The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).¹ After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,^2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.⁴ Adherence to guidelines have been shown to improve patient survival across several cancer types.^5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.^8,9

Stage III NSCLC is associated with poor survival rates.¹⁰ Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.⁴ Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.¹¹ Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.¹¹

A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.¹¹

Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.

Methods

The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.

The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.

This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.

Results

A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.

The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.

CRT Patients

The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.

Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.

Durvalumab Treatment

After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.

Discussion

NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.³

Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.⁴ Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.² Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.

Clinical Trials vs Real World

The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.¹² In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.¹³

Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.¹⁴

A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.¹ These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.

Limitations

Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.¹⁵ Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.^16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.¹⁹ Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.

Conlcusions

This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.

Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.¹² It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.

The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).¹ After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,^2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.⁴ Adherence to guidelines have been shown to improve patient survival across several cancer types.^5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.^8,9

Stage III NSCLC is associated with poor survival rates.¹⁰ Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.⁴ Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.¹¹ Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.¹¹

A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.¹¹

Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.

Methods

The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.

The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.

This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.

Results

A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.

The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.

CRT Patients

The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.

Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.

Durvalumab Treatment

After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.

Discussion

NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.³

Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.⁴ Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.² Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.

Clinical Trials vs Real World

The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.¹² In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.¹³

Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.¹⁴

A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.¹ These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.

Limitations

Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.¹⁵ Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.^16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.¹⁹ Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.

Conlcusions

This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.

Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.¹² It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.

The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).¹ After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,^2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.⁴ Adherence to guidelines have been shown to improve patient survival across several cancer types.^5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.^8,9

Stage III NSCLC is associated with poor survival rates.¹⁰ Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.⁴ Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.¹¹ Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.¹¹

A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.¹¹

Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.

Methods

The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.

The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.

This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.

Results

A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.

The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.

CRT Patients

The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.

Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.

Durvalumab Treatment

After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.

Discussion

NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.³

Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.⁴ Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.² Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.

Clinical Trials vs Real World

The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.¹² In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.¹³

Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.¹⁴

A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.¹ These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.

Limitations

Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.¹⁵ Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.^16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.¹⁹ Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.

Conlcusions

This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.

Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.¹² It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.

Psilocybin, the psychedelic compound in “magic mushrooms,” rapidly improves symptoms and produces remission in as little as two sessions for patients with major depression, new research suggests.

Results of a small randomized trial showed that treatment with psilocybin was associated with a greater than 50% reduction in depressive symptoms in 67% of study participants. In addition, 71% showed improvement at 4-week follow-up, with more than 50% achieving remission.

“The finding that the majority of people whom we treated showed efficacy was quite a remarkable and gratifying finding and really sets the stage for psilocybin as a treatment for major depression,” senior investigator Roland Griffiths, PhD, Oliver Lee McCabe III Professor in the Neuropsychopharmacology of Consciousness, Johns Hopkins University, Baltimore, said in a statement.

“Perhaps the most exciting aspect of this as a new therapy is that psilocybin works as a therapeutic intervention with a single session or a few sessions, and then the effects are enduring. In contrast, most conventional treatments for depression ... are given chronically and also have chronic side effects,” added Dr. Griffiths, who is also director of the Johns Hopkins Center for Psychedelic and Consciousness Research.

The study was published online Nov.4 in JAMA Psychiatry.
 

Growing evidence base

As previously reported, psilocybin improves depressive symptoms for patients with cancer. However, these patients might be regarded as having a “reactive depression” to their life-threatening illness, said Dr. Griffiths.

“This study built on that previous research by asking the question, is psilocybin effective in patients who have major depressive disorder, [which is] a much larger population?” he said.

In addition, prior studies of psilocybin-assisted therapy had no control group, lead author Alan Davis, PhD, adjunct assistant professor in the psychedelic research unit, Johns Hopkins University, said in an interview.

The researchers created a control condition by randomly assigning 24 individuals (mean age, 39.8 years; 67% women) who were currently experiencing a moderate or severe major depressive episode to receive either immediate treatment (IT) (n = 13) or delayed treatment (DT) (n = 11).

Participants had longstanding depression, with a mean of 22.4 months in the current depressive episode. They were required to avoid using other antidepressants for 4 weeks prior to screening and up to 4 months following enrollment.

Patients were also required to be medically stable; have no personal/family history of psychotic or bipolar disorders; no past-year alcohol, substance, or nicotine use disorder; and no substantial lifetime or recent use of ketamine or classic hallucinogens.

Depression was measured using the Structured Clinical Interview for DSM-5 and the GRID-Hamilton Depression Rating Scale (GRID-HAMD). A baseline score of ≥17 was required for enrollment.

Participants received eight preparatory meetings with two session facilitators before the first psilocybin session and then 2-3 hours of follow-up meetings after the psilocybin sessions. In addition, they received 13 sessions of psychotherapy.

After completing these preparatory sessions, they underwent two psilocybin sessions, administered a mean of 1.6 weeks apart.

Participants in the DT group were assessed for depressive symptoms weekly for 8 weeks prior to entering the treatment protocol.
 

‘Surprising’ findings

Participants in the IT group exhibited significantly lower depression scores on the GRID-HAMD at 1 and 4 weeks after the second psilocybin session in comparison with patients in the DT group during the corresponding weeks.

Moreover, the effect sizes at weeks 5 and 8 were “large” (d = 2.2; 95% confidence interval, 1.4-3.0; and d = 2.6; 95% CI, 1.7-3.6, respectively).

An analysis of outcomes showed that, for all 24 participants, at 1 and at 4 weeks following the psilocybin intervention, 67% and 71% of participants, respectively, had a “clinically significant response” in depressive symptoms; 60% and 56%, respectively, met criteria for remission.

Within-subject T tests likewise revealed significant decreases in depression scores from baseline to 1- and 4-week follow-ups (P < .001; d = 3.6; 95% CI, 2.2-5.0; and P < .001; d = 3.6; 95% CI, 2.2-4.9, respectively).

Importantly, participants experienced no serious adverse effects.

Dr. Griffiths said he was “surprised” by the findings. “We knew that psilocybin would be effective in reactive depression of the type associated with illness, but we did not know that this would be the case in the large number of individuals who qualify for having [major depressive disorder].”

Dr. Davis said the finding “represents a large effect of this treatment among people with major depressive disorder – an approximately 4 times larger effect, compared to studies of antidepressant drugs.”

Dr. Davis noted that psychotherapy was an “essential” component of the study protocol. “It is likely that the combination of psychotherapy and psilocybin is what makes this treatment efficacious and that this treatment will always have a psychotherapy component and will not be Food and Drug Administration approved as a standalone medication.”

Tipping point

Collin Reiff, MD, clinical assistant professor in the department of psychiatry at New York University noted that because psychedelics are “still stigmatized,” the publication of this study in “one of the highest-impact journals in all of psychiatry suggests that research into psychedelics is now in the mainstream and that the academic psychiatry research community is paying close attention to what is happening.” He described this as a “tipping point.”

Dr. Reiff, who was not involved with the study, noted that research had been conducted on psychedelic compounds until the 1960s, “when they left the research lab and went mainstream, leading to the shutting down and subsequent dormancy of the research for the next 30-40 years.”

Psychedelic research is “undergoing a renaissance and no longer regarded with as much skepticism, but it is important to take our time doing this research so we do not repeat what happened in the 1960s,” said Dr. Reiff.

In an accompanying editorial, Charles F. Reynolds III, MD, endowed professor in geriatric psychiatry at the University of Pittsburgh Medical Center, Pennsylvania, questioned “for whom psychedelic-assisted psychotherapy is appropriate (or not), particularly in patients with depression who are suicidal of have a history of suicide attempt.”

Dr. Reynolds, who is also director of the Aging Institute of UPMC, who was not involved with the study, wrote that “personalizing the management of depression has to entail an understanding of the multiple contexts in which depression occurs, including genetic, developmental, psychosocial, cultural, medical, neurocognitive, and spiritual.”

The study was supported by a crowdsourcing campaign organized by Tim Ferris, as well as by grants from the Riverstyx Foundation. The Center for Psychedelic and Consciousness Research is funded by the Steven and Alexandra Cohen Foundation and receives support from Tim Ferriss, Matt Mullenweg, Craig Nerenberg, and Blake Mycoskie. It is also supported by grants from the National Institute on Drug Abuse. Dr. Davis received support from the NIDA. Dr. Griffiths was partially supported by a NIDA grant. Disclosures for the other authors are listed in the original article. Reiff reports owning stock in Compass Pathways. Dr. Reynolds reported no relevant financial relationships.

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

Psilocybin, the psychedelic compound in “magic mushrooms,” rapidly improves symptoms and produces remission in as little as two sessions for patients with major depression, new research suggests.

Results of a small randomized trial showed that treatment with psilocybin was associated with a greater than 50% reduction in depressive symptoms in 67% of study participants. In addition, 71% showed improvement at 4-week follow-up, with more than 50% achieving remission.

“The finding that the majority of people whom we treated showed efficacy was quite a remarkable and gratifying finding and really sets the stage for psilocybin as a treatment for major depression,” senior investigator Roland Griffiths, PhD, Oliver Lee McCabe III Professor in the Neuropsychopharmacology of Consciousness, Johns Hopkins University, Baltimore, said in a statement.

“Perhaps the most exciting aspect of this as a new therapy is that psilocybin works as a therapeutic intervention with a single session or a few sessions, and then the effects are enduring. In contrast, most conventional treatments for depression ... are given chronically and also have chronic side effects,” added Dr. Griffiths, who is also director of the Johns Hopkins Center for Psychedelic and Consciousness Research.

The study was published online Nov.4 in JAMA Psychiatry.
 

Growing evidence base

As previously reported, psilocybin improves depressive symptoms for patients with cancer. However, these patients might be regarded as having a “reactive depression” to their life-threatening illness, said Dr. Griffiths.

“This study built on that previous research by asking the question, is psilocybin effective in patients who have major depressive disorder, [which is] a much larger population?” he said.

In addition, prior studies of psilocybin-assisted therapy had no control group, lead author Alan Davis, PhD, adjunct assistant professor in the psychedelic research unit, Johns Hopkins University, said in an interview.

The researchers created a control condition by randomly assigning 24 individuals (mean age, 39.8 years; 67% women) who were currently experiencing a moderate or severe major depressive episode to receive either immediate treatment (IT) (n = 13) or delayed treatment (DT) (n = 11).

Participants had longstanding depression, with a mean of 22.4 months in the current depressive episode. They were required to avoid using other antidepressants for 4 weeks prior to screening and up to 4 months following enrollment.

Patients were also required to be medically stable; have no personal/family history of psychotic or bipolar disorders; no past-year alcohol, substance, or nicotine use disorder; and no substantial lifetime or recent use of ketamine or classic hallucinogens.

Depression was measured using the Structured Clinical Interview for DSM-5 and the GRID-Hamilton Depression Rating Scale (GRID-HAMD). A baseline score of ≥17 was required for enrollment.

Participants received eight preparatory meetings with two session facilitators before the first psilocybin session and then 2-3 hours of follow-up meetings after the psilocybin sessions. In addition, they received 13 sessions of psychotherapy.

After completing these preparatory sessions, they underwent two psilocybin sessions, administered a mean of 1.6 weeks apart.

Participants in the DT group were assessed for depressive symptoms weekly for 8 weeks prior to entering the treatment protocol.
 

‘Surprising’ findings

Participants in the IT group exhibited significantly lower depression scores on the GRID-HAMD at 1 and 4 weeks after the second psilocybin session in comparison with patients in the DT group during the corresponding weeks.

Moreover, the effect sizes at weeks 5 and 8 were “large” (d = 2.2; 95% confidence interval, 1.4-3.0; and d = 2.6; 95% CI, 1.7-3.6, respectively).

An analysis of outcomes showed that, for all 24 participants, at 1 and at 4 weeks following the psilocybin intervention, 67% and 71% of participants, respectively, had a “clinically significant response” in depressive symptoms; 60% and 56%, respectively, met criteria for remission.

Within-subject T tests likewise revealed significant decreases in depression scores from baseline to 1- and 4-week follow-ups (P < .001; d = 3.6; 95% CI, 2.2-5.0; and P < .001; d = 3.6; 95% CI, 2.2-4.9, respectively).

Importantly, participants experienced no serious adverse effects.

Dr. Griffiths said he was “surprised” by the findings. “We knew that psilocybin would be effective in reactive depression of the type associated with illness, but we did not know that this would be the case in the large number of individuals who qualify for having [major depressive disorder].”

Dr. Davis said the finding “represents a large effect of this treatment among people with major depressive disorder – an approximately 4 times larger effect, compared to studies of antidepressant drugs.”

Dr. Davis noted that psychotherapy was an “essential” component of the study protocol. “It is likely that the combination of psychotherapy and psilocybin is what makes this treatment efficacious and that this treatment will always have a psychotherapy component and will not be Food and Drug Administration approved as a standalone medication.”

Tipping point

Collin Reiff, MD, clinical assistant professor in the department of psychiatry at New York University noted that because psychedelics are “still stigmatized,” the publication of this study in “one of the highest-impact journals in all of psychiatry suggests that research into psychedelics is now in the mainstream and that the academic psychiatry research community is paying close attention to what is happening.” He described this as a “tipping point.”

Dr. Reiff, who was not involved with the study, noted that research had been conducted on psychedelic compounds until the 1960s, “when they left the research lab and went mainstream, leading to the shutting down and subsequent dormancy of the research for the next 30-40 years.”

Psychedelic research is “undergoing a renaissance and no longer regarded with as much skepticism, but it is important to take our time doing this research so we do not repeat what happened in the 1960s,” said Dr. Reiff.

In an accompanying editorial, Charles F. Reynolds III, MD, endowed professor in geriatric psychiatry at the University of Pittsburgh Medical Center, Pennsylvania, questioned “for whom psychedelic-assisted psychotherapy is appropriate (or not), particularly in patients with depression who are suicidal of have a history of suicide attempt.”

Dr. Reynolds, who is also director of the Aging Institute of UPMC, who was not involved with the study, wrote that “personalizing the management of depression has to entail an understanding of the multiple contexts in which depression occurs, including genetic, developmental, psychosocial, cultural, medical, neurocognitive, and spiritual.”

The study was supported by a crowdsourcing campaign organized by Tim Ferris, as well as by grants from the Riverstyx Foundation. The Center for Psychedelic and Consciousness Research is funded by the Steven and Alexandra Cohen Foundation and receives support from Tim Ferriss, Matt Mullenweg, Craig Nerenberg, and Blake Mycoskie. It is also supported by grants from the National Institute on Drug Abuse. Dr. Davis received support from the NIDA. Dr. Griffiths was partially supported by a NIDA grant. Disclosures for the other authors are listed in the original article. Reiff reports owning stock in Compass Pathways. Dr. Reynolds reported no relevant financial relationships.

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

Psilocybin, the psychedelic compound in “magic mushrooms,” rapidly improves symptoms and produces remission in as little as two sessions for patients with major depression, new research suggests.

Results of a small randomized trial showed that treatment with psilocybin was associated with a greater than 50% reduction in depressive symptoms in 67% of study participants. In addition, 71% showed improvement at 4-week follow-up, with more than 50% achieving remission.

“The finding that the majority of people whom we treated showed efficacy was quite a remarkable and gratifying finding and really sets the stage for psilocybin as a treatment for major depression,” senior investigator Roland Griffiths, PhD, Oliver Lee McCabe III Professor in the Neuropsychopharmacology of Consciousness, Johns Hopkins University, Baltimore, said in a statement.

“Perhaps the most exciting aspect of this as a new therapy is that psilocybin works as a therapeutic intervention with a single session or a few sessions, and then the effects are enduring. In contrast, most conventional treatments for depression ... are given chronically and also have chronic side effects,” added Dr. Griffiths, who is also director of the Johns Hopkins Center for Psychedelic and Consciousness Research.

The study was published online Nov.4 in JAMA Psychiatry.
 

Growing evidence base

As previously reported, psilocybin improves depressive symptoms for patients with cancer. However, these patients might be regarded as having a “reactive depression” to their life-threatening illness, said Dr. Griffiths.

