit and increased risk. Identifying the primary condition causing distress and targeting treatment to that condition (ie, depression) is preferable to escalating opioids in an attempt to treat pain in the context of nonresponse. Assessing an individual’s aggregate response to opioids rather than relying on a single self-report is a useful addition to current pain management strategies.

The goal of this study was to pilot a method of identifying opioid-nonresponsive pain using administrative data, measure its prevalence in a PAC population of veterans, and explore clinical and demographic correlates with particular attention to variates that could indicate high levels of psychological and physical distress. Identifying pain that is poorly responsive to opioids would give clinicians the opportunity to avoid or minimize opioid use and prioritize treatments that are likely to improve the resident’s pain, quality of life, and physical function while minimizing recall bias. We hypothesized that pain that responds poorly to opioids would be prevalent among veterans residing in a PAC unit. We considered that veterans with pain poorly responsive to opioids would be more likely to have factors that would place them at increased risk of adverse effects, such as comorbid psychiatric conditions, history of SUD, and multimorbidity, providing further rationale for clinical equipoise in that population.⁶

Methods

This was a small, retrospective cross-sectional study using administrative data and chart review. The study included veterans who were administered opioids while residing in a single US Department of Veterans Affairs (VA) community living center PAC (CLC-PAC) unit during at least 1 of 4 nonconsecutive, random days in 2016 and 2017. The study was approved by the institutional review board of the Ann Arbor VA Health System (#2017-1034) as part of a larger project involving models of care in vulnerable older veterans.

Inclusion criteria were the presence of at least moderate pain (≥ 4 on a 0 to 10 scale); receiving ≥ 2 opioids ordered as needed over the prespecified 24-hour observation period; and having ≥ 2 pre-and postopioid administration pain scores during the observation period. Veterans who did not meet these criteria were excluded. At the time of initial sample selection, we did not capture information related to coprescribed analgesics, including a standing order of opioids. To obtain the sample, we initially characterized all veterans on the 4 days residing in the CLC-PAC unit as those reporting at least moderate pain (≥ 4) and those who reported no or mild pain (< 4). The cut point of 4 of 10 is consistent with moderate pain based on earlier work showing higher likelihood of pain that interferes with physical function.¹⁰ We then restricted the sample to veterans who received ≥ 2 opioids ordered as needed for pain and had ≥ 2 pre- and postopioid administration numeric pain rating scores during the 24-hour observation period. This methodology was chosen to enrich our sample for those who received opioids regularly for ongoing pain. Opioids were defined as full µ-opioid receptor agonists and included hydrocodone, oxycodone, morphine, hydromorphone, fentanyl, tramadol, and methadone.

Outcome of Interest

The primary outcome of interest was an individual’s response to as-needed opioids, which we defined as change in the pain score after opioid administration. The pre-opioid pain score was the score that immediately preceded administration of an as-needed opioid. The postopioid administration pain score was the first score after opioid administration if obtained within 3 hours of administration. Scores collected > 3 hours after opioid administration were excluded because they no longer accurately reflected the impact of the opioid due to the short half-lives. Observations were excluded if an opioid was administered without a recorded pain score; this occurred once for 6 individuals. Observations also were excluded if an opioid was administered but the data were captured on the following day (outside of the 24-hour window); this occurred once for 3 individuals.

We calculated a ∆ score by subtracting the postopioid pain rating score from the pre-opioid score. Individual ∆ scores were then averaged over the 24-hour period (range, 2-5 opioid doses). For example, if an individual reported a pre-opioid pain score of 10, and a postopioid pain score of 2, the ∆ was recorded as 8. If the individual’s next pre-opioid score was 10, and post-opioid score was 6, the ∆ was recorded as 4. ∆ scores over the 24-hour period were averaged together to determine that individual’s response to as-needed opioids. In the previous example, the mean ∆ score is 6. Lower mean ∆ scores reflect decreased responsiveness to opioids’ analgesic effect.

Demographic and clinical data were obtained from electronic health record review using a standardized assessment form. These data included information about medical and psychiatric comorbidities, specialist consultations, and CLC-PAC unit admission indications and diagnoses. Medications of interest were categorized as antidepressants, antipsychotics, benzodiazepines, muscle relaxants, hypnotics, stimulants, antiepileptic drugs/mood stabilizers (including gabapentin and pregabalin), and all adjuvant analgesics. Adjuvant analgesics were defined as medications administered for pain as documented by chart notes or those ordered as needed for pain, and analyzed as a composite variable. Antidepressants with analgesic properties (serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants) were considered adjuvant analgesics. Psychiatric information collected included presence of mood, anxiety, and psychotic disorders, and PTSD. SUD information was collected separately from other psychiatric disorders.

Analyses

The study population was described using tabulations for categorical data and means and standard deviations for continuous data. Responsiveness to opioids was analyzed as a continuous variable. Those with higher mean ∆ scores were considered to have pain relatively more responsive to opioids, while lower mean ∆ scores indicated pain less responsive to opioids. We constructed linear regression models controlling for average pre-opioid pain rating scores to explore associations between opioid responsiveness and variables of interest. All analyses were completed using Stata version 15. This study was not adequately powered to detect differences across the spectrum of opioid responsiveness, although the authors have reported differences in this article.

Results

Over the 4-day observational period there were 146 resident-days. Of these, 88 (60.3%) reported at least 1 pain score of ≥ 4. Of those, 61 (41.8%) received ≥ 1 as-needed opioid for pain. We identified 46 resident-days meeting study criteria of ≥ 2 pre- and postanalgesic scores. We identified 41 unique individuals (Figure 1). Two individuals were admitted to the CLC-PAC unit on 2 of the 4 observation days, and 1 individual was admitted to the CLC-PAC unit on 3 of the 4 observation days. For individuals admitted several days, we included data only from the initial observation day.

Response to opioids varied greatly in this sample. The mean (SD) ∆ pain score was 3.4 (1.6) and ranged from 0.5 to 6.3. Using linear regression, we found no relationship between admission indication, medical comorbidities (including active cancer), and opioid responsiveness (Table).

A poorer response to opioids was associated with a significantly higher as-needed opioid dosage (β = −0.02; 95% CI, −0.04 to −0.01; P = .002) as well as a trend toward higher total opioid dosage (β = −0.005; 95% CI, −0.01 to 0.0003; P = .06) (Figure 4). Thirty-eight (92.7%) participants received nonopioid adjuvant analgesics for pain. More than half (56.1%) received antidepressants or gabapentinoids (51.2%), although we did not assess whether they were prescribed for pain or another indication. We did not identify a relationship between any specific psychoactive drug class and opioid responsiveness in this sample.

Discussion

This exploratory study used readily available administrative data in a CLC-PAC unit to assess responsiveness to opioids via a numeric mean ∆ score, with higher values indicating more pain relief in response to opioids. We then constructed linear regression models to characterize the relationship between the mean ∆ score and factors known to be associated with difficult-to-control pain and psychosocial distress. As expected, opioid responsiveness was highly variable among residents; some residents experienced essentially no reduction in pain, on average, despite receiving opioids. Psychiatric comorbidity, higher dosage in OMEs, and the presence of a pain service consult significantly correlated with poorer response to opioids. To our knowledge, this is the first study to quantify opioid responsiveness and describe the relationship with clinical correlates in the understudied PAC population.