“This study built on that previous research by asking the question, is psilocybin effective in patients who have major depressive disorder, [which is] a much larger population?” he said.

In addition, prior studies of psilocybin-assisted therapy had no control group, lead author Alan Davis, PhD, adjunct assistant professor in the psychedelic research unit, Johns Hopkins University, said in an interview.

The researchers created a control condition by randomly assigning 24 individuals (mean age, 39.8 years; 67% women) who were currently experiencing a moderate or severe major depressive episode to receive either immediate treatment (IT) (n = 13) or delayed treatment (DT) (n = 11).

Participants had longstanding depression, with a mean of 22.4 months in the current depressive episode. They were required to avoid using other antidepressants for 4 weeks prior to screening and up to 4 months following enrollment.

Patients were also required to be medically stable; have no personal/family history of psychotic or bipolar disorders; no past-year alcohol, substance, or nicotine use disorder; and no substantial lifetime or recent use of ketamine or classic hallucinogens.

Depression was measured using the Structured Clinical Interview for DSM-5 and the GRID-Hamilton Depression Rating Scale (GRID-HAMD). A baseline score of ≥17 was required for enrollment.

Participants received eight preparatory meetings with two session facilitators before the first psilocybin session and then 2-3 hours of follow-up meetings after the psilocybin sessions. In addition, they received 13 sessions of psychotherapy.

After completing these preparatory sessions, they underwent two psilocybin sessions, administered a mean of 1.6 weeks apart.

Participants in the DT group were assessed for depressive symptoms weekly for 8 weeks prior to entering the treatment protocol.
 

‘Surprising’ findings

Participants in the IT group exhibited significantly lower depression scores on the GRID-HAMD at 1 and 4 weeks after the second psilocybin session in comparison with patients in the DT group during the corresponding weeks.

Moreover, the effect sizes at weeks 5 and 8 were “large” (d = 2.2; 95% confidence interval, 1.4-3.0; and d = 2.6; 95% CI, 1.7-3.6, respectively).

An analysis of outcomes showed that, for all 24 participants, at 1 and at 4 weeks following the psilocybin intervention, 67% and 71% of participants, respectively, had a “clinically significant response” in depressive symptoms; 60% and 56%, respectively, met criteria for remission.

Within-subject T tests likewise revealed significant decreases in depression scores from baseline to 1- and 4-week follow-ups (P < .001; d = 3.6; 95% CI, 2.2-5.0; and P < .001; d = 3.6; 95% CI, 2.2-4.9, respectively).

Importantly, participants experienced no serious adverse effects.

Dr. Griffiths said he was “surprised” by the findings. “We knew that psilocybin would be effective in reactive depression of the type associated with illness, but we did not know that this would be the case in the large number of individuals who qualify for having [major depressive disorder].”

Dr. Davis said the finding “represents a large effect of this treatment among people with major depressive disorder – an approximately 4 times larger effect, compared to studies of antidepressant drugs.”

Dr. Davis noted that psychotherapy was an “essential” component of the study protocol. “It is likely that the combination of psychotherapy and psilocybin is what makes this treatment efficacious and that this treatment will always have a psychotherapy component and will not be Food and Drug Administration approved as a standalone medication.”

Tipping point

Collin Reiff, MD, clinical assistant professor in the department of psychiatry at New York University noted that because psychedelics are “still stigmatized,” the publication of this study in “one of the highest-impact journals in all of psychiatry suggests that research into psychedelics is now in the mainstream and that the academic psychiatry research community is paying close attention to what is happening.” He described this as a “tipping point.”

Dr. Reiff, who was not involved with the study, noted that research had been conducted on psychedelic compounds until the 1960s, “when they left the research lab and went mainstream, leading to the shutting down and subsequent dormancy of the research for the next 30-40 years.”

Psychedelic research is “undergoing a renaissance and no longer regarded with as much skepticism, but it is important to take our time doing this research so we do not repeat what happened in the 1960s,” said Dr. Reiff.

In an accompanying editorial, Charles F. Reynolds III, MD, endowed professor in geriatric psychiatry at the University of Pittsburgh Medical Center, Pennsylvania, questioned “for whom psychedelic-assisted psychotherapy is appropriate (or not), particularly in patients with depression who are suicidal of have a history of suicide attempt.”

Dr. Reynolds, who is also director of the Aging Institute of UPMC, who was not involved with the study, wrote that “personalizing the management of depression has to entail an understanding of the multiple contexts in which depression occurs, including genetic, developmental, psychosocial, cultural, medical, neurocognitive, and spiritual.”

The study was supported by a crowdsourcing campaign organized by Tim Ferris, as well as by grants from the Riverstyx Foundation. The Center for Psychedelic and Consciousness Research is funded by the Steven and Alexandra Cohen Foundation and receives support from Tim Ferriss, Matt Mullenweg, Craig Nerenberg, and Blake Mycoskie. It is also supported by grants from the National Institute on Drug Abuse. Dr. Davis received support from the NIDA. Dr. Griffiths was partially supported by a NIDA grant. Disclosures for the other authors are listed in the original article. Reiff reports owning stock in Compass Pathways. Dr. Reynolds reported no relevant financial relationships.

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

Pembrolizumab plus axitinib continued to top sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (RCC) in an extended follow-up of the phase 3 KEYNOTE-426 trial.

The trial’s initial results, published in The New England Journal of Medicine in 2019, showed superior efficacy with the combination. Pembrolizumab plus axitinib was subsequently approved in the United States and elsewhere as first-line treatment for advanced RCC.

The latest results from KEYNOTE-426, published in The Lancet Oncology, show a continued survival benefit with pembrolizumab plus axitinib.

“Overall, the results of this study continue to support pembrolizumab plus axitinib as standard of care in patients with previously untreated advanced renal cell carcinoma,” wrote study author Thomas Powles, MD, of the Queen Mary University and Barts Cancer Centre, London, and colleagues.

However, the new findings “must be read and interpreted together with the existing published literature,” they added. This includes trials of nivolumab plus ipilimumab, avelumab plus axitinib, and atezolizumab plus bevacizumab for advanced RCC, all versus sunitinib.

“Given the impossibility of making direct comparisons between the different combinations ... clinical experience and knowledge of the disease and of our patients will be vital to optimize this new therapeutic arsenal and to be able to reach goals that, until a few years ago, were considered unattainable,” wrote authors of a related editorial in The Lancet Oncology.
 

Trial details and results

KEYNOTE-426 included 861 patients with newly diagnosed stage IV or recurrent metastatic RCC with clear cell histology.

Patients were randomized to sunitinib monotherapy (n = 429) or pembrolizumab plus axitinib (n = 432). Pembrolizumab was given at 200 mg intravenously every 3 weeks for up to 35 cycles, and axitinib was given at 5 mg orally twice daily. Sunitinib was given at 50 mg orally once daily for 4 weeks per 6-week cycle.

Baseline characteristics were similar between the treatment arms. The median age was 62 years in the combination arm and 61 years in the sunitinib arm. Most patients were men (71% and 75%, respectively).

At a median follow-up of 30.6 months, the median overall survival (OS) was 35.7 months in the sunitinib arm but not yet reached in the pembrolizumab-axitinib arm (hazard ratio, 0.68, 95% confidence interval, 0.55-0.85, P = .0003).

The updated hazard ratio for OS with the combination wasn’t as robust as the hazard ratio in the initial analysis (0.53), likely in part because 48% of patients in the sunitinib group subsequently received immunotherapy, according to Dr. Powles and colleagues.

The median progression free survival (PFS) was 11.1 months with sunitinib and 15.4 months with the combination (HR, 0.71, 95% CI, 0.60-0.84, P < .0001). The objective response rate was 60% with pembrolizumab plus axitinib and 40% in the sunitinib group (P < .0001).
 

Risk groups and response criteria

Although patients in the combination arm had better objective response rates and PFS across all risk categories, there was no OS benefit in the favorable-risk subgroup, perhaps because favorable-risk patients have more indolent disease, Dr. Powles and colleagues noted.

Even so, “the pembrolizumab plus axitinib combination achieved a nonnegligible rate of 11% complete responses in favorable-risk cases, suggesting a potential curative role in this setting,” the editorialists wrote.

Dr. Powles and colleagues raised the question of whether RECIST-defined response is adequate to capture the full benefit of the combination.

In a post hoc analysis, the researchers found that change in tumor size was prognostic for OS. Patients in the pembrolizumab-axitinib group with an “at least 80% reduction in target lesions within 6 months of randomization had a durable subsequent overall survival benefit (i.e., 36 months survival), similar to patients who had RECIST-defined complete response,” Dr. Powles and colleagues wrote.

“These data support a hypothesis that durable benefit to an immunotherapy-containing regimen in renal cell cancer is not limited to the subset of complete responders,” the researchers added. “Because RECIST categories might not classify all patients who achieve durable benefit, depth of response might also supplement objective response as an important clinical endpoint.”
 

Safety and discontinuation

There were no new safety signals and no new treatment-related deaths.

The most frequent grade 3 or higher adverse events (in the combination and sunitinib arms, respectively) were hypertension (22% and 20%), alanine aminotransferase elevations (13% and 3%), and diarrhea (11% and 5%).

Treatment-related adverse events led to pembrolizumab interruption in 44% of patients, axitinib interruption in 62%, and interruption of both in 30%. Treatment-related adverse events led to discontinuation of one or the other drug in about 20% of subjects and both in 7%.

The number of discontinuations and interruptions suggests “caution in optimizing the therapeutic choice in real-world patients,” the editorialists wrote.

“New treatment modalities, including intermittent administrations or an induction phase followed by single-agent maintenance, could be explored in future adaptive clinical trials, with undeniable advantages in terms of reducing clinical and financial toxicity,” they added.

The KEYNOTE-426 study was funded by Merck, maker of pembrolizumab. The investigators and the editorialists disclosed ties to Merck and other companies.

[email protected]

SOURCE: Powles T et al. Lancet Oncol. 2020 Oct. 23. doi: 10.1016/S1470-2045(20)30436-8.

Pembrolizumab plus axitinib continued to top sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (RCC) in an extended follow-up of the phase 3 KEYNOTE-426 trial.

The trial’s initial results, published in The New England Journal of Medicine in 2019, showed superior efficacy with the combination. Pembrolizumab plus axitinib was subsequently approved in the United States and elsewhere as first-line treatment for advanced RCC.

The latest results from KEYNOTE-426, published in The Lancet Oncology, show a continued survival benefit with pembrolizumab plus axitinib.

“Overall, the results of this study continue to support pembrolizumab plus axitinib as standard of care in patients with previously untreated advanced renal cell carcinoma,” wrote study author Thomas Powles, MD, of the Queen Mary University and Barts Cancer Centre, London, and colleagues.

However, the new findings “must be read and interpreted together with the existing published literature,” they added. This includes trials of nivolumab plus ipilimumab, avelumab plus axitinib, and atezolizumab plus bevacizumab for advanced RCC, all versus sunitinib.

“Given the impossibility of making direct comparisons between the different combinations ... clinical experience and knowledge of the disease and of our patients will be vital to optimize this new therapeutic arsenal and to be able to reach goals that, until a few years ago, were considered unattainable,” wrote authors of a related editorial in The Lancet Oncology.
 

Trial details and results

KEYNOTE-426 included 861 patients with newly diagnosed stage IV or recurrent metastatic RCC with clear cell histology.

Patients were randomized to sunitinib monotherapy (n = 429) or pembrolizumab plus axitinib (n = 432). Pembrolizumab was given at 200 mg intravenously every 3 weeks for up to 35 cycles, and axitinib was given at 5 mg orally twice daily. Sunitinib was given at 50 mg orally once daily for 4 weeks per 6-week cycle.

Baseline characteristics were similar between the treatment arms. The median age was 62 years in the combination arm and 61 years in the sunitinib arm. Most patients were men (71% and 75%, respectively).

At a median follow-up of 30.6 months, the median overall survival (OS) was 35.7 months in the sunitinib arm but not yet reached in the pembrolizumab-axitinib arm (hazard ratio, 0.68, 95% confidence interval, 0.55-0.85, P = .0003).

The updated hazard ratio for OS with the combination wasn’t as robust as the hazard ratio in the initial analysis (0.53), likely in part because 48% of patients in the sunitinib group subsequently received immunotherapy, according to Dr. Powles and colleagues.

The median progression free survival (PFS) was 11.1 months with sunitinib and 15.4 months with the combination (HR, 0.71, 95% CI, 0.60-0.84, P < .0001). The objective response rate was 60% with pembrolizumab plus axitinib and 40% in the sunitinib group (P < .0001).
 

Risk groups and response criteria

Although patients in the combination arm had better objective response rates and PFS across all risk categories, there was no OS benefit in the favorable-risk subgroup, perhaps because favorable-risk patients have more indolent disease, Dr. Powles and colleagues noted.

Even so, “the pembrolizumab plus axitinib combination achieved a nonnegligible rate of 11% complete responses in favorable-risk cases, suggesting a potential curative role in this setting,” the editorialists wrote.

Dr. Powles and colleagues raised the question of whether RECIST-defined response is adequate to capture the full benefit of the combination.

In a post hoc analysis, the researchers found that change in tumor size was prognostic for OS. Patients in the pembrolizumab-axitinib group with an “at least 80% reduction in target lesions within 6 months of randomization had a durable subsequent overall survival benefit (i.e., 36 months survival), similar to patients who had RECIST-defined complete response,” Dr. Powles and colleagues wrote.

“These data support a hypothesis that durable benefit to an immunotherapy-containing regimen in renal cell cancer is not limited to the subset of complete responders,” the researchers added. “Because RECIST categories might not classify all patients who achieve durable benefit, depth of response might also supplement objective response as an important clinical endpoint.”
 

Safety and discontinuation

There were no new safety signals and no new treatment-related deaths.

The most frequent grade 3 or higher adverse events (in the combination and sunitinib arms, respectively) were hypertension (22% and 20%), alanine aminotransferase elevations (13% and 3%), and diarrhea (11% and 5%).

Treatment-related adverse events led to pembrolizumab interruption in 44% of patients, axitinib interruption in 62%, and interruption of both in 30%. Treatment-related adverse events led to discontinuation of one or the other drug in about 20% of subjects and both in 7%.

The number of discontinuations and interruptions suggests “caution in optimizing the therapeutic choice in real-world patients,” the editorialists wrote.

“New treatment modalities, including intermittent administrations or an induction phase followed by single-agent maintenance, could be explored in future adaptive clinical trials, with undeniable advantages in terms of reducing clinical and financial toxicity,” they added.

The KEYNOTE-426 study was funded by Merck, maker of pembrolizumab. The investigators and the editorialists disclosed ties to Merck and other companies.

[email protected]

SOURCE: Powles T et al. Lancet Oncol. 2020 Oct. 23. doi: 10.1016/S1470-2045(20)30436-8.

Pembrolizumab plus axitinib continued to top sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (RCC) in an extended follow-up of the phase 3 KEYNOTE-426 trial.

The trial’s initial results, published in The New England Journal of Medicine in 2019, showed superior efficacy with the combination. Pembrolizumab plus axitinib was subsequently approved in the United States and elsewhere as first-line treatment for advanced RCC.

The latest results from KEYNOTE-426, published in The Lancet Oncology, show a continued survival benefit with pembrolizumab plus axitinib.

“Overall, the results of this study continue to support pembrolizumab plus axitinib as standard of care in patients with previously untreated advanced renal cell carcinoma,” wrote study author Thomas Powles, MD, of the Queen Mary University and Barts Cancer Centre, London, and colleagues.

However, the new findings “must be read and interpreted together with the existing published literature,” they added. This includes trials of nivolumab plus ipilimumab, avelumab plus axitinib, and atezolizumab plus bevacizumab for advanced RCC, all versus sunitinib.

“Given the impossibility of making direct comparisons between the different combinations ... clinical experience and knowledge of the disease and of our patients will be vital to optimize this new therapeutic arsenal and to be able to reach goals that, until a few years ago, were considered unattainable,” wrote authors of a related editorial in The Lancet Oncology.
 