Earlier research has demonstrated a relationship between the presence of psychiatric disorders and increased likelihood of receiving any analgesics among veterans residing in PAC.⁹ Our study adds to the literature by quantifying opioid response using readily available administrative data and examining associations with psychiatric diagnoses. These findings highlight the possibility that attempting to treat high levels of pain by escalating the opioid dosage in patients with a comorbid psychiatric diagnosis should be re-addressed, particularly if there is no meaningful pain reduction at lower opioid dosages. Our sample had a variety of admission diagnoses and medical comorbidities, however, we did not identify a relationship with opioid responsiveness, including an active cancer diagnosis. Although SUDs were highly prevalent in our sample, there was no relationship with opioid responsiveness. This suggests that lack of response to opioids is not merely a matter of drug tolerance or an indication of drug-seeking behavior.

Factors Impacting Response

Many factors could affect whether an individual obtains an adequate analgesic response to opioids or other pain medications, including variations in genes encoding opioid receptors and hepatic enzymes involved in drug metabolism and an individual’s opioid exposure history.¹³ The phenomenon of requiring more drug to produce the same relief after repeated exposures (ie, tolerance) is well known.¹⁴ Opioid-induced hyperalgesia is a phenomenon whereby a patient’s overall pain increases while receiving opioids, but each opioid dose might be perceived as beneficial.¹⁵ Increasingly, psychosocial distress is an important factor in opioid response. Adverse selection is the process culminating in those with psychosocial distress and/or SUDs being prescribed more opioids for longer durations.¹⁶ Our data suggests that this process could play a role in PAC settings. In addition, exaggerating pain to obtain additional opioids for nonmedical purposes, such as euphoria or relaxation, also is possible.¹⁷

When clinically assessing an individual whose pain is not well controlled despite escalating opioid dosages, prescribers must consider which of these factors likely is predominant. However, the first step of determining who has a poor opioid response is not straightforward. Directly asking patients is challenging; many individuals perceive opioids to be helpful while simultaneously reporting inadequately controlled pain.^7,8 The primary value of this study is the possibility of providing prescribers a quick, simple method of assessing a patient’s response to opioids. Using this method, individuals who are responding poorly to opioids, including those who might exaggerate pain for secondary gain, could be identified. Health care professionals could consider revisiting pain management strategies, assess for the presence of OUD, or evaluate other contributors to inadequately controlled pain. Although we only collected data regarding response to opioids in this study, any pain medication administered as needed (ie, nonsteroidal anti-inflammatory drugs, acetaminophen) could be analyzed using this methodology, allowing identification of other helpful pain management strategies. We began the validation process with extensive chart review, but further validation is required before this method can be applied to routine clinical practice.

Patients who report uncontrolled pain despite receiving opioids are a clinically challenging population. The traditional strategy has been to escalate opioids, which is recommended by the World Health Organization stepladder approach for patients with cancer pain and limited life expectancy.¹⁸ Applying this approach to a general population of patients with chronic pain is ineffective and dangerous.¹⁹ The CDC and the VA/US Department of Defense (VA/DoD) guidelines both recommend carefully reassessing risks and benefits at total daily dosages > 50 OME and avoid increasing dosages to > 90 OME daily in most circumstances.^5,20 Our finding that participants taking higher dosages of opioids were not more likely to have better control over their pain supports this recommendation.

Limitations

This study has several limitations, the most significant is its small sample size because of the exploratory nature of the project. Results are based on a small pilot sample enriched to include individuals with at least moderate pain who receive opioids frequently at 1 VA CLC-PAC unit; therefore, the results might not be representative of all veterans or a more general population. Our small sample size limits power to detect small differences. Data collected should be used to inform formal power calculations before subsequent larger studies to select adequate sample size. Validation studies, including samples from the same population using different dates, which reproduce findings are an important step. Moreover, we only had data on a single dimension of pain (intensity/severity), as measured by the pain scale, which nursing staff used to make a real-time clinical decision of whether to administer an as-needed opioid. Future studies should consider using pain measures that provide multidimensional assessment (ie, severity, functional interference) and/or were developed specifically for veterans, such as the Defense and Veterans Pain Rating Scale.²¹

Our study was cross-sectional in nature and addressed a single 24-hour period of data per participant. The years of data collection (2016 and 2017) followed a decline in overall opioid prescribing that has continued, likely influenced by CDC and VA/DoD guidelines.²² It is unclear whether our observations are an accurate reflection of individuals’ response over time or whether prescribing practices in PAC have shifted.

We did not consider the type of pain being treated or explore clinicians’ reasons for prescribing opioids, therefore limiting our ability to know whether opioids were indicated. Information regarding OUD and other SUDs was limited to what was documented in the chart during the CLC-PAC unit admission. We did not have information on length of exposure to opioids. It is possible that opioid tolerance could play a role in reducing opioid responsiveness. However, simple tolerance would not be expected to explain robust correlations with psychiatric comorbidities. Also, simple tolerance would be expected to be overcome with higher opioid dosages, whereas our study demonstrates less responsiveness. These data suggests that some individuals’ pain might be poorly opioid responsive, and psychiatric factors could increase this risk. We used a novel data source in combination with chart review; to our knowledge, barcode medication administration data have not been used in this manner previously. Future work needs to validate this method, using larger sample sizes and several clinical sites. Finally, we used regression models that controlled for average pre-opioid pain rating scores, which is only 1 covariate important for examining effects. Larger studies with adequate power should control for multiple covariates known to be associated with pain and opioid response.

Conclusions

Opioid responsiveness is important clinically yet challenging to assess. This pilot study identifies a way of classifying pain as relatively opioid nonresponsive using administrative data but requires further validation before considering scaling for more general use. The possibility that a substantial percentage of residents in a CLC-PAC unit could be receiving increasing dosages of opioids without adequate benefit justifies the need for more research and underscores the need for prescribers to assess individuals frequently for ongoing benefit of opioids regardless of diagnosis or mechanism of pain.

Acknowledgments

The authors thank Andrzej Galecki, Corey Powell, and the University of Michigan Consulting for Statistics, Computing and Analytics Research Center for assistance with statistical analysis.

A survey of 323 women cardiologists who were working while they were pregnant showed that nearly 75% experienced discriminatory maternity-leave practices, some of which were likely violations of the Family and Medical Leave Act (FMLA).

More than 40% saw their salaries decreased during their year of pregnancy, 38% were required to perform extra service or call before taking maternity leave, exposing them to occupational hazards such as radiation, and 40% experienced a pregnancy complication, significantly higher than the general population and other medical specialties.

Additionally, of those who performed extra service or call, 18% were placed on bedrest before delivery, compared with 7.4% who did not perform extra service or call.

More than half of respondents reported that pregnancy negatively impacted their careers, and 42.4% said they experienced pressure to return to work and a delay in promotions, both illegal practices under the FMLA.

The survey is published in the Journal of the American College of Cardiology.

“Childbearing is difficult for women in cardiology with more than double the rate of gestational complications of the U.S. population, frequent income loss out of proportion to reduced productivity, and for nearly half, has an adverse impact on their career,” lead author Martha Gulati, MD, University of Arizona, Phoenix, said in a statement.

“While many professions struggle to create environments supportive of pregnancy and child-rearing, the prevalence of illegal behavior in cardiology is quite high and presents substantial legal risk for employers,” Dr. Gulati added.

C. Noel Bairey Merz, MD, professor of cardiology at Cedars-Sinai Smidt Heart Institute, Los Angeles, and a coauthor of the survey, told this news organization that it’s not surprising that such a situation exists, even “in this day and age.”