Trial details and results

KEYNOTE-426 included 861 patients with newly diagnosed stage IV or recurrent metastatic RCC with clear cell histology.

Patients were randomized to sunitinib monotherapy (n = 429) or pembrolizumab plus axitinib (n = 432). Pembrolizumab was given at 200 mg intravenously every 3 weeks for up to 35 cycles, and axitinib was given at 5 mg orally twice daily. Sunitinib was given at 50 mg orally once daily for 4 weeks per 6-week cycle.

Baseline characteristics were similar between the treatment arms. The median age was 62 years in the combination arm and 61 years in the sunitinib arm. Most patients were men (71% and 75%, respectively).

At a median follow-up of 30.6 months, the median overall survival (OS) was 35.7 months in the sunitinib arm but not yet reached in the pembrolizumab-axitinib arm (hazard ratio, 0.68, 95% confidence interval, 0.55-0.85, P = .0003).

The updated hazard ratio for OS with the combination wasn’t as robust as the hazard ratio in the initial analysis (0.53), likely in part because 48% of patients in the sunitinib group subsequently received immunotherapy, according to Dr. Powles and colleagues.

The median progression free survival (PFS) was 11.1 months with sunitinib and 15.4 months with the combination (HR, 0.71, 95% CI, 0.60-0.84, P < .0001). The objective response rate was 60% with pembrolizumab plus axitinib and 40% in the sunitinib group (P < .0001).
 

Risk groups and response criteria

Although patients in the combination arm had better objective response rates and PFS across all risk categories, there was no OS benefit in the favorable-risk subgroup, perhaps because favorable-risk patients have more indolent disease, Dr. Powles and colleagues noted.

Even so, “the pembrolizumab plus axitinib combination achieved a nonnegligible rate of 11% complete responses in favorable-risk cases, suggesting a potential curative role in this setting,” the editorialists wrote.

Dr. Powles and colleagues raised the question of whether RECIST-defined response is adequate to capture the full benefit of the combination.

In a post hoc analysis, the researchers found that change in tumor size was prognostic for OS. Patients in the pembrolizumab-axitinib group with an “at least 80% reduction in target lesions within 6 months of randomization had a durable subsequent overall survival benefit (i.e., 36 months survival), similar to patients who had RECIST-defined complete response,” Dr. Powles and colleagues wrote.

“These data support a hypothesis that durable benefit to an immunotherapy-containing regimen in renal cell cancer is not limited to the subset of complete responders,” the researchers added. “Because RECIST categories might not classify all patients who achieve durable benefit, depth of response might also supplement objective response as an important clinical endpoint.”
 

Safety and discontinuation

There were no new safety signals and no new treatment-related deaths.

The most frequent grade 3 or higher adverse events (in the combination and sunitinib arms, respectively) were hypertension (22% and 20%), alanine aminotransferase elevations (13% and 3%), and diarrhea (11% and 5%).

Treatment-related adverse events led to pembrolizumab interruption in 44% of patients, axitinib interruption in 62%, and interruption of both in 30%. Treatment-related adverse events led to discontinuation of one or the other drug in about 20% of subjects and both in 7%.

The number of discontinuations and interruptions suggests “caution in optimizing the therapeutic choice in real-world patients,” the editorialists wrote.

“New treatment modalities, including intermittent administrations or an induction phase followed by single-agent maintenance, could be explored in future adaptive clinical trials, with undeniable advantages in terms of reducing clinical and financial toxicity,” they added.

The KEYNOTE-426 study was funded by Merck, maker of pembrolizumab. The investigators and the editorialists disclosed ties to Merck and other companies.

[email protected]

SOURCE: Powles T et al. Lancet Oncol. 2020 Oct. 23. doi: 10.1016/S1470-2045(20)30436-8.

New data document the global fallout for rheumatology patients when hydroxychloroquine (HCQ) supplies were being diverted to hospitals for COVID-19 patients.

Demand for HCQ soared on evidence-lacking claims that the drug was effective in treating and preventing SARS-CoV-2 infection. Further research has since shown HCQ to be ineffective for COVID-19 and potentially harmful to patients.

But during the height of the COVID-19-related hype, patients worldwide with autoimmune diseases, particularly lupus and rheumatoid arthritis, had trouble getting the pills at all or couldn’t get as many as they needed for their chronic conditions.

Emily Sirotich, MSc, a PhD student at McMaster University in Hamilton, Ont., presented data at the virtual annual meeting of the American College of Rheumatology demonstrating that the severity of shortages differed widely.

Whereas 26.7% of rheumatology patients in Africa and 21.4% in southeast Asia said their pharmacy ran short of HCQ – which was originally developed as an antimalarial drug but has been found effective in treating some rheumatic diseases – only 6.8% of patients in the Americas and 2.1% in European regions reported the shortages.

“There are large regional disparities in access to antimalarials whether they were caused by the COVID-19 pandemic or already existed,” she said in an interview.

Global survey polled patient experience

Ms. Sirotich’s team analyzed data from the Global Rheumatology Alliance Patient Experience Survey.

They found that from 9,393 respondents (average age 46.1 years and 90% female), 3,872 (41.2%) were taking antimalarials. Of these, 230 (6.2% globally) were unable to keep taking the drugs because their pharmacy ran out.

Researchers evaluated the effect of drug shortages on disease activity, mental health, and physical health by comparing mean values with two-sided independent t-tests to identify significant differences.

They found that patients who were unable to obtain antimalarials had significantly higher levels of rheumatic disease activity as well as poorer mental and physical health (all P < .001).

The survey was distributed online through patient support groups and on social media. Patients with rheumatic diseases or their parents anonymously entered data including their rheumatic disease diagnosis, medications, COVID-19 status, and disease outcomes.

Ms. Sirotich said they are currently gathering new data to see if the gaps in access to HCQ persist and whether the physical and mental consequences of not having the medications continue.

Hospitals stockpiled HCQ in the U.S.

Michael Ganio, PharmD, senior director of pharmacy practice and quality at the American Society of Health-System Pharmacists (ASHP), said in an interview that hospitals in the United States received large amounts of HCQ in late spring and early summer, donated by pharmaceutical companies for COVID-19 before the lack of evidence for efficacy became clear.

Hospitals found themselves sitting on large quantities of HCQ they couldn’t use while prescriptions for rheumatology outpatients were going unfilled.

It is only in recent months that the U.S. Department of Health and Human Services has given clear direction to hospitals on how to redistribute those supplies, Dr. Ganio said.

“There’s no good real good way to move a product from a hospital to a [drug store] down the street,” he said.

The Food and Drug Administration now lists the HCQ shortages as resolved.
 

Declined prescriptions have frustrated physicians

Brett Smith, DO, a pediatric and adult rheumatologist in Alcoa, Tenn., said he was frustrated by pharmacies declining his prescriptions for HCQ for patients with rheumatoid arthritis.

“I got notes from pharmacies that I should consider alternative agents,” he said in an interview. But the safety profiles of the alternatives were not as good, he said.

“Hydroxychloroquine has no risk of infection and no risk of malignancy, and they were proposing alternative agents that carry those risks,” he said.

“I had some people with RA who couldn’t get [HCQ] who had a substantial increase in swollen joints and pain without it,” he said.

Dr. Smith said some patients who use HCQ for off-label uses such as certain skin disorders still aren’t getting the drug, as off-label use has been discouraged to make sure those with lupus and RA have enough, he said.

Saira Sheikh, MD, director of the University of North Carolina Rheumatology Lupus Clinic in Chapel Hill, said in an interview that during the summer months pharmacists required additional documentation of the diagnosis of autoimmune disease, resulting in unnecessary delays even when patients had been on the medication for many years.

She said emerging research has found patient-reported barriers to filling prescriptions, interruptions in HCQ treatment, and reported emotional stress and anxiety related to medication access during the COVID-19 pandemic.

“This experience with HCQ during the COVID-19 pandemic teaches us that while swift action and progress to address the immediate threats of the pandemic should be commended, it is important that we move forward in a conscious manner, guided by an evidence base that comes from high-quality research, not from rushed judgments based on preliminary studies, or pressure from political leaders,” Dr. Sheikh said.

Ms. Sirotich, Dr. Smith, Dr. Sheikh, and Dr. Ganio have disclosed no relevant financial relationships.

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

New data document the global fallout for rheumatology patients when hydroxychloroquine (HCQ) supplies were being diverted to hospitals for COVID-19 patients.

Demand for HCQ soared on evidence-lacking claims that the drug was effective in treating and preventing SARS-CoV-2 infection. Further research has since shown HCQ to be ineffective for COVID-19 and potentially harmful to patients.

But during the height of the COVID-19-related hype, patients worldwide with autoimmune diseases, particularly lupus and rheumatoid arthritis, had trouble getting the pills at all or couldn’t get as many as they needed for their chronic conditions.

Emily Sirotich, MSc, a PhD student at McMaster University in Hamilton, Ont., presented data at the virtual annual meeting of the American College of Rheumatology demonstrating that the severity of shortages differed widely.

Whereas 26.7% of rheumatology patients in Africa and 21.4% in southeast Asia said their pharmacy ran short of HCQ – which was originally developed as an antimalarial drug but has been found effective in treating some rheumatic diseases – only 6.8% of patients in the Americas and 2.1% in European regions reported the shortages.

“There are large regional disparities in access to antimalarials whether they were caused by the COVID-19 pandemic or already existed,” she said in an interview.

Global survey polled patient experience

Ms. Sirotich’s team analyzed data from the Global Rheumatology Alliance Patient Experience Survey.

They found that from 9,393 respondents (average age 46.1 years and 90% female), 3,872 (41.2%) were taking antimalarials. Of these, 230 (6.2% globally) were unable to keep taking the drugs because their pharmacy ran out.

Researchers evaluated the effect of drug shortages on disease activity, mental health, and physical health by comparing mean values with two-sided independent t-tests to identify significant differences.

They found that patients who were unable to obtain antimalarials had significantly higher levels of rheumatic disease activity as well as poorer mental and physical health (all P < .001).

The survey was distributed online through patient support groups and on social media. Patients with rheumatic diseases or their parents anonymously entered data including their rheumatic disease diagnosis, medications, COVID-19 status, and disease outcomes.

Ms. Sirotich said they are currently gathering new data to see if the gaps in access to HCQ persist and whether the physical and mental consequences of not having the medications continue.

Hospitals stockpiled HCQ in the U.S.

Michael Ganio, PharmD, senior director of pharmacy practice and quality at the American Society of Health-System Pharmacists (ASHP), said in an interview that hospitals in the United States received large amounts of HCQ in late spring and early summer, donated by pharmaceutical companies for COVID-19 before the lack of evidence for efficacy became clear.

Hospitals found themselves sitting on large quantities of HCQ they couldn’t use while prescriptions for rheumatology outpatients were going unfilled.

It is only in recent months that the U.S. Department of Health and Human Services has given clear direction to hospitals on how to redistribute those supplies, Dr. Ganio said.

“There’s no good real good way to move a product from a hospital to a [drug store] down the street,” he said.

The Food and Drug Administration now lists the HCQ shortages as resolved.
 

Declined prescriptions have frustrated physicians

Brett Smith, DO, a pediatric and adult rheumatologist in Alcoa, Tenn., said he was frustrated by pharmacies declining his prescriptions for HCQ for patients with rheumatoid arthritis.

“I got notes from pharmacies that I should consider alternative agents,” he said in an interview. But the safety profiles of the alternatives were not as good, he said.

“Hydroxychloroquine has no risk of infection and no risk of malignancy, and they were proposing alternative agents that carry those risks,” he said.

“I had some people with RA who couldn’t get [HCQ] who had a substantial increase in swollen joints and pain without it,” he said.

Dr. Smith said some patients who use HCQ for off-label uses such as certain skin disorders still aren’t getting the drug, as off-label use has been discouraged to make sure those with lupus and RA have enough, he said.

Saira Sheikh, MD, director of the University of North Carolina Rheumatology Lupus Clinic in Chapel Hill, said in an interview that during the summer months pharmacists required additional documentation of the diagnosis of autoimmune disease, resulting in unnecessary delays even when patients had been on the medication for many years.

She said emerging research has found patient-reported barriers to filling prescriptions, interruptions in HCQ treatment, and reported emotional stress and anxiety related to medication access during the COVID-19 pandemic.

“This experience with HCQ during the COVID-19 pandemic teaches us that while swift action and progress to address the immediate threats of the pandemic should be commended, it is important that we move forward in a conscious manner, guided by an evidence base that comes from high-quality research, not from rushed judgments based on preliminary studies, or pressure from political leaders,” Dr. Sheikh said.

Ms. Sirotich, Dr. Smith, Dr. Sheikh, and Dr. Ganio have disclosed no relevant financial relationships.

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

New data document the global fallout for rheumatology patients when hydroxychloroquine (HCQ) supplies were being diverted to hospitals for COVID-19 patients.

Demand for HCQ soared on evidence-lacking claims that the drug was effective in treating and preventing SARS-CoV-2 infection. Further research has since shown HCQ to be ineffective for COVID-19 and potentially harmful to patients.

But during the height of the COVID-19-related hype, patients worldwide with autoimmune diseases, particularly lupus and rheumatoid arthritis, had trouble getting the pills at all or couldn’t get as many as they needed for their chronic conditions.

Emily Sirotich, MSc, a PhD student at McMaster University in Hamilton, Ont., presented data at the virtual annual meeting of the American College of Rheumatology demonstrating that the severity of shortages differed widely.

Whereas 26.7% of rheumatology patients in Africa and 21.4% in southeast Asia said their pharmacy ran short of HCQ – which was originally developed as an antimalarial drug but has been found effective in treating some rheumatic diseases – only 6.8% of patients in the Americas and 2.1% in European regions reported the shortages.

“There are large regional disparities in access to antimalarials whether they were caused by the COVID-19 pandemic or already existed,” she said in an interview.

Global survey polled patient experience

Ms. Sirotich’s team analyzed data from the Global Rheumatology Alliance Patient Experience Survey.

They found that from 9,393 respondents (average age 46.1 years and 90% female), 3,872 (41.2%) were taking antimalarials. Of these, 230 (6.2% globally) were unable to keep taking the drugs because their pharmacy ran out.

Researchers evaluated the effect of drug shortages on disease activity, mental health, and physical health by comparing mean values with two-sided independent t-tests to identify significant differences.

They found that patients who were unable to obtain antimalarials had significantly higher levels of rheumatic disease activity as well as poorer mental and physical health (all P < .001).

The survey was distributed online through patient support groups and on social media. Patients with rheumatic diseases or their parents anonymously entered data including their rheumatic disease diagnosis, medications, COVID-19 status, and disease outcomes.

Ms. Sirotich said they are currently gathering new data to see if the gaps in access to HCQ persist and whether the physical and mental consequences of not having the medications continue.

Hospitals stockpiled HCQ in the U.S.

Michael Ganio, PharmD, senior director of pharmacy practice and quality at the American Society of Health-System Pharmacists (ASHP), said in an interview that hospitals in the United States received large amounts of HCQ in late spring and early summer, donated by pharmaceutical companies for COVID-19 before the lack of evidence for efficacy became clear.

Hospitals found themselves sitting on large quantities of HCQ they couldn’t use while prescriptions for rheumatology outpatients were going unfilled.

It is only in recent months that the U.S. Department of Health and Human Services has given clear direction to hospitals on how to redistribute those supplies, Dr. Ganio said.

“There’s no good real good way to move a product from a hospital to a [drug store] down the street,” he said.

The Food and Drug Administration now lists the HCQ shortages as resolved.
 

Declined prescriptions have frustrated physicians

Brett Smith, DO, a pediatric and adult rheumatologist in Alcoa, Tenn., said he was frustrated by pharmacies declining his prescriptions for HCQ for patients with rheumatoid arthritis.

“I got notes from pharmacies that I should consider alternative agents,” he said in an interview. But the safety profiles of the alternatives were not as good, he said.

“Hydroxychloroquine has no risk of infection and no risk of malignancy, and they were proposing alternative agents that carry those risks,” he said.