“I’m not surprised as a woman in cardiology myself. I was told by my training director that if I took off more than my allowed sick leave when I had my first and second children, I would have to repeat the year of training, so not surprised at all. I hear this from colleagues all the time,” Dr. Bairey Merz said.

The exchange left her feeling fearful for her career.

“Who wants to repeat a year? It pushes you back from a career standpoint, financially, everything. It also made me angry. I had a colleague who busted his leg in a motorcycle accident. He was unable to do any procedures for 16 weeks, and he didn’t have to repeat the year,” she pointed out.

The challenge that pregnancy represents is frequently cited by women as a deterrent for applying for a cardiology fellowship, Laxmi S. Mehta, MD, Ohio State University, Columbus, and colleagues wrote in an accompanying editorial.

The findings from the survey “reveal restrictive maternity leave data in a profession that has historically and currently continues to have a diversity problem,” they wrote.

“Maternity and pregnancy issues are a thing in cardiology,” Dr. Mehta said in an interview. “It’s one of the reasons why women get deterred from going into the field. It makes it challenging to choose cardiology if you perceive that the culture is negative, that it’s hard to be pregnant, or to bear children, or to take care of them post partum. It is problematic and it should not be occurring now.”

Leadership that condones such restrictive policies or even promotes them through ignorance and inaction needs to be held accountable, she added.

“We need to move forward from this negativity and make it more warm and welcoming to have families, whether you are a trainee or a practicing cardiologist, male or female. We need transparent and consistent parental leave policies and things like lactation support when a woman returns to work. That is a big issue,” Dr. Mehta said.

Having cardiovascular leaders champion the cause of adequate maternity and paternity leave are crucial to creating a newer, inclusive environment in cardiology.

As an example, Dr. Mehta recounted her own experience when she was in training 17 years ago.

“When I interviewed for a cardiology fellowship, one of the female program directors asked me if I was planning to have children, because if I did, the other fellows wouldn’t like it if they had to cover for me,” she said. “I ended up doing my fellowship where the chief of cardiology encouraged me to have children. He said: ‘Have your children during training, we will support you.’ And he did. I still had to do all of the call make-up and that stuff, but I worked in a supportive environment, and it made all the difference.”

“It’s about allyship,” she added. “You will have some people who are supportive and some who are not, but when you have the chief supporting you, you have a strong ally.”

The researchers suggest that one strategy is to temporarily replace cardiologists on maternity leave with locums, or “deepen the bench of coverage for clinical work, as is done for other absences. Given the expanding coverage of parental and family medical leaves, and awareness of these issues nationally, the need for this is likely to become less of an exception and more the rule.”

For example, nine states and Washington, D.C. now provide paid parental leave, they wrote, “and there is pending legislation in others.”

Dr. Bairey Merz and Dr. Mehta reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A survey of 323 women cardiologists who were working while they were pregnant showed that nearly 75% experienced discriminatory maternity-leave practices, some of which were likely violations of the Family and Medical Leave Act (FMLA).

More than 40% saw their salaries decreased during their year of pregnancy, 38% were required to perform extra service or call before taking maternity leave, exposing them to occupational hazards such as radiation, and 40% experienced a pregnancy complication, significantly higher than the general population and other medical specialties.

Additionally, of those who performed extra service or call, 18% were placed on bedrest before delivery, compared with 7.4% who did not perform extra service or call.

More than half of respondents reported that pregnancy negatively impacted their careers, and 42.4% said they experienced pressure to return to work and a delay in promotions, both illegal practices under the FMLA.

The survey is published in the Journal of the American College of Cardiology.

“Childbearing is difficult for women in cardiology with more than double the rate of gestational complications of the U.S. population, frequent income loss out of proportion to reduced productivity, and for nearly half, has an adverse impact on their career,” lead author Martha Gulati, MD, University of Arizona, Phoenix, said in a statement.

“While many professions struggle to create environments supportive of pregnancy and child-rearing, the prevalence of illegal behavior in cardiology is quite high and presents substantial legal risk for employers,” Dr. Gulati added.

C. Noel Bairey Merz, MD, professor of cardiology at Cedars-Sinai Smidt Heart Institute, Los Angeles, and a coauthor of the survey, told this news organization that it’s not surprising that such a situation exists, even “in this day and age.”

“I’m not surprised as a woman in cardiology myself. I was told by my training director that if I took off more than my allowed sick leave when I had my first and second children, I would have to repeat the year of training, so not surprised at all. I hear this from colleagues all the time,” Dr. Bairey Merz said.

The exchange left her feeling fearful for her career.

“Who wants to repeat a year? It pushes you back from a career standpoint, financially, everything. It also made me angry. I had a colleague who busted his leg in a motorcycle accident. He was unable to do any procedures for 16 weeks, and he didn’t have to repeat the year,” she pointed out.

The challenge that pregnancy represents is frequently cited by women as a deterrent for applying for a cardiology fellowship, Laxmi S. Mehta, MD, Ohio State University, Columbus, and colleagues wrote in an accompanying editorial.

The findings from the survey “reveal restrictive maternity leave data in a profession that has historically and currently continues to have a diversity problem,” they wrote.

“Maternity and pregnancy issues are a thing in cardiology,” Dr. Mehta said in an interview. “It’s one of the reasons why women get deterred from going into the field. It makes it challenging to choose cardiology if you perceive that the culture is negative, that it’s hard to be pregnant, or to bear children, or to take care of them post partum. It is problematic and it should not be occurring now.”

Leadership that condones such restrictive policies or even promotes them through ignorance and inaction needs to be held accountable, she added.

“We need to move forward from this negativity and make it more warm and welcoming to have families, whether you are a trainee or a practicing cardiologist, male or female. We need transparent and consistent parental leave policies and things like lactation support when a woman returns to work. That is a big issue,” Dr. Mehta said.

Having cardiovascular leaders champion the cause of adequate maternity and paternity leave are crucial to creating a newer, inclusive environment in cardiology.

As an example, Dr. Mehta recounted her own experience when she was in training 17 years ago.

“When I interviewed for a cardiology fellowship, one of the female program directors asked me if I was planning to have children, because if I did, the other fellows wouldn’t like it if they had to cover for me,” she said. “I ended up doing my fellowship where the chief of cardiology encouraged me to have children. He said: ‘Have your children during training, we will support you.’ And he did. I still had to do all of the call make-up and that stuff, but I worked in a supportive environment, and it made all the difference.”

“It’s about allyship,” she added. “You will have some people who are supportive and some who are not, but when you have the chief supporting you, you have a strong ally.”

The researchers suggest that one strategy is to temporarily replace cardiologists on maternity leave with locums, or “deepen the bench of coverage for clinical work, as is done for other absences. Given the expanding coverage of parental and family medical leaves, and awareness of these issues nationally, the need for this is likely to become less of an exception and more the rule.”

For example, nine states and Washington, D.C. now provide paid parental leave, they wrote, “and there is pending legislation in others.”

Dr. Bairey Merz and Dr. Mehta reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A survey of 323 women cardiologists who were working while they were pregnant showed that nearly 75% experienced discriminatory maternity-leave practices, some of which were likely violations of the Family and Medical Leave Act (FMLA).

More than 40% saw their salaries decreased during their year of pregnancy, 38% were required to perform extra service or call before taking maternity leave, exposing them to occupational hazards such as radiation, and 40% experienced a pregnancy complication, significantly higher than the general population and other medical specialties.

Additionally, of those who performed extra service or call, 18% were placed on bedrest before delivery, compared with 7.4% who did not perform extra service or call.

More than half of respondents reported that pregnancy negatively impacted their careers, and 42.4% said they experienced pressure to return to work and a delay in promotions, both illegal practices under the FMLA.

The survey is published in the Journal of the American College of Cardiology.

“Childbearing is difficult for women in cardiology with more than double the rate of gestational complications of the U.S. population, frequent income loss out of proportion to reduced productivity, and for nearly half, has an adverse impact on their career,” lead author Martha Gulati, MD, University of Arizona, Phoenix, said in a statement.

“While many professions struggle to create environments supportive of pregnancy and child-rearing, the prevalence of illegal behavior in cardiology is quite high and presents substantial legal risk for employers,” Dr. Gulati added.

C. Noel Bairey Merz, MD, professor of cardiology at Cedars-Sinai Smidt Heart Institute, Los Angeles, and a coauthor of the survey, told this news organization that it’s not surprising that such a situation exists, even “in this day and age.”

“I’m not surprised as a woman in cardiology myself. I was told by my training director that if I took off more than my allowed sick leave when I had my first and second children, I would have to repeat the year of training, so not surprised at all. I hear this from colleagues all the time,” Dr. Bairey Merz said.

The exchange left her feeling fearful for her career.

“Who wants to repeat a year? It pushes you back from a career standpoint, financially, everything. It also made me angry. I had a colleague who busted his leg in a motorcycle accident. He was unable to do any procedures for 16 weeks, and he didn’t have to repeat the year,” she pointed out.

The challenge that pregnancy represents is frequently cited by women as a deterrent for applying for a cardiology fellowship, Laxmi S. Mehta, MD, Ohio State University, Columbus, and colleagues wrote in an accompanying editorial.

The findings from the survey “reveal restrictive maternity leave data in a profession that has historically and currently continues to have a diversity problem,” they wrote.

“Maternity and pregnancy issues are a thing in cardiology,” Dr. Mehta said in an interview. “It’s one of the reasons why women get deterred from going into the field. It makes it challenging to choose cardiology if you perceive that the culture is negative, that it’s hard to be pregnant, or to bear children, or to take care of them post partum. It is problematic and it should not be occurring now.”

Leadership that condones such restrictive policies or even promotes them through ignorance and inaction needs to be held accountable, she added.

“We need to move forward from this negativity and make it more warm and welcoming to have families, whether you are a trainee or a practicing cardiologist, male or female. We need transparent and consistent parental leave policies and things like lactation support when a woman returns to work. That is a big issue,” Dr. Mehta said.

Having cardiovascular leaders champion the cause of adequate maternity and paternity leave are crucial to creating a newer, inclusive environment in cardiology.

As an example, Dr. Mehta recounted her own experience when she was in training 17 years ago.

“When I interviewed for a cardiology fellowship, one of the female program directors asked me if I was planning to have children, because if I did, the other fellows wouldn’t like it if they had to cover for me,” she said. “I ended up doing my fellowship where the chief of cardiology encouraged me to have children. He said: ‘Have your children during training, we will support you.’ And he did. I still had to do all of the call make-up and that stuff, but I worked in a supportive environment, and it made all the difference.”

“It’s about allyship,” she added. “You will have some people who are supportive and some who are not, but when you have the chief supporting you, you have a strong ally.”

The researchers suggest that one strategy is to temporarily replace cardiologists on maternity leave with locums, or “deepen the bench of coverage for clinical work, as is done for other absences. Given the expanding coverage of parental and family medical leaves, and awareness of these issues nationally, the need for this is likely to become less of an exception and more the rule.”

For example, nine states and Washington, D.C. now provide paid parental leave, they wrote, “and there is pending legislation in others.”

Dr. Bairey Merz and Dr. Mehta reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved donepezil transdermal system (Adlarity) for patients with mild, moderate, or severe Alzheimer’s disease, the manufacturer has announced.

Adlarity is the first and only once-weekly patch to continuously deliver consistent doses of the acetylcholinesterase inhibitor through the skin, bypassing the digestive system and resulting in low likelihood of gastrointestinal side effects associated with oral donepezil, the company said in a press release.

Each patch delivers either 5 mg or 10 mg of donepezil daily for 7 days. After that, it is removed and a new patch is applied.

“The availability of a once-weekly patch formulation of donepezil has the potential to substantially benefit patients, caregivers, and health care providers,” Pierre Tariot, MD, director of the Banner Alzheimer’s Institute, Phoenix, said in the release.

“It offers effective, well-tolerated, and stable dosing for 7 days for patients who cannot take daily oral donepezil reliably because of impaired memory. It can also offer benefits for those patients who have diminished ability to swallow or have GI side effects associated with ingestion of oral donepezil,” Dr. Tariot added.

The FDA approved Adlarity through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

The company expects the donepezil transdermal patch to be available in early Fall 2022.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved donepezil transdermal system (Adlarity) for patients with mild, moderate, or severe Alzheimer’s disease, the manufacturer has announced.

Adlarity is the first and only once-weekly patch to continuously deliver consistent doses of the acetylcholinesterase inhibitor through the skin, bypassing the digestive system and resulting in low likelihood of gastrointestinal side effects associated with oral donepezil, the company said in a press release.

Each patch delivers either 5 mg or 10 mg of donepezil daily for 7 days. After that, it is removed and a new patch is applied.

“The availability of a once-weekly patch formulation of donepezil has the potential to substantially benefit patients, caregivers, and health care providers,” Pierre Tariot, MD, director of the Banner Alzheimer’s Institute, Phoenix, said in the release.

“It offers effective, well-tolerated, and stable dosing for 7 days for patients who cannot take daily oral donepezil reliably because of impaired memory. It can also offer benefits for those patients who have diminished ability to swallow or have GI side effects associated with ingestion of oral donepezil,” Dr. Tariot added.

The FDA approved Adlarity through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

The company expects the donepezil transdermal patch to be available in early Fall 2022.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved donepezil transdermal system (Adlarity) for patients with mild, moderate, or severe Alzheimer’s disease, the manufacturer has announced.

Adlarity is the first and only once-weekly patch to continuously deliver consistent doses of the acetylcholinesterase inhibitor through the skin, bypassing the digestive system and resulting in low likelihood of gastrointestinal side effects associated with oral donepezil, the company said in a press release.

Each patch delivers either 5 mg or 10 mg of donepezil daily for 7 days. After that, it is removed and a new patch is applied.

“The availability of a once-weekly patch formulation of donepezil has the potential to substantially benefit patients, caregivers, and health care providers,” Pierre Tariot, MD, director of the Banner Alzheimer’s Institute, Phoenix, said in the release.

“It offers effective, well-tolerated, and stable dosing for 7 days for patients who cannot take daily oral donepezil reliably because of impaired memory. It can also offer benefits for those patients who have diminished ability to swallow or have GI side effects associated with ingestion of oral donepezil,” Dr. Tariot added.

The FDA approved Adlarity through the 505(b)(2) regulatory pathway, which allows the agency to refer to previous findings of safety and efficacy for an already-approved product, as well as to review findings from further studies of the product.

The company expects the donepezil transdermal patch to be available in early Fall 2022.

A version of this article first appeared on Medscape.com.

Severe food insecurity was associated with metabolic syndrome and unfavorable cardiometabolic markers in Hispanic/Latino youth, researchers report.

The findings, published March 16 in Pediatrics, highlight the need to investigate interventions that address food insecurity among Hispanic/Latino youth, a segment of the U.S. population at high risk of cardiometabolic complications.