“I had some people with RA who couldn’t get [HCQ] who had a substantial increase in swollen joints and pain without it,” he said.

Dr. Smith said some patients who use HCQ for off-label uses such as certain skin disorders still aren’t getting the drug, as off-label use has been discouraged to make sure those with lupus and RA have enough, he said.

Saira Sheikh, MD, director of the University of North Carolina Rheumatology Lupus Clinic in Chapel Hill, said in an interview that during the summer months pharmacists required additional documentation of the diagnosis of autoimmune disease, resulting in unnecessary delays even when patients had been on the medication for many years.

She said emerging research has found patient-reported barriers to filling prescriptions, interruptions in HCQ treatment, and reported emotional stress and anxiety related to medication access during the COVID-19 pandemic.

“This experience with HCQ during the COVID-19 pandemic teaches us that while swift action and progress to address the immediate threats of the pandemic should be commended, it is important that we move forward in a conscious manner, guided by an evidence base that comes from high-quality research, not from rushed judgments based on preliminary studies, or pressure from political leaders,” Dr. Sheikh said.

Ms. Sirotich, Dr. Smith, Dr. Sheikh, and Dr. Ganio have disclosed no relevant financial relationships.

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

Endocrine diseases of any type – not just diabetes – can represent a cardiovascular risk and patients with those disorders should be screened for high cholesterol, according to a new clinical practice guideline from the Endocrine Society.

“The simple recommendation to check a lipid panel in patients with endocrine diseases and calculate cardiovascular risk may be practice changing because that is not done routinely,” Connie Newman, MD, chair of the Endocrine Society committee that developed the guideline, said in an interview.

“Usually the focus is on assessment and treatment of the endocrine disease, rather than on assessment and treatment of atherosclerotic cardiovascular disease risk,” said Newman, an adjunct professor of medicine in the department of medicine, division of endocrinology, diabetes & metabolism, at New York University.

Whereas diabetes, well-known for its increased cardiovascular risk profile, is commonly addressed in other cardiovascular and cholesterol practice management guidelines, the array of other endocrine diseases are not typically included.

“This guideline is the first of its kind,” Dr. Newman said. “The Endocrine Society has not previously issued a guideline on lipid management in endocrine disorders [and] other organizations have not written guidelines on this topic. 

“Rather, guidelines have been written on cholesterol management, but these do not describe cholesterol management in patients with endocrine diseases such as thyroid disease [hypothyroidism and hyperthyroidism], Cushing’s syndrome, acromegaly, growth hormone deficiency, menopause, male hypogonadism, and obesity,” she noted.

But these conditions carry a host of cardiovascular risk factors that may require careful monitoring and management.

“Although endocrine hormones, such as thyroid hormone, cortisol, estrogen, testosterone, growth hormone, and insulin, affect pathways for lipid metabolism, physicians lack guidance on lipid abnormalities, cardiovascular risk, and treatment to reduce lipids and cardiovascular risk in patients with endocrine diseases,” she explained.

Vinaya Simha, MD, an internal medicine specialist at the Mayo Clinic in Rochester, Minn., agrees that the guideline is notable in addressing an unmet need.

Recommendations that stand out to Dr. Simha include the suggestion of adding eicosapentaenoic acid (EPA) ethyl ester to reduce the risk of cardiovascular disease in adults with diabetes or atherosclerotic cardiovascular disease who have elevated triglyceride levels despite statin treatment.

James L. Rosenzweig, MD, an endocrinologist at Hebrew SeniorLife in Boston, agreed that this is an important addition to an area that needs more guidance.

“Many of these clinical situations can exacerbate dyslipidemia and some also increase the cardiovascular risk to a greater extent in combination with elevated cholesterol and/or triglycerides,” he said in an interview. 

“In many cases, treatment of the underlying disorder appropriately can have an important impact in resolving the lipid disorder. In others, more aggressive pharmacological treatment is indicated,” he said.

“I think that this will be a valuable resource, especially for endocrinologists, but it can be used as well by providers in other disciplines.”
 

Key recommendations for different endocrine conditions

The guideline, published in the Journal of Clinical Endocrinology & Metabolism, details those risks and provides evidence-based recommendations on their management and treatment.

Key recommendations include:

• Obtain a lipid panel and evaluate cardiovascular risk factors in all adults with endocrine disorders.
• In patients with  and risk factors for cardiovascular disease, start statin therapy in addition to lifestyle modification to reduce cardiovascular risk. “This could mean earlier treatment because other guidelines recommend consideration of therapy at age 40,” Dr. Newman said.
• Statin therapy is also recommended for adults over 40 with  with a duration of diabetes of more than 20 years and/or microvascular complications, regardless of their cardiovascular risk score. “This means earlier treatment of patients with type 1 diabetes with statins in order to reduce cardiovascular disease risk,” Dr. Newman noted.
• In patients with hyperlipidemia, rule out  as the cause before treating with lipid-lowering medications. And among patients who are found to have hypothyroidism, reevaluate the lipid profile when the patient has thyroid hormone levels in the normal range.
• Adults with persistent endogenous Cushing’s syndrome should have their lipid profile monitored. Statin therapy should be considered in addition to lifestyle modifications, irrespective of the cardiovascular risk score.
• In postmenopausal women, high cholesterol or triglycerides should be treated with statins rather than hormone therapy.
• Evaluate and treat lipids and other cardiovascular risk factors in women who enter menopause early (before the age of 40-45 years).

Nice summary of ‘risk-enhancing’ endocrine disorders

Dr. Simha said in an interview that the new guideline is “probably the first comprehensive statement addressing lipid treatment in patients with a broad range of endocrine disorders besides diabetes.”

“Most of the treatment recommendations are congruent with other current guidelines such as the American College of Cardiology/American Heart Association [guidelines], but there is specific mention of which endocrine disorders represent enhanced cardiovascular risk,” she explained.

The new recommendations are notable for including “a nice summary of how different endocrine disorders affect lipid values, and also which endocrine disorders need to be considered as ‘risk-enhancing factors,’ ” Dr. Simha noted.

“The use of EPA in patients with hypertriglyceridemia is novel, compared to the ACC/AHA recommendation. This reflects new data which is now available,” she added.

The American Association of Clinical Endocrinologists also just issued a new algorithm on lipid management and prevention of cardiovascular disease in which treatment of hypertriglyceridemia is emphasized.

In addition, the new Endocrine Society guideline “also mentions an LDL [cholesterol] treatment threshold of 70 mg/dL, and 55 mg/dL in some patient categories, which previous guidelines have not,” Dr. Simha noted.

Overall, Dr. Newman added that the goal of the guideline is to increase awareness of key issues with endocrine diseases that may not necessarily be on clinicians’ radars.

“We hope that it will make a lipid panel and cardiovascular risk evaluation routine in adults with endocrine diseases and cause a greater focus on therapies to reduce heart disease and stroke,” she said.

Dr. Newman, Dr. Simha, and Dr. Rosenzweig reported no relevant financial relationships.

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

Endocrine diseases of any type – not just diabetes – can represent a cardiovascular risk and patients with those disorders should be screened for high cholesterol, according to a new clinical practice guideline from the Endocrine Society.

“The simple recommendation to check a lipid panel in patients with endocrine diseases and calculate cardiovascular risk may be practice changing because that is not done routinely,” Connie Newman, MD, chair of the Endocrine Society committee that developed the guideline, said in an interview.

“Usually the focus is on assessment and treatment of the endocrine disease, rather than on assessment and treatment of atherosclerotic cardiovascular disease risk,” said Newman, an adjunct professor of medicine in the department of medicine, division of endocrinology, diabetes & metabolism, at New York University.

Whereas diabetes, well-known for its increased cardiovascular risk profile, is commonly addressed in other cardiovascular and cholesterol practice management guidelines, the array of other endocrine diseases are not typically included.

“This guideline is the first of its kind,” Dr. Newman said. “The Endocrine Society has not previously issued a guideline on lipid management in endocrine disorders [and] other organizations have not written guidelines on this topic. 

“Rather, guidelines have been written on cholesterol management, but these do not describe cholesterol management in patients with endocrine diseases such as thyroid disease [hypothyroidism and hyperthyroidism], Cushing’s syndrome, acromegaly, growth hormone deficiency, menopause, male hypogonadism, and obesity,” she noted.

But these conditions carry a host of cardiovascular risk factors that may require careful monitoring and management.

“Although endocrine hormones, such as thyroid hormone, cortisol, estrogen, testosterone, growth hormone, and insulin, affect pathways for lipid metabolism, physicians lack guidance on lipid abnormalities, cardiovascular risk, and treatment to reduce lipids and cardiovascular risk in patients with endocrine diseases,” she explained.

Vinaya Simha, MD, an internal medicine specialist at the Mayo Clinic in Rochester, Minn., agrees that the guideline is notable in addressing an unmet need.

Recommendations that stand out to Dr. Simha include the suggestion of adding eicosapentaenoic acid (EPA) ethyl ester to reduce the risk of cardiovascular disease in adults with diabetes or atherosclerotic cardiovascular disease who have elevated triglyceride levels despite statin treatment.

James L. Rosenzweig, MD, an endocrinologist at Hebrew SeniorLife in Boston, agreed that this is an important addition to an area that needs more guidance.

“Many of these clinical situations can exacerbate dyslipidemia and some also increase the cardiovascular risk to a greater extent in combination with elevated cholesterol and/or triglycerides,” he said in an interview. 

“In many cases, treatment of the underlying disorder appropriately can have an important impact in resolving the lipid disorder. In others, more aggressive pharmacological treatment is indicated,” he said.

“I think that this will be a valuable resource, especially for endocrinologists, but it can be used as well by providers in other disciplines.”
 

Key recommendations for different endocrine conditions

The guideline, published in the Journal of Clinical Endocrinology & Metabolism, details those risks and provides evidence-based recommendations on their management and treatment.

Key recommendations include:

• Obtain a lipid panel and evaluate cardiovascular risk factors in all adults with endocrine disorders.
• In patients with  and risk factors for cardiovascular disease, start statin therapy in addition to lifestyle modification to reduce cardiovascular risk. “This could mean earlier treatment because other guidelines recommend consideration of therapy at age 40,” Dr. Newman said.
• Statin therapy is also recommended for adults over 40 with  with a duration of diabetes of more than 20 years and/or microvascular complications, regardless of their cardiovascular risk score. “This means earlier treatment of patients with type 1 diabetes with statins in order to reduce cardiovascular disease risk,” Dr. Newman noted.
• In patients with hyperlipidemia, rule out  as the cause before treating with lipid-lowering medications. And among patients who are found to have hypothyroidism, reevaluate the lipid profile when the patient has thyroid hormone levels in the normal range.
• Adults with persistent endogenous Cushing’s syndrome should have their lipid profile monitored. Statin therapy should be considered in addition to lifestyle modifications, irrespective of the cardiovascular risk score.
• In postmenopausal women, high cholesterol or triglycerides should be treated with statins rather than hormone therapy.
• Evaluate and treat lipids and other cardiovascular risk factors in women who enter menopause early (before the age of 40-45 years).

Nice summary of ‘risk-enhancing’ endocrine disorders

Dr. Simha said in an interview that the new guideline is “probably the first comprehensive statement addressing lipid treatment in patients with a broad range of endocrine disorders besides diabetes.”

“Most of the treatment recommendations are congruent with other current guidelines such as the American College of Cardiology/American Heart Association [guidelines], but there is specific mention of which endocrine disorders represent enhanced cardiovascular risk,” she explained.

The new recommendations are notable for including “a nice summary of how different endocrine disorders affect lipid values, and also which endocrine disorders need to be considered as ‘risk-enhancing factors,’ ” Dr. Simha noted.

“The use of EPA in patients with hypertriglyceridemia is novel, compared to the ACC/AHA recommendation. This reflects new data which is now available,” she added.

The American Association of Clinical Endocrinologists also just issued a new algorithm on lipid management and prevention of cardiovascular disease in which treatment of hypertriglyceridemia is emphasized.

In addition, the new Endocrine Society guideline “also mentions an LDL [cholesterol] treatment threshold of 70 mg/dL, and 55 mg/dL in some patient categories, which previous guidelines have not,” Dr. Simha noted.

Overall, Dr. Newman added that the goal of the guideline is to increase awareness of key issues with endocrine diseases that may not necessarily be on clinicians’ radars.

“We hope that it will make a lipid panel and cardiovascular risk evaluation routine in adults with endocrine diseases and cause a greater focus on therapies to reduce heart disease and stroke,” she said.

Dr. Newman, Dr. Simha, and Dr. Rosenzweig reported no relevant financial relationships.

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

Endocrine diseases of any type – not just diabetes – can represent a cardiovascular risk and patients with those disorders should be screened for high cholesterol, according to a new clinical practice guideline from the Endocrine Society.

“The simple recommendation to check a lipid panel in patients with endocrine diseases and calculate cardiovascular risk may be practice changing because that is not done routinely,” Connie Newman, MD, chair of the Endocrine Society committee that developed the guideline, said in an interview.

“Usually the focus is on assessment and treatment of the endocrine disease, rather than on assessment and treatment of atherosclerotic cardiovascular disease risk,” said Newman, an adjunct professor of medicine in the department of medicine, division of endocrinology, diabetes & metabolism, at New York University.

Whereas diabetes, well-known for its increased cardiovascular risk profile, is commonly addressed in other cardiovascular and cholesterol practice management guidelines, the array of other endocrine diseases are not typically included.

“This guideline is the first of its kind,” Dr. Newman said. “The Endocrine Society has not previously issued a guideline on lipid management in endocrine disorders [and] other organizations have not written guidelines on this topic. 

“Rather, guidelines have been written on cholesterol management, but these do not describe cholesterol management in patients with endocrine diseases such as thyroid disease [hypothyroidism and hyperthyroidism], Cushing’s syndrome, acromegaly, growth hormone deficiency, menopause, male hypogonadism, and obesity,” she noted.

But these conditions carry a host of cardiovascular risk factors that may require careful monitoring and management.

“Although endocrine hormones, such as thyroid hormone, cortisol, estrogen, testosterone, growth hormone, and insulin, affect pathways for lipid metabolism, physicians lack guidance on lipid abnormalities, cardiovascular risk, and treatment to reduce lipids and cardiovascular risk in patients with endocrine diseases,” she explained.

Vinaya Simha, MD, an internal medicine specialist at the Mayo Clinic in Rochester, Minn., agrees that the guideline is notable in addressing an unmet need.

Recommendations that stand out to Dr. Simha include the suggestion of adding eicosapentaenoic acid (EPA) ethyl ester to reduce the risk of cardiovascular disease in adults with diabetes or atherosclerotic cardiovascular disease who have elevated triglyceride levels despite statin treatment.

James L. Rosenzweig, MD, an endocrinologist at Hebrew SeniorLife in Boston, agreed that this is an important addition to an area that needs more guidance.

“Many of these clinical situations can exacerbate dyslipidemia and some also increase the cardiovascular risk to a greater extent in combination with elevated cholesterol and/or triglycerides,” he said in an interview. 

“In many cases, treatment of the underlying disorder appropriately can have an important impact in resolving the lipid disorder. In others, more aggressive pharmacological treatment is indicated,” he said.

“I think that this will be a valuable resource, especially for endocrinologists, but it can be used as well by providers in other disciplines.”
 

Key recommendations for different endocrine conditions

The guideline, published in the Journal of Clinical Endocrinology & Metabolism, details those risks and provides evidence-based recommendations on their management and treatment.