“Among Hispanic/Latino youth, no study, to our knowledge has evaluated food insecurity’s role in metabolic syndrome and metabolic syndrome–relevant cardiometabolic markers in this population,” lead author Luis E. Maldonado, PhD, of the University of North Carolina at Chapel Hill, and colleagues explained.

The researchers conducted a cross-sectional study to evaluate the associations between lower household and child food security and metabolic syndrome, as well as clinically measured cardiometabolic markers, including fasting plasma glucose, waist circumference, triglycerides, systolic and diastolic blood pressure, and high-density lipoprotein cholesterol (HDL-C).

Household food security (high, marginal, low, very low) and child food security (high, marginal, low/very low) measures were evaluated separately, and were adjusted for participant age, sex, site, parental education, and poverty-income ratio.

Data were obtained from the Hispanic Community Children’s Health Study/Study of Latino Youth, a study of offspring of adults enrolled in the Hispanic Community Health Survey/Study of Latinos.
 

Results

The study cohort included 1,325 Hispanic/Latino youth aged 8-16 years. For both household food security and child food security, youth in the lowest food security category had significantly lower HDL-C compared with youth with high food security (household food security, –3.17; 95% confidence interval, –5.65 to –0.70; child food security, –1.81; 95% CI, –3.54 to –0.09).

In addition, low/very low compared with high child food security was associated with higher triglycerides (beta, 8.68; 95% CI, 1.75-15.61), higher fasting plasma glucose (beta, 1.37; 95% CI, 0.08-2.65), and metabolic syndrome composite variable expected log counts (beta, 2.12; 95% CI, 0.02-0.45).

Furthermore, the researchers found statistically significant interactions between each of the two food security measures and receipt of any food assistance in the previous year in models of triglycerides (P for interactions: household food security, .03 and child food security, .005) and HDL-C (P for interactions: household food security, .01 and child food security, .04).

After evaluating the effect of parental place of birth, they found a statistically significant association for triglycerides only (P for interactions: household food security, .05 and child food security, .008).

“Our study is among the first to document adverse associations between household and child food security measures with a metabolic syndrome score variable and several metabolic syndrome–relevant cardiometabolic markers among US Hispanic/Latino youth,” the researchers wrote.

The researchers acknowledged that the cross-sectional nature of the study was a key limitation; thus, causality could not be inferred.

“In the future, we plan to conduct more qualitative work to better understand how Hispanic/Latino families respond to food insecurity, which may identify the factors that shape their response,” study author Sandra S. Albrecht, PhD, of Columbia University, New York, NY, said in an interview.
 

Recommendations for pediatricians

Food insecurity researcher Yankun Wang, PhD candidate at Indiana University, Bloomington, commented: “I would recommend pediatricians pay more attention to children from low-income households since they are more likely to have mental and physical health issues due to food insecurity.

“It can be very helpful if pediatricians could help families obtain SNAP benefits, enroll youth in the school breakfast and lunch programs, and promote nutrition education in schools,” Mr. Wang added.

This study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported no relevant disclosures.

Severe food insecurity was associated with metabolic syndrome and unfavorable cardiometabolic markers in Hispanic/Latino youth, researchers report.

The findings, published March 16 in Pediatrics, highlight the need to investigate interventions that address food insecurity among Hispanic/Latino youth, a segment of the U.S. population at high risk of cardiometabolic complications.

“Among Hispanic/Latino youth, no study, to our knowledge has evaluated food insecurity’s role in metabolic syndrome and metabolic syndrome–relevant cardiometabolic markers in this population,” lead author Luis E. Maldonado, PhD, of the University of North Carolina at Chapel Hill, and colleagues explained.

The researchers conducted a cross-sectional study to evaluate the associations between lower household and child food security and metabolic syndrome, as well as clinically measured cardiometabolic markers, including fasting plasma glucose, waist circumference, triglycerides, systolic and diastolic blood pressure, and high-density lipoprotein cholesterol (HDL-C).

Household food security (high, marginal, low, very low) and child food security (high, marginal, low/very low) measures were evaluated separately, and were adjusted for participant age, sex, site, parental education, and poverty-income ratio.

Data were obtained from the Hispanic Community Children’s Health Study/Study of Latino Youth, a study of offspring of adults enrolled in the Hispanic Community Health Survey/Study of Latinos.
 

Results

The study cohort included 1,325 Hispanic/Latino youth aged 8-16 years. For both household food security and child food security, youth in the lowest food security category had significantly lower HDL-C compared with youth with high food security (household food security, –3.17; 95% confidence interval, –5.65 to –0.70; child food security, –1.81; 95% CI, –3.54 to –0.09).

In addition, low/very low compared with high child food security was associated with higher triglycerides (beta, 8.68; 95% CI, 1.75-15.61), higher fasting plasma glucose (beta, 1.37; 95% CI, 0.08-2.65), and metabolic syndrome composite variable expected log counts (beta, 2.12; 95% CI, 0.02-0.45).

Furthermore, the researchers found statistically significant interactions between each of the two food security measures and receipt of any food assistance in the previous year in models of triglycerides (P for interactions: household food security, .03 and child food security, .005) and HDL-C (P for interactions: household food security, .01 and child food security, .04).

After evaluating the effect of parental place of birth, they found a statistically significant association for triglycerides only (P for interactions: household food security, .05 and child food security, .008).

“Our study is among the first to document adverse associations between household and child food security measures with a metabolic syndrome score variable and several metabolic syndrome–relevant cardiometabolic markers among US Hispanic/Latino youth,” the researchers wrote.

The researchers acknowledged that the cross-sectional nature of the study was a key limitation; thus, causality could not be inferred.

“In the future, we plan to conduct more qualitative work to better understand how Hispanic/Latino families respond to food insecurity, which may identify the factors that shape their response,” study author Sandra S. Albrecht, PhD, of Columbia University, New York, NY, said in an interview.
 

Recommendations for pediatricians

Food insecurity researcher Yankun Wang, PhD candidate at Indiana University, Bloomington, commented: “I would recommend pediatricians pay more attention to children from low-income households since they are more likely to have mental and physical health issues due to food insecurity.

“It can be very helpful if pediatricians could help families obtain SNAP benefits, enroll youth in the school breakfast and lunch programs, and promote nutrition education in schools,” Mr. Wang added.

This study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported no relevant disclosures.

Severe food insecurity was associated with metabolic syndrome and unfavorable cardiometabolic markers in Hispanic/Latino youth, researchers report.

The findings, published March 16 in Pediatrics, highlight the need to investigate interventions that address food insecurity among Hispanic/Latino youth, a segment of the U.S. population at high risk of cardiometabolic complications.

“Among Hispanic/Latino youth, no study, to our knowledge has evaluated food insecurity’s role in metabolic syndrome and metabolic syndrome–relevant cardiometabolic markers in this population,” lead author Luis E. Maldonado, PhD, of the University of North Carolina at Chapel Hill, and colleagues explained.

The researchers conducted a cross-sectional study to evaluate the associations between lower household and child food security and metabolic syndrome, as well as clinically measured cardiometabolic markers, including fasting plasma glucose, waist circumference, triglycerides, systolic and diastolic blood pressure, and high-density lipoprotein cholesterol (HDL-C).

Household food security (high, marginal, low, very low) and child food security (high, marginal, low/very low) measures were evaluated separately, and were adjusted for participant age, sex, site, parental education, and poverty-income ratio.

Data were obtained from the Hispanic Community Children’s Health Study/Study of Latino Youth, a study of offspring of adults enrolled in the Hispanic Community Health Survey/Study of Latinos.
 

Results

The study cohort included 1,325 Hispanic/Latino youth aged 8-16 years. For both household food security and child food security, youth in the lowest food security category had significantly lower HDL-C compared with youth with high food security (household food security, –3.17; 95% confidence interval, –5.65 to –0.70; child food security, –1.81; 95% CI, –3.54 to –0.09).

In addition, low/very low compared with high child food security was associated with higher triglycerides (beta, 8.68; 95% CI, 1.75-15.61), higher fasting plasma glucose (beta, 1.37; 95% CI, 0.08-2.65), and metabolic syndrome composite variable expected log counts (beta, 2.12; 95% CI, 0.02-0.45).

Furthermore, the researchers found statistically significant interactions between each of the two food security measures and receipt of any food assistance in the previous year in models of triglycerides (P for interactions: household food security, .03 and child food security, .005) and HDL-C (P for interactions: household food security, .01 and child food security, .04).

After evaluating the effect of parental place of birth, they found a statistically significant association for triglycerides only (P for interactions: household food security, .05 and child food security, .008).

“Our study is among the first to document adverse associations between household and child food security measures with a metabolic syndrome score variable and several metabolic syndrome–relevant cardiometabolic markers among US Hispanic/Latino youth,” the researchers wrote.

The researchers acknowledged that the cross-sectional nature of the study was a key limitation; thus, causality could not be inferred.

“In the future, we plan to conduct more qualitative work to better understand how Hispanic/Latino families respond to food insecurity, which may identify the factors that shape their response,” study author Sandra S. Albrecht, PhD, of Columbia University, New York, NY, said in an interview.
 

Recommendations for pediatricians

Food insecurity researcher Yankun Wang, PhD candidate at Indiana University, Bloomington, commented: “I would recommend pediatricians pay more attention to children from low-income households since they are more likely to have mental and physical health issues due to food insecurity.

“It can be very helpful if pediatricians could help families obtain SNAP benefits, enroll youth in the school breakfast and lunch programs, and promote nutrition education in schools,” Mr. Wang added.

This study was supported by grant funding from the National Heart, Lung, and Blood Institute. The authors reported no relevant disclosures.

The American Academy of Neurology (AAN) has released new expert guidance on palliative care for patients with stroke, dementia, Parkinson’s disease, and other neurologic disorders.

Palliative care includes much more than hospice services, lead author of the new position statement Lynne P. Taylor, MD, University of Washington, Seattle, and a fellow of the AAN, said in a press release.

“Neurologists provide palliative care to people living with life-altering neurologic illnesses not just at the end of life but throughout the course of a disease, improving their lives with symptom control,” Dr. Taylor added.

The position paper, developed by a joint committee of the AAN, American Neurological Association, and Child Neurology Society, was published online March 8 in Neurology.
 

Guidance across the lifespan

The new paper, an update of previous position statements, includes palliative care guidance for different neurologic disorders across the lifespan. For example, neuropalliative care for neonates deserves “extra consideration,” because one-third of pediatric deaths occur during the neonatal period, most often in the neonatal intensive care unit, and after withdrawal of life-sustaining interventions, the authors note.

For older children, neuropalliative care consultation benefits families trying to maximize the quality of the remainder of their child’s life. Decisionmaking must consider the child’s cognitive abilities, the diagnosis, the perceived level of suffering, parental values, and the family’s understanding of the prognosis, the authors note.

They note that discussions about prognosis are often difficult but critical. Previous research “supports that patients desire prognostic information even when prognosis is uncertain and appreciate when their physicians disclose the presence of that uncertainty,” the authors note.

Also important is engaging in shared decisionmaking with patients and families. “This approach requires the physician to elicit a patient’s goals, make recommendations based on whether medical treatments are likely to achieve those goals, and work with patients and families to finalize a treatment plan,” according to the new guidance.
 

Ethical considerations

When treatments are physiologically futile, clinicians need to explain why interventions that may cause harm and have no benefit are not offered.

The authors cite cardiopulmonary resuscitation in the setting of cardiac arrest from irreversible herniation as an example of futility in the context of neurologic disease.

When life-prolonging care is no longer an option, clinicians have an obligation to shift the focus of care to preserving quality of life and comfort as much as possible, they add.

Hospices, which provide comfort-focused medical care as well as psychosocial and spiritual support, are reserved for patients believed to be in the last 6 months of their life if their disease follows the expected course.

The investigators also broached ethical considerations for individual neurologic conditions. Concerns for disorders of consciousness include misdiagnosis or inaccurate prognostication, and serial examinations are needed to re-evaluate levels of cognition, psychological state, decisionmaking capacity, and disease trajectory.

In patients with locked-in syndrome, a state of irreversible paralysis, often with respiratory and vocal paralysis, consciousness may range from a chronic minimally conscious state to intact cognition.

Without careful examination, patients with preserved consciousness may be mistaken as having a disorder of consciousness and risk their decisional capacity being ignored, the researchers note.

These patients may need assistance from speech pathologists to identify techniques to enhance communication, such as careful “yes/no” questioning, communication boards, or advanced eye-gaze technology, they add.
 

Stroke, dementia, Parkinson’s guidance

For stroke, the guidance suggests neurologists encourage patients with retained decisionmaking capacity to complete advance care planning given the risk of recurrent stroke and loss of capacity in the future.

For dementia, a proper and timely diagnosis can help patients and their families prepare for the consequences of cognitive dysfunction and loss of autonomy while respecting their identified values, the authors write.

They note that for Parkinson’s disease, which is marked by slow functional and cognitive decline, neurologists must aim to anticipate and treat symptoms, address psychosocial and spiritual distress and caregiver burden, and engage patients and families in advance care planning before onset of cognitive impairment.

For patients with amyotrophic lateral sclerosis (ALS) and related disorders, clinicians should aim to document goals and treatment preferences prior to extreme weakness and aphonia.

It is also important to anticipate patient preferences for future disability-specific decisions, such as those related to feeding tubes and mechanical ventilation, and to identify the patient’s minimal acceptable outcome from these life-sustaining interventions.

On the topic of withdrawal of treatment, the paper notes that competent patients have the right to refuse life-prolonging therapies, including artificial nutrition, hydration, mechanical ventilation, and antibiotics. If physicians have a moral objection to removing life-support systems, they are obligated to transfer the care of the patient to another physician, the authors add.

Once a decision is made to forgo life-sustaining treatment, physicians should minimize subsequent suffering. The investigators note most symptoms at the end of life can be managed without sedation.

In broaching the “gap” in neurology training programs, the statement referred to a survey of 49 neurology residency programs. Results showed that 42% of respondents reported being dissatisfied with their palliative care education.
 

Well-timed update

Kate T. Brizzi, MD, a Boston neurologist with experience in hospice and palliative care, said the updated position statement is “well-timed” as neuropalliative care has evolved dramatically over the last decade.

“In the last several years, I’ve witnessed a significant increase in trainee interest in the field, and there is growing recognition of how a palliative care approach can improve patient care and hopefully outcomes,” said Dr. Brizzi.

She praised the authors for doing “an excellent job” in highlighting the ethical challenges facing the neurology provider, particularly as it relates to prognostication in an uncertain setting.

Dr. Brizzi noted communication tools that help facilitate discussions around shared decisionmaking “have enhanced our ability to meet the palliative care needs of our patients and can be incorporated by any provider.”