Key recommendations include:

• Obtain a lipid panel and evaluate cardiovascular risk factors in all adults with endocrine disorders.
• In patients with  and risk factors for cardiovascular disease, start statin therapy in addition to lifestyle modification to reduce cardiovascular risk. “This could mean earlier treatment because other guidelines recommend consideration of therapy at age 40,” Dr. Newman said.
• Statin therapy is also recommended for adults over 40 with  with a duration of diabetes of more than 20 years and/or microvascular complications, regardless of their cardiovascular risk score. “This means earlier treatment of patients with type 1 diabetes with statins in order to reduce cardiovascular disease risk,” Dr. Newman noted.
• In patients with hyperlipidemia, rule out  as the cause before treating with lipid-lowering medications. And among patients who are found to have hypothyroidism, reevaluate the lipid profile when the patient has thyroid hormone levels in the normal range.
• Adults with persistent endogenous Cushing’s syndrome should have their lipid profile monitored. Statin therapy should be considered in addition to lifestyle modifications, irrespective of the cardiovascular risk score.
• In postmenopausal women, high cholesterol or triglycerides should be treated with statins rather than hormone therapy.
• Evaluate and treat lipids and other cardiovascular risk factors in women who enter menopause early (before the age of 40-45 years).

Nice summary of ‘risk-enhancing’ endocrine disorders

Dr. Simha said in an interview that the new guideline is “probably the first comprehensive statement addressing lipid treatment in patients with a broad range of endocrine disorders besides diabetes.”

“Most of the treatment recommendations are congruent with other current guidelines such as the American College of Cardiology/American Heart Association [guidelines], but there is specific mention of which endocrine disorders represent enhanced cardiovascular risk,” she explained.

The new recommendations are notable for including “a nice summary of how different endocrine disorders affect lipid values, and also which endocrine disorders need to be considered as ‘risk-enhancing factors,’ ” Dr. Simha noted.

“The use of EPA in patients with hypertriglyceridemia is novel, compared to the ACC/AHA recommendation. This reflects new data which is now available,” she added.

The American Association of Clinical Endocrinologists also just issued a new algorithm on lipid management and prevention of cardiovascular disease in which treatment of hypertriglyceridemia is emphasized.

In addition, the new Endocrine Society guideline “also mentions an LDL [cholesterol] treatment threshold of 70 mg/dL, and 55 mg/dL in some patient categories, which previous guidelines have not,” Dr. Simha noted.

Overall, Dr. Newman added that the goal of the guideline is to increase awareness of key issues with endocrine diseases that may not necessarily be on clinicians’ radars.

“We hope that it will make a lipid panel and cardiovascular risk evaluation routine in adults with endocrine diseases and cause a greater focus on therapies to reduce heart disease and stroke,” she said.

Dr. Newman, Dr. Simha, and Dr. Rosenzweig reported no relevant financial relationships.

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

To the Editor: Normally I would skip the editorial; however, the title “The Other Pandemic: Addiction” caught my eye (Fed Pract. 2020;37[10]:440-441). This will, of course, require me going in for eye care in the next couple of days, but my concerns are low. After all, the hook you used wasn’t that big.

Bravo! Your choice to focus on the effects of isolation was a masterful touch. I started skimming with the assumption that you would say something along the lines of ‘COVID bad, everybody depressed, blah, blah.’ But you cut into the abscess of the issue cleanly, exposing the core—isolation “amplifies negative thoughts, dysphoria, and fearful emotions.” A deadly combination for our patients and ourselves.

I have been a physician assistant in the US Army, and as a civilian at Brooke Army Medical Center and US Department of Veterans Affairs (VA) Puget Sound Health Care System. One thing I have seen throughout that time was the effects of isolation on the active duty enlisted young, and even more so on retired older warriors. Throughout the time of our military service, we transfer to many places and make a lot of friends, but more so, we lose track of them over time.

I have cared for many older warriors who cannot get something as simple as a colonoscopy because they do not have someone to drive them home after they have been sedated. Family and friends were scattered over the country, or the world. At the VA, many older warriors come not just for an appointment, but also as a time to socialize and ‘BS’ with those who understand them.

One goal I set for myself many years ago was to have the warrior laughing before they left my office. If I did that, I knew I had made a difference. Thank you for your editorial.

Anthony J Passaniti, PA, USA (ret) [email protected]

To the Editor: Normally I would skip the editorial; however, the title “The Other Pandemic: Addiction” caught my eye (Fed Pract. 2020;37[10]:440-441). This will, of course, require me going in for eye care in the next couple of days, but my concerns are low. After all, the hook you used wasn’t that big.

Bravo! Your choice to focus on the effects of isolation was a masterful touch. I started skimming with the assumption that you would say something along the lines of ‘COVID bad, everybody depressed, blah, blah.’ But you cut into the abscess of the issue cleanly, exposing the core—isolation “amplifies negative thoughts, dysphoria, and fearful emotions.” A deadly combination for our patients and ourselves.

I have been a physician assistant in the US Army, and as a civilian at Brooke Army Medical Center and US Department of Veterans Affairs (VA) Puget Sound Health Care System. One thing I have seen throughout that time was the effects of isolation on the active duty enlisted young, and even more so on retired older warriors. Throughout the time of our military service, we transfer to many places and make a lot of friends, but more so, we lose track of them over time.

I have cared for many older warriors who cannot get something as simple as a colonoscopy because they do not have someone to drive them home after they have been sedated. Family and friends were scattered over the country, or the world. At the VA, many older warriors come not just for an appointment, but also as a time to socialize and ‘BS’ with those who understand them.

One goal I set for myself many years ago was to have the warrior laughing before they left my office. If I did that, I knew I had made a difference. Thank you for your editorial.

Anthony J Passaniti, PA, USA (ret) [email protected]

To the Editor: Normally I would skip the editorial; however, the title “The Other Pandemic: Addiction” caught my eye (Fed Pract. 2020;37[10]:440-441). This will, of course, require me going in for eye care in the next couple of days, but my concerns are low. After all, the hook you used wasn’t that big.

Bravo! Your choice to focus on the effects of isolation was a masterful touch. I started skimming with the assumption that you would say something along the lines of ‘COVID bad, everybody depressed, blah, blah.’ But you cut into the abscess of the issue cleanly, exposing the core—isolation “amplifies negative thoughts, dysphoria, and fearful emotions.” A deadly combination for our patients and ourselves.

I have been a physician assistant in the US Army, and as a civilian at Brooke Army Medical Center and US Department of Veterans Affairs (VA) Puget Sound Health Care System. One thing I have seen throughout that time was the effects of isolation on the active duty enlisted young, and even more so on retired older warriors. Throughout the time of our military service, we transfer to many places and make a lot of friends, but more so, we lose track of them over time.

I have cared for many older warriors who cannot get something as simple as a colonoscopy because they do not have someone to drive them home after they have been sedated. Family and friends were scattered over the country, or the world. At the VA, many older warriors come not just for an appointment, but also as a time to socialize and ‘BS’ with those who understand them.

One goal I set for myself many years ago was to have the warrior laughing before they left my office. If I did that, I knew I had made a difference. Thank you for your editorial.

Anthony J Passaniti, PA, USA (ret) [email protected]

There’s a reason they’re called smartphones.

Indeed, how patients use their smartphones and where they take them provides insight into what has been termed their “digital phenotype.” It’s information that, analyzed correctly, becomes useful in differentiating bipolar disorder from borderline personality disorder, a distinction that’s often challenging in clinical practice, Kate E.A. Saunders, MD, DPhil, said at the virtual congress of the European College of Neuropsychopharmacology.

Dr. Saunders, a psychiatrist at the University of Oxford (England), and colleagues have developed a smartphone app enabling patients to briefly characterize their current mood on a daily basis, as well as a machine learning model to analyze this data stream as patients’ moods evolve over time. In their prospective longitudinal Automated Monitoring of Symptom Severity (AMoSS) study of 48 patients with a confirmed diagnosis of bipolar disorder, 31 with borderline personality disorder, and 51 healthy volunteers, the tool correctly classified 75% of participants into the correct diagnostic category on the basis of 20 daily mood ratings (Transl Psychiatry. 2018 Dec 13;81:274. doi: 10.1038/s41398-018-0334-0).

The app also monitors activity via accelerometry and geolocation to assess an individual’s circadian rest-activity patterns, as well as telephone use and texting behavior. In another report from AMoSS, Dr. Saunders and coinvestigators showed that these patterns also distinguish persons with bipolar disorder from those with borderline personality disorder, who in turn differ from healthy controls (Transl Psychiatry. 2019 Aug 20;91:195. doi: 10.1038/s41398-019-0526-2).

“I think we can use these approaches to inform our diagnostic practice. It doesn’t replace doctors, but clearly it can add to diagnostic accuracy,” she said.

Borderline personality disorder and bipolar disorder are common diagnoses with quite different treatment approaches and prognoses. Studies have shown that rates of misdiagnosis of the two disorders are significant. The challenge is that they share overlapping diagnostic criteria, including prominent mood instability, which is difficult to assess reliably in clinical practice. That’s because the assessment relies on retrospective self-report of how patients felt in the past, which is often colored by their present mood state. The smartphone app sidesteps that limitation by having patients rate their mood daily digitally across six categories – anxiety, elation, sadness, anger, irritability, and energy – on a 1-7 scale.

The machine learning model that analyzes this information organizes the voluminous data into what Dr. Saunders called “signatures of mood” and breaks them down using rough path theory, a mathematical concept based upon differential equations. Dr. Saunders and colleagues have demonstrated that the shifting daily mood self-rating patterns can be used not only to sharpen the differential diagnosis between bipolar disorder and borderline personality disorder, but also to predict future mood. Automated analysis of the past 20 previous mood self-ratings predicted the next day’s mood in healthy controls with 89%-98% accuracy, depending upon which of the six mood categories was under scrutiny.

The predictive power in patients with bipolar disorder was also good, ranging from 82% accuracy for the energetic and anxious domains to 90% for the angry mood category. This ability to predict future mood states could have clinical value by assisting bipolar patients in enhancing proactive self-management and managing their mood stability to avoid depressive or manic relapse, although this has yet to be studied.

“For borderline personality disorder the predictive accuracy was not so good – 70%-78% – but perhaps that doesn’t matter,” Dr. Saunders said. “Perhaps that difficulty in predicting mood may actually be quite a useful diagnostic marker.”

‘Mr. Jones, the doctor is ready to see your phone now.’

The app’s accelerometry and geolocation capabilities can also enhance diagnostic accuracy, as has been shown in the AMoSS study.

The geolocation analysis generates data on the places a patient has gone and how much time was spent there. Feeding that information into the machine learning model predicted the presence or absence of depression with 85% accuracy for bipolar disorder, but couldn’t predict depression at all in borderline personality disorder.

“So we get a sense that people with bipolar disorder have behavioral manifestations of their mood symptoms which are much more consistent with one another and appear to change very consistently with their mood state, whereas borderline personality disorder seems to be characterized by something that’s much more unstable and unpredictable – and we can pick up these predictive variables using our smartphones,” Dr. Saunders said.

As depressive symptoms arise in patients with bipolar disorder, affected individuals display much less day-to-day variability in movement as measured by accelerometry. These changes predicted bipolar disorder with 76% specificity and 48% sensitivity.

“That’s OK. But we can’t do that at all in people with borderline personality disorder, again highlighting the fact that behavioral manifestations and symptoms in these groups are very, very different,” Dr. Saunders observed.

In AMoSS, analysis of activity, geolocation, and distal temperature rhythms showed that the individuals with borderline personality disorder displayed evidence of delayed circadian function, with a distinctive rest-activity pattern that differed from persons with bipolar disorder. This delayed circadian function might provide a novel therapeutic target in borderline personality disorder, a condition for which there is a notable lack of effective pharmacologic and psychotherapeutic interventions.

Phone use patterns were revealing. Patients with bipolar disorder had an increased total telephone call frequency relative to the healthy controls, whereas those with borderline personality disorder used text messaging much more frequently, consistent with the notion that borderline patients have difficulty in interpersonal communication.

Smartphone-based diagnostic differentiation between bipolar disorder and borderline personality disorder isn’t ready for prime time use in clinical practice, Dr. Saunders said. This is groundbreaking work that needs to be refined and replicated in larger studies. There are important ethical and data protection issues that require attention. But patients are gung-ho. Dr. Saunders noted that participant compliance in AMoSS was “extraordinarily good,” at 82%. Moreover, even though the study lasted for 3 months, more than 60% of subjects continued filing mood reports for 12 months.

“Smartphones may also give us an improved understanding of the lived experience of people with mental health problems. That’s certainly the feedback we got a lot from patients. They enjoy using this technology. They feel it’s helpful to be able to show their clinician this is what it’s like for them,” Dr. Saunders said.
 

Clinical usefulness is limited

The study was interesting as a pilot, and it is technologically very innovative. However, at this stage, it is unclear how the results can be used clinically, said Igor Galynker, MD, PhD, when asked about the findings.

There is a place for using this type of technology for patients living in remote areas, for example. However, Dr. Galynker, director of the Richard and Cynthia Zirinsky Center for Bipolar Disorder in New York, said such technology should be viewed as augmentation rather than as a substitute for face-to-face treatment.

“Typically, if clinicians have enough time to speak to the patient and to take history, they can differentiate between bipolar disorder and borderline personality disorder: The former is cyclical, the latter is less so. However, this is hard to do without face-to-face contact, or when you only have 10 minutes,” said Dr. Galynker, professor of psychiatry at the Icahn School of Medicine and director of the Galynker Research and Prevention Laboratory, both at Mount Sinai in New York.

Dr. Saunders’ work is funded by the Wellcome Trust and the National Institute for Health Research. Dr. Galynker reported receiving funding from the National Institute of Mental Health and the American Foundation for Suicide Prevention. He has no other disclosures.

[email protected]

SOURCE: ECNP 2020. Session S21.

There’s a reason they’re called smartphones.

Indeed, how patients use their smartphones and where they take them provides insight into what has been termed their “digital phenotype.” It’s information that, analyzed correctly, becomes useful in differentiating bipolar disorder from borderline personality disorder, a distinction that’s often challenging in clinical practice, Kate E.A. Saunders, MD, DPhil, said at the virtual congress of the European College of Neuropsychopharmacology.

Dr. Saunders, a psychiatrist at the University of Oxford (England), and colleagues have developed a smartphone app enabling patients to briefly characterize their current mood on a daily basis, as well as a machine learning model to analyze this data stream as patients’ moods evolve over time. In their prospective longitudinal Automated Monitoring of Symptom Severity (AMoSS) study of 48 patients with a confirmed diagnosis of bipolar disorder, 31 with borderline personality disorder, and 51 healthy volunteers, the tool correctly classified 75% of participants into the correct diagnostic category on the basis of 20 daily mood ratings (Transl Psychiatry. 2018 Dec 13;81:274. doi: 10.1038/s41398-018-0334-0).

The app also monitors activity via accelerometry and geolocation to assess an individual’s circadian rest-activity patterns, as well as telephone use and texting behavior. In another report from AMoSS, Dr. Saunders and coinvestigators showed that these patterns also distinguish persons with bipolar disorder from those with borderline personality disorder, who in turn differ from healthy controls (Transl Psychiatry. 2019 Aug 20;91:195. doi: 10.1038/s41398-019-0526-2).

“I think we can use these approaches to inform our diagnostic practice. It doesn’t replace doctors, but clearly it can add to diagnostic accuracy,” she said.

Borderline personality disorder and bipolar disorder are common diagnoses with quite different treatment approaches and prognoses. Studies have shown that rates of misdiagnosis of the two disorders are significant. The challenge is that they share overlapping diagnostic criteria, including prominent mood instability, which is difficult to assess reliably in clinical practice. That’s because the assessment relies on retrospective self-report of how patients felt in the past, which is often colored by their present mood state. The smartphone app sidesteps that limitation by having patients rate their mood daily digitally across six categories – anxiety, elation, sadness, anger, irritability, and energy – on a 1-7 scale.

The machine learning model that analyzes this information organizes the voluminous data into what Dr. Saunders called “signatures of mood” and breaks them down using rough path theory, a mathematical concept based upon differential equations. Dr. Saunders and colleagues have demonstrated that the shifting daily mood self-rating patterns can be used not only to sharpen the differential diagnosis between bipolar disorder and borderline personality disorder, but also to predict future mood. Automated analysis of the past 20 previous mood self-ratings predicted the next day’s mood in healthy controls with 89%-98% accuracy, depending upon which of the six mood categories was under scrutiny.