However, she added that the paper only briefly comments on the role of the neurologist in “lawful physician-hastened death.”

“I anticipate that this will be an area of further discussion in the neurology and palliative care community in the future, as requests for hastened death are frequently encountered from patients with serious neurologic illness,” she said.

Dr. Brizzi also noted the importance of understanding the reasons behind the request – and addressing patient worries related to end-of-life care, which can frequently help alleviate distress.

There was no targeted funding for this paper. Coauthor Salvador Cruz-Flores, MD, department of neurology, Texas Tech University Center, El Paso, reported participation on member adjudication committees for clinical trials for Novo Nordisk, Sunovion, and Galapagos. The remaining authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The American Academy of Neurology (AAN) has released new expert guidance on palliative care for patients with stroke, dementia, Parkinson’s disease, and other neurologic disorders.

Palliative care includes much more than hospice services, lead author of the new position statement Lynne P. Taylor, MD, University of Washington, Seattle, and a fellow of the AAN, said in a press release.

“Neurologists provide palliative care to people living with life-altering neurologic illnesses not just at the end of life but throughout the course of a disease, improving their lives with symptom control,” Dr. Taylor added.

The position paper, developed by a joint committee of the AAN, American Neurological Association, and Child Neurology Society, was published online March 8 in Neurology.
 

Guidance across the lifespan

The new paper, an update of previous position statements, includes palliative care guidance for different neurologic disorders across the lifespan. For example, neuropalliative care for neonates deserves “extra consideration,” because one-third of pediatric deaths occur during the neonatal period, most often in the neonatal intensive care unit, and after withdrawal of life-sustaining interventions, the authors note.

For older children, neuropalliative care consultation benefits families trying to maximize the quality of the remainder of their child’s life. Decisionmaking must consider the child’s cognitive abilities, the diagnosis, the perceived level of suffering, parental values, and the family’s understanding of the prognosis, the authors note.

They note that discussions about prognosis are often difficult but critical. Previous research “supports that patients desire prognostic information even when prognosis is uncertain and appreciate when their physicians disclose the presence of that uncertainty,” the authors note.

Also important is engaging in shared decisionmaking with patients and families. “This approach requires the physician to elicit a patient’s goals, make recommendations based on whether medical treatments are likely to achieve those goals, and work with patients and families to finalize a treatment plan,” according to the new guidance.
 

Ethical considerations

When treatments are physiologically futile, clinicians need to explain why interventions that may cause harm and have no benefit are not offered.

The authors cite cardiopulmonary resuscitation in the setting of cardiac arrest from irreversible herniation as an example of futility in the context of neurologic disease.

When life-prolonging care is no longer an option, clinicians have an obligation to shift the focus of care to preserving quality of life and comfort as much as possible, they add.

Hospices, which provide comfort-focused medical care as well as psychosocial and spiritual support, are reserved for patients believed to be in the last 6 months of their life if their disease follows the expected course.

The investigators also broached ethical considerations for individual neurologic conditions. Concerns for disorders of consciousness include misdiagnosis or inaccurate prognostication, and serial examinations are needed to re-evaluate levels of cognition, psychological state, decisionmaking capacity, and disease trajectory.

In patients with locked-in syndrome, a state of irreversible paralysis, often with respiratory and vocal paralysis, consciousness may range from a chronic minimally conscious state to intact cognition.

Without careful examination, patients with preserved consciousness may be mistaken as having a disorder of consciousness and risk their decisional capacity being ignored, the researchers note.

These patients may need assistance from speech pathologists to identify techniques to enhance communication, such as careful “yes/no” questioning, communication boards, or advanced eye-gaze technology, they add.
 

Stroke, dementia, Parkinson’s guidance

For stroke, the guidance suggests neurologists encourage patients with retained decisionmaking capacity to complete advance care planning given the risk of recurrent stroke and loss of capacity in the future.

For dementia, a proper and timely diagnosis can help patients and their families prepare for the consequences of cognitive dysfunction and loss of autonomy while respecting their identified values, the authors write.

They note that for Parkinson’s disease, which is marked by slow functional and cognitive decline, neurologists must aim to anticipate and treat symptoms, address psychosocial and spiritual distress and caregiver burden, and engage patients and families in advance care planning before onset of cognitive impairment.

For patients with amyotrophic lateral sclerosis (ALS) and related disorders, clinicians should aim to document goals and treatment preferences prior to extreme weakness and aphonia.

It is also important to anticipate patient preferences for future disability-specific decisions, such as those related to feeding tubes and mechanical ventilation, and to identify the patient’s minimal acceptable outcome from these life-sustaining interventions.

On the topic of withdrawal of treatment, the paper notes that competent patients have the right to refuse life-prolonging therapies, including artificial nutrition, hydration, mechanical ventilation, and antibiotics. If physicians have a moral objection to removing life-support systems, they are obligated to transfer the care of the patient to another physician, the authors add.

Once a decision is made to forgo life-sustaining treatment, physicians should minimize subsequent suffering. The investigators note most symptoms at the end of life can be managed without sedation.

In broaching the “gap” in neurology training programs, the statement referred to a survey of 49 neurology residency programs. Results showed that 42% of respondents reported being dissatisfied with their palliative care education.
 

Well-timed update

Kate T. Brizzi, MD, a Boston neurologist with experience in hospice and palliative care, said the updated position statement is “well-timed” as neuropalliative care has evolved dramatically over the last decade.

“In the last several years, I’ve witnessed a significant increase in trainee interest in the field, and there is growing recognition of how a palliative care approach can improve patient care and hopefully outcomes,” said Dr. Brizzi.

She praised the authors for doing “an excellent job” in highlighting the ethical challenges facing the neurology provider, particularly as it relates to prognostication in an uncertain setting.

Dr. Brizzi noted communication tools that help facilitate discussions around shared decisionmaking “have enhanced our ability to meet the palliative care needs of our patients and can be incorporated by any provider.”

However, she added that the paper only briefly comments on the role of the neurologist in “lawful physician-hastened death.”

“I anticipate that this will be an area of further discussion in the neurology and palliative care community in the future, as requests for hastened death are frequently encountered from patients with serious neurologic illness,” she said.

Dr. Brizzi also noted the importance of understanding the reasons behind the request – and addressing patient worries related to end-of-life care, which can frequently help alleviate distress.

There was no targeted funding for this paper. Coauthor Salvador Cruz-Flores, MD, department of neurology, Texas Tech University Center, El Paso, reported participation on member adjudication committees for clinical trials for Novo Nordisk, Sunovion, and Galapagos. The remaining authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The American Academy of Neurology (AAN) has released new expert guidance on palliative care for patients with stroke, dementia, Parkinson’s disease, and other neurologic disorders.

Palliative care includes much more than hospice services, lead author of the new position statement Lynne P. Taylor, MD, University of Washington, Seattle, and a fellow of the AAN, said in a press release.

“Neurologists provide palliative care to people living with life-altering neurologic illnesses not just at the end of life but throughout the course of a disease, improving their lives with symptom control,” Dr. Taylor added.

The position paper, developed by a joint committee of the AAN, American Neurological Association, and Child Neurology Society, was published online March 8 in Neurology.
 

Guidance across the lifespan

The new paper, an update of previous position statements, includes palliative care guidance for different neurologic disorders across the lifespan. For example, neuropalliative care for neonates deserves “extra consideration,” because one-third of pediatric deaths occur during the neonatal period, most often in the neonatal intensive care unit, and after withdrawal of life-sustaining interventions, the authors note.

For older children, neuropalliative care consultation benefits families trying to maximize the quality of the remainder of their child’s life. Decisionmaking must consider the child’s cognitive abilities, the diagnosis, the perceived level of suffering, parental values, and the family’s understanding of the prognosis, the authors note.

They note that discussions about prognosis are often difficult but critical. Previous research “supports that patients desire prognostic information even when prognosis is uncertain and appreciate when their physicians disclose the presence of that uncertainty,” the authors note.

Also important is engaging in shared decisionmaking with patients and families. “This approach requires the physician to elicit a patient’s goals, make recommendations based on whether medical treatments are likely to achieve those goals, and work with patients and families to finalize a treatment plan,” according to the new guidance.
 

Ethical considerations

When treatments are physiologically futile, clinicians need to explain why interventions that may cause harm and have no benefit are not offered.

The authors cite cardiopulmonary resuscitation in the setting of cardiac arrest from irreversible herniation as an example of futility in the context of neurologic disease.

When life-prolonging care is no longer an option, clinicians have an obligation to shift the focus of care to preserving quality of life and comfort as much as possible, they add.

Hospices, which provide comfort-focused medical care as well as psychosocial and spiritual support, are reserved for patients believed to be in the last 6 months of their life if their disease follows the expected course.

The investigators also broached ethical considerations for individual neurologic conditions. Concerns for disorders of consciousness include misdiagnosis or inaccurate prognostication, and serial examinations are needed to re-evaluate levels of cognition, psychological state, decisionmaking capacity, and disease trajectory.

In patients with locked-in syndrome, a state of irreversible paralysis, often with respiratory and vocal paralysis, consciousness may range from a chronic minimally conscious state to intact cognition.

Without careful examination, patients with preserved consciousness may be mistaken as having a disorder of consciousness and risk their decisional capacity being ignored, the researchers note.

These patients may need assistance from speech pathologists to identify techniques to enhance communication, such as careful “yes/no” questioning, communication boards, or advanced eye-gaze technology, they add.
 

Stroke, dementia, Parkinson’s guidance

For stroke, the guidance suggests neurologists encourage patients with retained decisionmaking capacity to complete advance care planning given the risk of recurrent stroke and loss of capacity in the future.

For dementia, a proper and timely diagnosis can help patients and their families prepare for the consequences of cognitive dysfunction and loss of autonomy while respecting their identified values, the authors write.

They note that for Parkinson’s disease, which is marked by slow functional and cognitive decline, neurologists must aim to anticipate and treat symptoms, address psychosocial and spiritual distress and caregiver burden, and engage patients and families in advance care planning before onset of cognitive impairment.

For patients with amyotrophic lateral sclerosis (ALS) and related disorders, clinicians should aim to document goals and treatment preferences prior to extreme weakness and aphonia.

It is also important to anticipate patient preferences for future disability-specific decisions, such as those related to feeding tubes and mechanical ventilation, and to identify the patient’s minimal acceptable outcome from these life-sustaining interventions.

On the topic of withdrawal of treatment, the paper notes that competent patients have the right to refuse life-prolonging therapies, including artificial nutrition, hydration, mechanical ventilation, and antibiotics. If physicians have a moral objection to removing life-support systems, they are obligated to transfer the care of the patient to another physician, the authors add.

Once a decision is made to forgo life-sustaining treatment, physicians should minimize subsequent suffering. The investigators note most symptoms at the end of life can be managed without sedation.

In broaching the “gap” in neurology training programs, the statement referred to a survey of 49 neurology residency programs. Results showed that 42% of respondents reported being dissatisfied with their palliative care education.
 

Well-timed update

Kate T. Brizzi, MD, a Boston neurologist with experience in hospice and palliative care, said the updated position statement is “well-timed” as neuropalliative care has evolved dramatically over the last decade.

“In the last several years, I’ve witnessed a significant increase in trainee interest in the field, and there is growing recognition of how a palliative care approach can improve patient care and hopefully outcomes,” said Dr. Brizzi.

She praised the authors for doing “an excellent job” in highlighting the ethical challenges facing the neurology provider, particularly as it relates to prognostication in an uncertain setting.

Dr. Brizzi noted communication tools that help facilitate discussions around shared decisionmaking “have enhanced our ability to meet the palliative care needs of our patients and can be incorporated by any provider.”

However, she added that the paper only briefly comments on the role of the neurologist in “lawful physician-hastened death.”

“I anticipate that this will be an area of further discussion in the neurology and palliative care community in the future, as requests for hastened death are frequently encountered from patients with serious neurologic illness,” she said.

Dr. Brizzi also noted the importance of understanding the reasons behind the request – and addressing patient worries related to end-of-life care, which can frequently help alleviate distress.

There was no targeted funding for this paper. Coauthor Salvador Cruz-Flores, MD, department of neurology, Texas Tech University Center, El Paso, reported participation on member adjudication committees for clinical trials for Novo Nordisk, Sunovion, and Galapagos. The remaining authors have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Colonoscopy performed with an artificial intelligence (AI)–based computer-aided detection (CADe) system decreased the adenoma miss rate (AMR) by roughly half, compared with standard colonoscopy without AI assistance in a randomized controlled trial.

“Such reduction is achieved by reducing the error in detecting subtle, small lesions that can be missed by the human eye,” lead investigator Cesare Hassan, MD, PhD, with the gastroenterology unit at Nuovo Regina Margherita Hospital in Rome, Italy, told this news organization.

The study was published online March 15 in Gastroenterology.
 

Tandem colonoscopy study

Investigators behind the study enrolled 230 adults undergoing colorectal cancer screening or surveillance at eight centers in Italy, the United Kingdom, and the United States.

All participants underwent two same-day, back-to-back colonoscopies with or without the GI-Genius (Medtronic) AI deep-learning CADe program in two different arms. In one arm, AI was followed by standard colonoscopy; in the other arm, standard colonoscopy was followed by AI.

The primary outcome of the study was AMR, defined as the number of histologically confirmed lesions detected during the second colonoscopy divided by the total number of lesions detected during both procedures.

Bowel preparation and quality of the examinations were similar for the study groups.

The AMR was significantly lower with AI-assisted colonoscopy first than non-AI first (15.5% vs. 32.4%; adjusted odds ratio, 0.38; 95% confidence interval, 0.23-0.62). This was largely due to a decrease in the miss rate of flat and small lesions in the proximal and distal colon.

Among adenomas less than 10 mm, the AMR with AI first was 16.5%, compared with 33.8% with standard non-AI colonoscopy first (OR, 0.39; 95% CI, 0.25-0.61). The AMR was also significantly lower with AI first for adenomas less than or equal to 5 mm (15.9% vs. 35.8%; OR, 0.34; 95% CI, 0.21-0.55). No differences in AMR were evident for adenomas measuring 6-9 mm or greater than or equal to 10 mm.

With regard to morphology, the miss rate of non-polypoid lesions was significantly lower with AI first (16.8% vs. 45.8%; OR, 0.24; 95% CI, 0.13-0.45), and there was a numerical decrease in the miss rate of polypoid lesions with AI that did not reach statistical significance.

The use of AI was also associated with a statistically significant reduction in the false negative rate (6.8% vs. 29.6%; OR, 0.17; 95% CI, 0.05-0.67).

The authors say their findings offer indirect support to the higher adenoma detection rate demonstrated with this CADe system in two previous randomized controlled trials.