The predictive power in patients with bipolar disorder was also good, ranging from 82% accuracy for the energetic and anxious domains to 90% for the angry mood category. This ability to predict future mood states could have clinical value by assisting bipolar patients in enhancing proactive self-management and managing their mood stability to avoid depressive or manic relapse, although this has yet to be studied.

“For borderline personality disorder the predictive accuracy was not so good – 70%-78% – but perhaps that doesn’t matter,” Dr. Saunders said. “Perhaps that difficulty in predicting mood may actually be quite a useful diagnostic marker.”

‘Mr. Jones, the doctor is ready to see your phone now.’

The app’s accelerometry and geolocation capabilities can also enhance diagnostic accuracy, as has been shown in the AMoSS study.

The geolocation analysis generates data on the places a patient has gone and how much time was spent there. Feeding that information into the machine learning model predicted the presence or absence of depression with 85% accuracy for bipolar disorder, but couldn’t predict depression at all in borderline personality disorder.

“So we get a sense that people with bipolar disorder have behavioral manifestations of their mood symptoms which are much more consistent with one another and appear to change very consistently with their mood state, whereas borderline personality disorder seems to be characterized by something that’s much more unstable and unpredictable – and we can pick up these predictive variables using our smartphones,” Dr. Saunders said.

As depressive symptoms arise in patients with bipolar disorder, affected individuals display much less day-to-day variability in movement as measured by accelerometry. These changes predicted bipolar disorder with 76% specificity and 48% sensitivity.

“That’s OK. But we can’t do that at all in people with borderline personality disorder, again highlighting the fact that behavioral manifestations and symptoms in these groups are very, very different,” Dr. Saunders observed.

In AMoSS, analysis of activity, geolocation, and distal temperature rhythms showed that the individuals with borderline personality disorder displayed evidence of delayed circadian function, with a distinctive rest-activity pattern that differed from persons with bipolar disorder. This delayed circadian function might provide a novel therapeutic target in borderline personality disorder, a condition for which there is a notable lack of effective pharmacologic and psychotherapeutic interventions.

Phone use patterns were revealing. Patients with bipolar disorder had an increased total telephone call frequency relative to the healthy controls, whereas those with borderline personality disorder used text messaging much more frequently, consistent with the notion that borderline patients have difficulty in interpersonal communication.

Smartphone-based diagnostic differentiation between bipolar disorder and borderline personality disorder isn’t ready for prime time use in clinical practice, Dr. Saunders said. This is groundbreaking work that needs to be refined and replicated in larger studies. There are important ethical and data protection issues that require attention. But patients are gung-ho. Dr. Saunders noted that participant compliance in AMoSS was “extraordinarily good,” at 82%. Moreover, even though the study lasted for 3 months, more than 60% of subjects continued filing mood reports for 12 months.

“Smartphones may also give us an improved understanding of the lived experience of people with mental health problems. That’s certainly the feedback we got a lot from patients. They enjoy using this technology. They feel it’s helpful to be able to show their clinician this is what it’s like for them,” Dr. Saunders said.
 

Clinical usefulness is limited

The study was interesting as a pilot, and it is technologically very innovative. However, at this stage, it is unclear how the results can be used clinically, said Igor Galynker, MD, PhD, when asked about the findings.

There is a place for using this type of technology for patients living in remote areas, for example. However, Dr. Galynker, director of the Richard and Cynthia Zirinsky Center for Bipolar Disorder in New York, said such technology should be viewed as augmentation rather than as a substitute for face-to-face treatment.

“Typically, if clinicians have enough time to speak to the patient and to take history, they can differentiate between bipolar disorder and borderline personality disorder: The former is cyclical, the latter is less so. However, this is hard to do without face-to-face contact, or when you only have 10 minutes,” said Dr. Galynker, professor of psychiatry at the Icahn School of Medicine and director of the Galynker Research and Prevention Laboratory, both at Mount Sinai in New York.

Dr. Saunders’ work is funded by the Wellcome Trust and the National Institute for Health Research. Dr. Galynker reported receiving funding from the National Institute of Mental Health and the American Foundation for Suicide Prevention. He has no other disclosures.

[email protected]

SOURCE: ECNP 2020. Session S21.

There’s a reason they’re called smartphones.

Indeed, how patients use their smartphones and where they take them provides insight into what has been termed their “digital phenotype.” It’s information that, analyzed correctly, becomes useful in differentiating bipolar disorder from borderline personality disorder, a distinction that’s often challenging in clinical practice, Kate E.A. Saunders, MD, DPhil, said at the virtual congress of the European College of Neuropsychopharmacology.

Dr. Saunders, a psychiatrist at the University of Oxford (England), and colleagues have developed a smartphone app enabling patients to briefly characterize their current mood on a daily basis, as well as a machine learning model to analyze this data stream as patients’ moods evolve over time. In their prospective longitudinal Automated Monitoring of Symptom Severity (AMoSS) study of 48 patients with a confirmed diagnosis of bipolar disorder, 31 with borderline personality disorder, and 51 healthy volunteers, the tool correctly classified 75% of participants into the correct diagnostic category on the basis of 20 daily mood ratings (Transl Psychiatry. 2018 Dec 13;81:274. doi: 10.1038/s41398-018-0334-0).

The app also monitors activity via accelerometry and geolocation to assess an individual’s circadian rest-activity patterns, as well as telephone use and texting behavior. In another report from AMoSS, Dr. Saunders and coinvestigators showed that these patterns also distinguish persons with bipolar disorder from those with borderline personality disorder, who in turn differ from healthy controls (Transl Psychiatry. 2019 Aug 20;91:195. doi: 10.1038/s41398-019-0526-2).

“I think we can use these approaches to inform our diagnostic practice. It doesn’t replace doctors, but clearly it can add to diagnostic accuracy,” she said.

Borderline personality disorder and bipolar disorder are common diagnoses with quite different treatment approaches and prognoses. Studies have shown that rates of misdiagnosis of the two disorders are significant. The challenge is that they share overlapping diagnostic criteria, including prominent mood instability, which is difficult to assess reliably in clinical practice. That’s because the assessment relies on retrospective self-report of how patients felt in the past, which is often colored by their present mood state. The smartphone app sidesteps that limitation by having patients rate their mood daily digitally across six categories – anxiety, elation, sadness, anger, irritability, and energy – on a 1-7 scale.

The machine learning model that analyzes this information organizes the voluminous data into what Dr. Saunders called “signatures of mood” and breaks them down using rough path theory, a mathematical concept based upon differential equations. Dr. Saunders and colleagues have demonstrated that the shifting daily mood self-rating patterns can be used not only to sharpen the differential diagnosis between bipolar disorder and borderline personality disorder, but also to predict future mood. Automated analysis of the past 20 previous mood self-ratings predicted the next day’s mood in healthy controls with 89%-98% accuracy, depending upon which of the six mood categories was under scrutiny.

The predictive power in patients with bipolar disorder was also good, ranging from 82% accuracy for the energetic and anxious domains to 90% for the angry mood category. This ability to predict future mood states could have clinical value by assisting bipolar patients in enhancing proactive self-management and managing their mood stability to avoid depressive or manic relapse, although this has yet to be studied.

“For borderline personality disorder the predictive accuracy was not so good – 70%-78% – but perhaps that doesn’t matter,” Dr. Saunders said. “Perhaps that difficulty in predicting mood may actually be quite a useful diagnostic marker.”

‘Mr. Jones, the doctor is ready to see your phone now.’

The app’s accelerometry and geolocation capabilities can also enhance diagnostic accuracy, as has been shown in the AMoSS study.

The geolocation analysis generates data on the places a patient has gone and how much time was spent there. Feeding that information into the machine learning model predicted the presence or absence of depression with 85% accuracy for bipolar disorder, but couldn’t predict depression at all in borderline personality disorder.

“So we get a sense that people with bipolar disorder have behavioral manifestations of their mood symptoms which are much more consistent with one another and appear to change very consistently with their mood state, whereas borderline personality disorder seems to be characterized by something that’s much more unstable and unpredictable – and we can pick up these predictive variables using our smartphones,” Dr. Saunders said.

As depressive symptoms arise in patients with bipolar disorder, affected individuals display much less day-to-day variability in movement as measured by accelerometry. These changes predicted bipolar disorder with 76% specificity and 48% sensitivity.

“That’s OK. But we can’t do that at all in people with borderline personality disorder, again highlighting the fact that behavioral manifestations and symptoms in these groups are very, very different,” Dr. Saunders observed.

In AMoSS, analysis of activity, geolocation, and distal temperature rhythms showed that the individuals with borderline personality disorder displayed evidence of delayed circadian function, with a distinctive rest-activity pattern that differed from persons with bipolar disorder. This delayed circadian function might provide a novel therapeutic target in borderline personality disorder, a condition for which there is a notable lack of effective pharmacologic and psychotherapeutic interventions.

Phone use patterns were revealing. Patients with bipolar disorder had an increased total telephone call frequency relative to the healthy controls, whereas those with borderline personality disorder used text messaging much more frequently, consistent with the notion that borderline patients have difficulty in interpersonal communication.

Smartphone-based diagnostic differentiation between bipolar disorder and borderline personality disorder isn’t ready for prime time use in clinical practice, Dr. Saunders said. This is groundbreaking work that needs to be refined and replicated in larger studies. There are important ethical and data protection issues that require attention. But patients are gung-ho. Dr. Saunders noted that participant compliance in AMoSS was “extraordinarily good,” at 82%. Moreover, even though the study lasted for 3 months, more than 60% of subjects continued filing mood reports for 12 months.

“Smartphones may also give us an improved understanding of the lived experience of people with mental health problems. That’s certainly the feedback we got a lot from patients. They enjoy using this technology. They feel it’s helpful to be able to show their clinician this is what it’s like for them,” Dr. Saunders said.
 

Clinical usefulness is limited

The study was interesting as a pilot, and it is technologically very innovative. However, at this stage, it is unclear how the results can be used clinically, said Igor Galynker, MD, PhD, when asked about the findings.

There is a place for using this type of technology for patients living in remote areas, for example. However, Dr. Galynker, director of the Richard and Cynthia Zirinsky Center for Bipolar Disorder in New York, said such technology should be viewed as augmentation rather than as a substitute for face-to-face treatment.

“Typically, if clinicians have enough time to speak to the patient and to take history, they can differentiate between bipolar disorder and borderline personality disorder: The former is cyclical, the latter is less so. However, this is hard to do without face-to-face contact, or when you only have 10 minutes,” said Dr. Galynker, professor of psychiatry at the Icahn School of Medicine and director of the Galynker Research and Prevention Laboratory, both at Mount Sinai in New York.

Dr. Saunders’ work is funded by the Wellcome Trust and the National Institute for Health Research. Dr. Galynker reported receiving funding from the National Institute of Mental Health and the American Foundation for Suicide Prevention. He has no other disclosures.

[email protected]

SOURCE: ECNP 2020. Session S21.

Case Presentation: A 45-year-old US Coast Guard veteran with a medical history of asthma and chronic back pain was referred to the VA Boston Healthcare System (VABHS) for evaluation of progressive, unexplained dyspnea. Two years prior to presentation, the patient was an avid outdoorsman and highly active. At the time of his initial primary care physician (PCP) evaluation he reported dyspnea on exertion, and symptoms consistent with an upper respiratory tract infection (URTI) and a recent tick bite with an associated rash. He was treated with intranasal fluticasone and a course of antibiotics. His URTI symptoms and rash improved; however the dyspnea persisted and progressed over the ensuing winter and he was referred for pulmonary function testing. Additional history included a 20 pack-year history of smoking (resolved 10 years prior to the first VABHS clinical encounter) and a family history of premature coronary artery disease (CAD) in his father and 2 paternal uncles. He lived in northern New England where he previously worked as a cemetery groundskeeper.

►Kristopher Clark, MD, Chief Medical Resident, VABHS and Boston University/Boston Medical Center: Dr. Goldstein, how do you approach a patient who presents with progressive dyspnea?

►Ronald Goldstein, MD, Chief of Pulmonary and Critical Care VABHS: The evaluation of dyspnea is a common problem for pulmonary physicians. The sensation of dyspnea may originate from a wide variety of etiologies that involve pulmonary and cardiovascular disorders, neuromuscular impairment, deconditioning, or psychological issues. It is important to characterize the temporal pattern, severity, progression, relation to exertion or other triggers, the smoking history, environmental and occupational exposures to pulmonary toxins, associated symptoms, and the history of pulmonary problems.¹

The physical examination may help to identify an airway or parenchymal disorder. Wheezing on chest examination would point to an obstructive defect and crackles to a possible restrictive problem, including pulmonary fibrosis. A cardiac examination should be performed to assess for evidence of heart failure, valvular heart disease, or the presence of loud P2 suggestive of pulmonary hypertension (PH). Laboratory studies, including complete blood counts are indicated.

A more complete pulmonary evaluation usually involves pulmonary function tests (PFTs), oximetry with exertion, and chest imaging. Additional cardiac testing might include electrocardiogram (ECG) and cardiac echocardiogram, followed by an exercise study, if needed. A B-natriuretic peptide determination could be considered if there is concern for congestive heart failure.²

►Dr. Clark: The initial physical examination was normal and laboratory tests were unrevealing. Given his history of asthma, he underwent spirometry testing (Table 1).

Dr. Goldstein, aside from unexplained dyspnea, what are other indications for spirometry and when should we consider ordering a full PFT, including lung volumes and diffusion capacity? Can you interpret this patient’s spirometry results?
 

►Dr. Goldstein: Spirometry is indicated to evaluate for a suspected obstructive defect. The test is usually performed with and without a bronchodilator to assess airway reactivity. A change in > 12% and > 200 mL suggests acute bronchodilator responsiveness. Periodic spirometry determinations are useful to assess the effect of medications or progression of disease. A reduction in forced vital capacity (FVC) may suggest a restrictive component. This possibility requires measure of lung volumes.

A full set of PFTs (ie, spirometry plus assessment of lung volumes and diffusion capacity) is required to evaluate the abnormalities associated with chronic obstructive pulmonary disease (COPD), interstitial diseases, vascular abnormalities (particularly PH), as well as for certain preoperative assessments. The single breath diffusing capacity for carbon monoxide is a measure of the overall capillary alveolar surface area of the lung. It is decreased in emphysema and interstitial disease as well as pulmonary vascular disorders. It would be particularly useful in this case as the spirometry studies were normal.

In this case, the normal FVC renders a significant restrictive disorder unlikely and his normal forced expiratory volume (FEV₁) and FEV₁/FVC make a significant obstructive disorder unlikely. He did not show any bronchodilator response; however, this finding does not exclude the presence of underlying asthma or reactive airway disease as patients often will not show a bronchodilator response at time of testing if they are not experiencing active bronchospasm or constriction. Further provocative testing with a methacholine challenge could be used to assess for reactive airway disease.

►Dr. Clark: The patient continued to have dyspnea when he returned to his PCP. Given his family history of premature CAD, an ECG was obtained that showed normal sinus rhythm at a rate of 70 beats per minute. A cardiology consult was placed, and he was referred for cardiac stress testing.

Dr. Maron, there are many forms of cardiac stress tests. In this case, the patient is referred for a stress test due his dyspnea. Does that symptom help you decide which test to order? How often does dyspnea present as an anginal equivalent in the absence of other cardiovascular symptoms or known cardiovascular disease?

►Bradley Maron, MD, Codirector, Pulmonary Vascular Disease Center, VABHS: In this case, stress testing should include a functional (ie, exercise) assessment if possible. Exercise capacity is a critical determinant of prognosis across the spectrum of cardiovascular disease and in a young person can be particularly informative on global health status. Furthermore, the chief complaint from this patient is dyspnea on exertion, and therefore, exercise testing is likely to be needed to reproduce or provoke the main symptom in this case. Estimates for dyspnea as a presenting symptom for ischemic heart disease vary but may be as high as 25%.³ It should be noted that cardiopulmonary exercise testing is useful for evaluating patients with unexplained dyspnea, as exercise hypoxemia, blunted decrease in V_D/V_T (ventilatory dead space/tidal volume), and evidence of a pulmonary mechanical limit to physical activity can inform the differential diagnosis.

►Dr. Clark: The patient underwent exercise treadmill testing and was able reach the target heart rate (> 85% age-predicted maximal heart rate) and achieve 11 metabolic equivalents. He had no chest pain or diagnostic ECG changes. The report made no mention of whether he experienced dyspnea during the test and was read as negative for exercise-induced ischemia.

He was seen by a cardiologist who noted an increased intensity S2 heart sound on examination without any other cardiopulmonary findings. It was noted that his symptoms occurred when tamping the ground or starting to walk up a hill but resolved with rest. It was also noted that his symptoms did not occur with gradual increased activity such as that performed during an exercise tolerance test. A 2-view chest X-ray was obtained and read as normal. Given the data from this evaluation thus far, the patient was told that his symptoms were most likely a result of his asthma exacerbated by dirt and dust exposure. Continued use of albuterol inhaler therapy was recommended, and no further diagnostic assessment was pursued.

Approximately 11 months later, the patient presented again to his PCP and reported progressive dyspnea. He had delayed seeking further care as he started to “feel like my symptoms were possibly in my head” given his prior negative workup. His symptoms had escalated drastically to the point where he felt short of breath with minimal exertion in addition to feeling sweaty, dizzy, fatigued, and having near-syncope when standing.

He was referred for a transthoracic echocardiogram (TTE) that revealed a left ventricular ejection fraction (LVEF) of 55 to 60% with diastolic relaxation abnormality and a normal-sized left atrium. The TTE also showed (qualitatively) a moderately dilated right ventricle with reduced systolic function, moderately severe tricuspid regurgitation, and severe elevation (> 60 mm Hg) in estimated right ventricular systolic pressure.

Dr. Maron, can you comment on how these findings may explain the patient’s symptoms? What differential diagnoses would you now consider?
 

►Dr. Maron: These echocardiography results exclude left ventricular systolic dysfunction or primary left-sided valvular disease at rest as a cause of the patient’s symptoms. In light of the patient’s prior normal stress test, high grade coronary disease in the absence of LV systolic dysfunction on echocardiography also seems unlikely. Estimated pulmonary artery systolic pressure > 60 mm Hg by echocardiography is highly suggestive of PH, but in and of itself does not diagnose PH nor inform pulmonary artery wedge pressure or pulmonary vascular resistance. Along with a direct measurement of pulmonary artery (PA) pressure, these data are needed to establish, classify, and prognosticate PH clinically.

►Dr. Clark: The patient was referred to a pulmonologist. His examination included bibasilar crackles and an enhanced P2 heart sound. A comprehensive pulmonary history was obtained, which noted his smoking history, possible asbestos exposure while serving in the Coast Guard, nighttime snoring without witnessed apnea events, and no personal or family history of thromboembolism or connective tissue disease.

Dr. Goldstein, is there anything in this patient’s history that could explain his symptoms and echocardiograph findings? Which tests would you order next?
 

►Dr. Goldstein: PH may be secondary to a wide variety of disorders including left heart disease (Group 2), advanced COPD, interstitial fibrosis, obstructive sleep apnea (OSA), or other lung diseases (Group 3), thromboembolic disorders (Group 4), and other systemic diseases such as sarcoidosis (Group 5). Group 1 is pulmonary arterial hypertension. (Table 2).

A right heart catheterization should be done to confirm the PA pressures estimated by echocardiogram. As to a cause, clinically he does not have heart failure. The limited smoking history and spirometry data do not support advanced COPD. He was noted to have crackles on physical examination suggesting an interstitial disorder. To assess the extent of interstitial disease, we would obtain a noncontrast computed tomography (CT) of the chest. The history of snoring suggesting the possibility of OSA indicating the need for overnight oximetry as significant nocturnal hypoxemia is a possible contributing cause to PH. A polysomnogram would be required to fully evaluate a sleep disturbance. The possible asbestos exposure is not likely a contributing factor as asbestosis requires significant exposure. We would obtain a ventilation/perfusion (V/Q) scan to rule out chronic thromboembolic disease. Targeted tests for causes of Group 5 disease should also be done.
 

►Dr. Clark: The impression from his pulmonologist was that the patient has severe PH, though the specific etiology was not yet known. Dr. Maron, can you review for us the pathophysiology behind PH and describe how the disease is classified?

►Dr. Maron: Elevated mean pulmonary artery pressure (> 20 mm Hg) diagnosed by supine right heart catheterization is the sine qua non of PH.⁴ However, this alone does not inform pathophysiology. As Dr. Goldstein noted, elevated PA pressure may be due to left heart disease, primary parenchymal lung disease/sleep-disordered breathing, in situ thrombotic remodeling of pulmonary arterioles following prior luminal pulmonary embolism, or in the setting of various specific predisposing conditions, such as sickle cell disease and sarcoidosis among others.⁵

Alternatively, pulmonary arterial hypertension (PAH) is suspected in patients with no identifiable cause of PH, pulmonary artery wedge pressure 15 mm Hg and pulmonary vascular resistance of 3.0 Wood units.⁶ Importantly, PAH is not synonymous with PH but is a circumspect PH disease subgroup. In turn, PAH may be idiopathic, hereditary, or associated with other select, predisposing disorders, namely systemic sclerosis. In PAH, the interplay between genetic and molecular factors results in effacement of distal pulmonary arterioles due to plexigenic, fibrotic, and/or concentric hypertrophic remodeling. Increased vascular resistance promotes early right ventricular dilation and impaired systolic function. As a result, patients with PAH are at particularly elevated risk for cor pulmonale.
 

►Dr. Clark: Overnight oximetry revealed baseline oxygen saturation of 94%, an oxygen nadir of 84% with a total of 7 minutes with oxygen < 90%. On a 6-minute walk test, the patient had a max heart rate of 116 and oxygen nadir of 93%. Chest CT with and without contrast showed no evidence of pulmonary emboli but noted mild emphysematous changes. A V/Q revealed no evidence of acute or chronic pulmonary thromboembolic disease. Coronary catheterization showed normal coronary anatomy without significant CAD. A right heart catheterization showed findings consistent with severe PH with normal left-sided filling pressures (Table 3).

The patient returned a normal antinuclear antibody, C-reactive protein, HIV, and liver function panel. Based on these findings, a presumptive diagnosis of group 1 PH (idiopathic PAH) was made. Given the severity of his right heart dysfunction, he was transferred to the cardiac care unit and initiated on epoprostenol.

Dr. Maron, can you review the different treatment options for idiopathic PAH and explain why epoprostenol was chosen for this patient?
 

►Dr. Maron: There are 14 US Food and Drug Administration-approved drug therapies for patients with PAH, which all target either nitric oxide signaling, endothelin receptors, or the prostacyclin pathway. In the current era, treatment-naïve patients with PAH are generally initiated on calcium channel antagonist therapy if there is evidence of vasoreactivity during right heart catheterization (following nitric oxide administration), dual therapy most often with an endothelin receptor antagonist and phosphodiesterase inhibitor, or parenteral prostacyclin therapy. Since < 5% of patients will demonstrate vasoreactivity, the decision at point of care in incident patients with PAH often focuses on dual oral therapy or initiation of parenteral prostacyclin therapy. In this case, the patient reported presyncope with minimal physical activity (eg, bending over or walking up stairs) and severely decreased functional status (ie, New York Heart Association Functional [NYHA] Class III – IV), and he had a cardiac index within the range of cardiogenic shock (< 2.0 L/min/m²). Collectively, this clinical profile is considered particularly high risk, therefore, a recommendation for parenteral continuous prostacyclin therapy was made.

► Dr. Clark: The patient tolerated epoprostenol and reported improvement in his symptoms. He had a tunneled line catheter placed for continuous epoprostenol infusion. He was discharged home and scheduled for outpatient follow-up in a PH clinic. At 4 months following discharge, he was reporting steady clinical and functional improvement as well as improvement in his dyspnea. A second therapy (oral phosphodiesterase type-V inhibitor) was initiated and tolerated well. Overall, he reported resolution of presyncope, NYHA Functional Class II symptoms, and the absence of important drug effects.

Case Presentation: A 45-year-old US Coast Guard veteran with a medical history of asthma and chronic back pain was referred to the VA Boston Healthcare System (VABHS) for evaluation of progressive, unexplained dyspnea. Two years prior to presentation, the patient was an avid outdoorsman and highly active. At the time of his initial primary care physician (PCP) evaluation he reported dyspnea on exertion, and symptoms consistent with an upper respiratory tract infection (URTI) and a recent tick bite with an associated rash. He was treated with intranasal fluticasone and a course of antibiotics. His URTI symptoms and rash improved; however the dyspnea persisted and progressed over the ensuing winter and he was referred for pulmonary function testing. Additional history included a 20 pack-year history of smoking (resolved 10 years prior to the first VABHS clinical encounter) and a family history of premature coronary artery disease (CAD) in his father and 2 paternal uncles. He lived in northern New England where he previously worked as a cemetery groundskeeper.

►Kristopher Clark, MD, Chief Medical Resident, VABHS and Boston University/Boston Medical Center: Dr. Goldstein, how do you approach a patient who presents with progressive dyspnea?

►Ronald Goldstein, MD, Chief of Pulmonary and Critical Care VABHS: The evaluation of dyspnea is a common problem for pulmonary physicians. The sensation of dyspnea may originate from a wide variety of etiologies that involve pulmonary and cardiovascular disorders, neuromuscular impairment, deconditioning, or psychological issues. It is important to characterize the temporal pattern, severity, progression, relation to exertion or other triggers, the smoking history, environmental and occupational exposures to pulmonary toxins, associated symptoms, and the history of pulmonary problems.¹

The physical examination may help to identify an airway or parenchymal disorder. Wheezing on chest examination would point to an obstructive defect and crackles to a possible restrictive problem, including pulmonary fibrosis. A cardiac examination should be performed to assess for evidence of heart failure, valvular heart disease, or the presence of loud P2 suggestive of pulmonary hypertension (PH). Laboratory studies, including complete blood counts are indicated.

A more complete pulmonary evaluation usually involves pulmonary function tests (PFTs), oximetry with exertion, and chest imaging. Additional cardiac testing might include electrocardiogram (ECG) and cardiac echocardiogram, followed by an exercise study, if needed. A B-natriuretic peptide determination could be considered if there is concern for congestive heart failure.²

►Dr. Clark: The initial physical examination was normal and laboratory tests were unrevealing. Given his history of asthma, he underwent spirometry testing (Table 1).

Dr. Goldstein, aside from unexplained dyspnea, what are other indications for spirometry and when should we consider ordering a full PFT, including lung volumes and diffusion capacity? Can you interpret this patient’s spirometry results?
 

►Dr. Goldstein: Spirometry is indicated to evaluate for a suspected obstructive defect. The test is usually performed with and without a bronchodilator to assess airway reactivity. A change in > 12% and > 200 mL suggests acute bronchodilator responsiveness. Periodic spirometry determinations are useful to assess the effect of medications or progression of disease. A reduction in forced vital capacity (FVC) may suggest a restrictive component. This possibility requires measure of lung volumes.

A full set of PFTs (ie, spirometry plus assessment of lung volumes and diffusion capacity) is required to evaluate the abnormalities associated with chronic obstructive pulmonary disease (COPD), interstitial diseases, vascular abnormalities (particularly PH), as well as for certain preoperative assessments. The single breath diffusing capacity for carbon monoxide is a measure of the overall capillary alveolar surface area of the lung. It is decreased in emphysema and interstitial disease as well as pulmonary vascular disorders. It would be particularly useful in this case as the spirometry studies were normal.

In this case, the normal FVC renders a significant restrictive disorder unlikely and his normal forced expiratory volume (FEV₁) and FEV₁/FVC make a significant obstructive disorder unlikely. He did not show any bronchodilator response; however, this finding does not exclude the presence of underlying asthma or reactive airway disease as patients often will not show a bronchodilator response at time of testing if they are not experiencing active bronchospasm or constriction. Further provocative testing with a methacholine challenge could be used to assess for reactive airway disease.

►Dr. Clark: The patient continued to have dyspnea when he returned to his PCP. Given his family history of premature CAD, an ECG was obtained that showed normal sinus rhythm at a rate of 70 beats per minute. A cardiology consult was placed, and he was referred for cardiac stress testing.

Dr. Maron, there are many forms of cardiac stress tests. In this case, the patient is referred for a stress test due his dyspnea. Does that symptom help you decide which test to order? How often does dyspnea present as an anginal equivalent in the absence of other cardiovascular symptoms or known cardiovascular disease?

►Bradley Maron, MD, Codirector, Pulmonary Vascular Disease Center, VABHS: In this case, stress testing should include a functional (ie, exercise) assessment if possible. Exercise capacity is a critical determinant of prognosis across the spectrum of cardiovascular disease and in a young person can be particularly informative on global health status. Furthermore, the chief complaint from this patient is dyspnea on exertion, and therefore, exercise testing is likely to be needed to reproduce or provoke the main symptom in this case. Estimates for dyspnea as a presenting symptom for ischemic heart disease vary but may be as high as 25%.³ It should be noted that cardiopulmonary exercise testing is useful for evaluating patients with unexplained dyspnea, as exercise hypoxemia, blunted decrease in V_D/V_T (ventilatory dead space/tidal volume), and evidence of a pulmonary mechanical limit to physical activity can inform the differential diagnosis.

►Dr. Clark: The patient underwent exercise treadmill testing and was able reach the target heart rate (> 85% age-predicted maximal heart rate) and achieve 11 metabolic equivalents. He had no chest pain or diagnostic ECG changes. The report made no mention of whether he experienced dyspnea during the test and was read as negative for exercise-induced ischemia.

He was seen by a cardiologist who noted an increased intensity S2 heart sound on examination without any other cardiopulmonary findings. It was noted that his symptoms occurred when tamping the ground or starting to walk up a hill but resolved with rest. It was also noted that his symptoms did not occur with gradual increased activity such as that performed during an exercise tolerance test. A 2-view chest X-ray was obtained and read as normal. Given the data from this evaluation thus far, the patient was told that his symptoms were most likely a result of his asthma exacerbated by dirt and dust exposure. Continued use of albuterol inhaler therapy was recommended, and no further diagnostic assessment was pursued.

Approximately 11 months later, the patient presented again to his PCP and reported progressive dyspnea. He had delayed seeking further care as he started to “feel like my symptoms were possibly in my head” given his prior negative workup. His symptoms had escalated drastically to the point where he felt short of breath with minimal exertion in addition to feeling sweaty, dizzy, fatigued, and having near-syncope when standing.

He was referred for a transthoracic echocardiogram (TTE) that revealed a left ventricular ejection fraction (LVEF) of 55 to 60% with diastolic relaxation abnormality and a normal-sized left atrium. The TTE also showed (qualitatively) a moderately dilated right ventricle with reduced systolic function, moderately severe tricuspid regurgitation, and severe elevation (> 60 mm Hg) in estimated right ventricular systolic pressure.

Dr. Maron, can you comment on how these findings may explain the patient’s symptoms? What differential diagnoses would you now consider?
 

►Dr. Maron: These echocardiography results exclude left ventricular systolic dysfunction or primary left-sided valvular disease at rest as a cause of the patient’s symptoms. In light of the patient’s prior normal stress test, high grade coronary disease in the absence of LV systolic dysfunction on echocardiography also seems unlikely. Estimated pulmonary artery systolic pressure > 60 mm Hg by echocardiography is highly suggestive of PH, but in and of itself does not diagnose PH nor inform pulmonary artery wedge pressure or pulmonary vascular resistance. Along with a direct measurement of pulmonary artery (PA) pressure, these data are needed to establish, classify, and prognosticate PH clinically.

►Dr. Clark: The patient was referred to a pulmonologist. His examination included bibasilar crackles and an enhanced P2 heart sound. A comprehensive pulmonary history was obtained, which noted his smoking history, possible asbestos exposure while serving in the Coast Guard, nighttime snoring without witnessed apnea events, and no personal or family history of thromboembolism or connective tissue disease.

Dr. Goldstein, is there anything in this patient’s history that could explain his symptoms and echocardiograph findings? Which tests would you order next?
 

►Dr. Goldstein: PH may be secondary to a wide variety of disorders including left heart disease (Group 2), advanced COPD, interstitial fibrosis, obstructive sleep apnea (OSA), or other lung diseases (Group 3), thromboembolic disorders (Group 4), and other systemic diseases such as sarcoidosis (Group 5). Group 1 is pulmonary arterial hypertension. (Table 2).

A right heart catheterization should be done to confirm the PA pressures estimated by echocardiogram. As to a cause, clinically he does not have heart failure. The limited smoking history and spirometry data do not support advanced COPD. He was noted to have crackles on physical examination suggesting an interstitial disorder. To assess the extent of interstitial disease, we would obtain a noncontrast computed tomography (CT) of the chest. The history of snoring suggesting the possibility of OSA indicating the need for overnight oximetry as significant nocturnal hypoxemia is a possible contributing cause to PH. A polysomnogram would be required to fully evaluate a sleep disturbance. The possible asbestos exposure is not likely a contributing factor as asbestosis requires significant exposure. We would obtain a ventilation/perfusion (V/Q) scan to rule out chronic thromboembolic disease. Targeted tests for causes of Group 5 disease should also be done.
 

►Dr. Clark: The impression from his pulmonologist was that the patient has severe PH, though the specific etiology was not yet known. Dr. Maron, can you review for us the pathophysiology behind PH and describe how the disease is classified?

►Dr. Maron: Elevated mean pulmonary artery pressure (> 20 mm Hg) diagnosed by supine right heart catheterization is the sine qua non of PH.⁴ However, this alone does not inform pathophysiology. As Dr. Goldstein noted, elevated PA pressure may be due to left heart disease, primary parenchymal lung disease/sleep-disordered breathing, in situ thrombotic remodeling of pulmonary arterioles following prior luminal pulmonary embolism, or in the setting of various specific predisposing conditions, such as sickle cell disease and sarcoidosis among others.⁵

Alternatively, pulmonary arterial hypertension (PAH) is suspected in patients with no identifiable cause of PH, pulmonary artery wedge pressure 15 mm Hg and pulmonary vascular resistance of 3.0 Wood units.⁶ Importantly, PAH is not synonymous with PH but is a circumspect PH disease subgroup. In turn, PAH may be idiopathic, hereditary, or associated with other select, predisposing disorders, namely systemic sclerosis. In PAH, the interplay between genetic and molecular factors results in effacement of distal pulmonary arterioles due to plexigenic, fibrotic, and/or concentric hypertrophic remodeling. Increased vascular resistance promotes early right ventricular dilation and impaired systolic function. As a result, patients with PAH are at particularly elevated risk for cor pulmonale.
 

►Dr. Clark: Overnight oximetry revealed baseline oxygen saturation of 94%, an oxygen nadir of 84% with a total of 7 minutes with oxygen < 90%. On a 6-minute walk test, the patient had a max heart rate of 116 and oxygen nadir of 93%. Chest CT with and without contrast showed no evidence of pulmonary emboli but noted mild emphysematous changes. A V/Q revealed no evidence of acute or chronic pulmonary thromboembolic disease. Coronary catheterization showed normal coronary anatomy without significant CAD. A right heart catheterization showed findings consistent with severe PH with normal left-sided filling pressures (Table 3).

The patient returned a normal antinuclear antibody, C-reactive protein, HIV, and liver function panel. Based on these findings, a presumptive diagnosis of group 1 PH (idiopathic PAH) was made. Given the severity of his right heart dysfunction, he was transferred to the cardiac care unit and initiated on epoprostenol.

Dr. Maron, can you review the different treatment options for idiopathic PAH and explain why epoprostenol was chosen for this patient?
 

►Dr. Maron: There are 14 US Food and Drug Administration-approved drug therapies for patients with PAH, which all target either nitric oxide signaling, endothelin receptors, or the prostacyclin pathway. In the current era, treatment-naïve patients with PAH are generally initiated on calcium channel antagonist therapy if there is evidence of vasoreactivity during right heart catheterization (following nitric oxide administration), dual therapy most often with an endothelin receptor antagonist and phosphodiesterase inhibitor, or parenteral prostacyclin therapy. Since < 5% of patients will demonstrate vasoreactivity, the decision at point of care in incident patients with PAH often focuses on dual oral therapy or initiation of parenteral prostacyclin therapy. In this case, the patient reported presyncope with minimal physical activity (eg, bending over or walking up stairs) and severely decreased functional status (ie, New York Heart Association Functional [NYHA] Class III – IV), and he had a cardiac index within the range of cardiogenic shock (< 2.0 L/min/m²). Collectively, this clinical profile is considered particularly high risk, therefore, a recommendation for parenteral continuous prostacyclin therapy was made.

► Dr. Clark: The patient tolerated epoprostenol and reported improvement in his symptoms. He had a tunneled line catheter placed for continuous epoprostenol infusion. He was discharged home and scheduled for outpatient follow-up in a PH clinic. At 4 months following discharge, he was reporting steady clinical and functional improvement as well as improvement in his dyspnea. A second therapy (oral phosphodiesterase type-V inhibitor) was initiated and tolerated well. Overall, he reported resolution of presyncope, NYHA Functional Class II symptoms, and the absence of important drug effects.

Case Presentation: A 45-year-old US Coast Guard veteran with a medical history of asthma and chronic back pain was referred to the VA Boston Healthcare System (VABHS) for evaluation of progressive, unexplained dyspnea. Two years prior to presentation, the patient was an avid outdoorsman and highly active. At the time of his initial primary care physician (PCP) evaluation he reported dyspnea on exertion, and symptoms consistent with an upper respiratory tract infection (URTI) and a recent tick bite with an associated rash. He was treated with intranasal fluticasone and a course of antibiotics. His URTI symptoms and rash improved; however the dyspnea persisted and progressed over the ensuing winter and he was referred for pulmonary function testing. Additional history included a 20 pack-year history of smoking (resolved 10 years prior to the first VABHS clinical encounter) and a family history of premature coronary artery disease (CAD) in his father and 2 paternal uncles. He lived in northern New England where he previously worked as a cemetery groundskeeper.

►Kristopher Clark, MD, Chief Medical Resident, VABHS and Boston University/Boston Medical Center: Dr. Goldstein, how do you approach a patient who presents with progressive dyspnea?

►Ronald Goldstein, MD, Chief of Pulmonary and Critical Care VABHS: The evaluation of dyspnea is a common problem for pulmonary physicians. The sensation of dyspnea may originate from a wide variety of etiologies that involve pulmonary and cardiovascular disorders, neuromuscular impairment, deconditioning, or psychological issues. It is important to characterize the temporal pattern, severity, progression, relation to exertion or other triggers, the smoking history, environmental and occupational exposures to pulmonary toxins, associated symptoms, and the history of pulmonary problems.¹

The physical examination may help to identify an airway or parenchymal disorder. Wheezing on chest examination would point to an obstructive defect and crackles to a possible restrictive problem, including pulmonary fibrosis. A cardiac examination should be performed to assess for evidence of heart failure, valvular heart disease, or the presence of loud P2 suggestive of pulmonary hypertension (PH). Laboratory studies, including complete blood counts are indicated.

A more complete pulmonary evaluation usually involves pulmonary function tests (PFTs), oximetry with exertion, and chest imaging. Additional cardiac testing might include electrocardiogram (ECG) and cardiac echocardiogram, followed by an exercise study, if needed. A B-natriuretic peptide determination could be considered if there is concern for congestive heart failure.²

►Dr. Clark: The initial physical examination was normal and laboratory tests were unrevealing. Given his history of asthma, he underwent spirometry testing (Table 1).

Dr. Goldstein, aside from unexplained dyspnea, what are other indications for spirometry and when should we consider ordering a full PFT, including lung volumes and diffusion capacity? Can you interpret this patient’s spirometry results?
 

►Dr. Goldstein: Spirometry is indicated to evaluate for a suspected obstructive defect. The test is usually performed with and without a bronchodilator to assess airway reactivity. A change in > 12% and > 200 mL suggests acute bronchodilator responsiveness. Periodic spirometry determinations are useful to assess the effect of medications or progression of disease. A reduction in forced vital capacity (FVC) may suggest a restrictive component. This possibility requires measure of lung volumes.

A full set of PFTs (ie, spirometry plus assessment of lung volumes and diffusion capacity) is required to evaluate the abnormalities associated with chronic obstructive pulmonary disease (COPD), interstitial diseases, vascular abnormalities (particularly PH), as well as for certain preoperative assessments. The single breath diffusing capacity for carbon monoxide is a measure of the overall capillary alveolar surface area of the lung. It is decreased in emphysema and interstitial disease as well as pulmonary vascular disorders. It would be particularly useful in this case as the spirometry studies were normal.

In this case, the normal FVC renders a significant restrictive disorder unlikely and his normal forced expiratory volume (FEV₁) and FEV₁/FVC make a significant obstructive disorder unlikely. He did not show any bronchodilator response; however, this finding does not exclude the presence of underlying asthma or reactive airway disease as patients often will not show a bronchodilator response at time of testing if they are not experiencing active bronchospasm or constriction. Further provocative testing with a methacholine challenge could be used to assess for reactive airway disease.

►Dr. Clark: The patient continued to have dyspnea when he returned to his PCP. Given his family history of premature CAD, an ECG was obtained that showed normal sinus rhythm at a rate of 70 beats per minute. A cardiology consult was placed, and he was referred for cardiac stress testing.

Dr. Maron, there are many forms of cardiac stress tests. In this case, the patient is referred for a stress test due his dyspnea. Does that symptom help you decide which test to order? How often does dyspnea present as an anginal equivalent in the absence of other cardiovascular symptoms or known cardiovascular disease?

►Bradley Maron, MD, Codirector, Pulmonary Vascular Disease Center, VABHS: In this case, stress testing should include a functional (ie, exercise) assessment if possible. Exercise capacity is a critical determinant of prognosis across the spectrum of cardiovascular disease and in a young person can be particularly informative on global health status. Furthermore, the chief complaint from this patient is dyspnea on exertion, and therefore, exercise testing is likely to be needed to reproduce or provoke the main symptom in this case. Estimates for dyspnea as a presenting symptom for ischemic heart disease vary but may be as high as 25%.³ It should be noted that cardiopulmonary exercise testing is useful for evaluating patients with unexplained dyspnea, as exercise hypoxemia, blunted decrease in V_D/V_T (ventilatory dead space/tidal volume), and evidence of a pulmonary mechanical limit to physical activity can inform the differential diagnosis.

►Dr. Clark: The patient underwent exercise treadmill testing and was able reach the target heart rate (> 85% age-predicted maximal heart rate) and achieve 11 metabolic equivalents. He had no chest pain or diagnostic ECG changes. The report made no mention of whether he experienced dyspnea during the test and was read as negative for exercise-induced ischemia.

He was seen by a cardiologist who noted an increased intensity S2 heart sound on examination without any other cardiopulmonary findings. It was noted that his symptoms occurred when tamping the ground or starting to walk up a hill but resolved with rest. It was also noted that his symptoms did not occur with gradual increased activity such as that performed during an exercise tolerance test. A 2-view chest X-ray was obtained and read as normal. Given the data from this evaluation thus far, the patient was told that his symptoms were most likely a result of his asthma exacerbated by dirt and dust exposure. Continued use of albuterol inhaler therapy was recommended, and no further diagnostic assessment was pursued.

Approximately 11 months later, the patient presented again to his PCP and reported progressive dyspnea. He had delayed seeking further care as he started to “feel like my symptoms were possibly in my head” given his prior negative workup. His symptoms had escalated drastically to the point where he felt short of breath with minimal exertion in addition to feeling sweaty, dizzy, fatigued, and having near-syncope when standing.

He was referred for a transthoracic echocardiogram (TTE) that revealed a left ventricular ejection fraction (LVEF) of 55 to 60% with diastolic relaxation abnormality and a normal-sized left atrium. The TTE also showed (qualitatively) a moderately dilated right ventricle with reduced systolic function, moderately severe tricuspid regurgitation, and severe elevation (> 60 mm Hg) in estimated right ventricular systolic pressure.

Dr. Maron, can you comment on how these findings may explain the patient’s symptoms? What differential diagnoses would you now consider?
 

►Dr. Maron: These echocardiography results exclude left ventricular systolic dysfunction or primary left-sided valvular disease at rest as a cause of the patient’s symptoms. In light of the patient’s prior normal stress test, high grade coronary disease in the absence of LV systolic dysfunction on echocardiography also seems unlikely. Estimated pulmonary artery systolic pressure > 60 mm Hg by echocardiography is highly suggestive of PH, but in and of itself does not diagnose PH nor inform pulmonary artery wedge pressure or pulmonary vascular resistance. Along with a direct measurement of pulmonary artery (PA) pressure, these data are needed to establish, classify, and prognosticate PH clinically.

►Dr. Clark: The patient was referred to a pulmonologist. His examination included bibasilar crackles and an enhanced P2 heart sound. A comprehensive pulmonary history was obtained, which noted his smoking history, possible asbestos exposure while serving in the Coast Guard, nighttime snoring without witnessed apnea events, and no personal or family history of thromboembolism or connective tissue disease.

Dr. Goldstein, is there anything in this patient’s history that could explain his symptoms and echocardiograph findings? Which tests would you order next?
 

►Dr. Goldstein: PH may be secondary to a wide variety of disorders including left heart disease (Group 2), advanced COPD, interstitial fibrosis, obstructive sleep apnea (OSA), or other lung diseases (Group 3), thromboembolic disorders (Group 4), and other systemic diseases such as sarcoidosis (Group 5). Group 1 is pulmonary arterial hypertension. (Table 2).

A right heart catheterization should be done to confirm the PA pressures estimated by echocardiogram. As to a cause, clinically he does not have heart failure. The limited smoking history and spirometry data do not support advanced COPD. He was noted to have crackles on physical examination suggesting an interstitial disorder. To assess the extent of interstitial disease, we would obtain a noncontrast computed tomography (CT) of the chest. The history of snoring suggesting the possibility of OSA indicating the need for overnight oximetry as significant nocturnal hypoxemia is a possible contributing cause to PH. A polysomnogram would be required to fully evaluate a sleep disturbance. The possible asbestos exposure is not likely a contributing factor as asbestosis requires significant exposure. We would obtain a ventilation/perfusion (V/Q) scan to rule out chronic thromboembolic disease. Targeted tests for causes of Group 5 disease should also be done.
 

►Dr. Clark: The impression from his pulmonologist was that the patient has severe PH, though the specific etiology was not yet known. Dr. Maron, can you review for us the pathophysiology behind PH and describe how the disease is classified?

►Dr. Maron: Elevated mean pulmonary artery pressure (> 20 mm Hg) diagnosed by supine right heart catheterization is the sine qua non of PH.⁴ However, this alone does not inform pathophysiology. As Dr. Goldstein noted, elevated PA pressure may be due to left heart disease, primary parenchymal lung disease/sleep-disordered breathing, in situ thrombotic remodeling of pulmonary arterioles following prior luminal pulmonary embolism, or in the setting of various specific predisposing conditions, such as sickle cell disease and sarcoidosis among others.⁵

Alternatively, pulmonary arterial hypertension (PAH) is suspected in patients with no identifiable cause of PH, pulmonary artery wedge pressure 15 mm Hg and pulmonary vascular resistance of 3.0 Wood units.⁶ Importantly, PAH is not synonymous with PH but is a circumspect PH disease subgroup. In turn, PAH may be idiopathic, hereditary, or associated with other select, predisposing disorders, namely systemic sclerosis. In PAH, the interplay between genetic and molecular factors results in effacement of distal pulmonary arterioles due to plexigenic, fibrotic, and/or concentric hypertrophic remodeling. Increased vascular resistance promotes early right ventricular dilation and impaired systolic function. As a result, patients with PAH are at particularly elevated risk for cor pulmonale.
 

►Dr. Clark: Overnight oximetry revealed baseline oxygen saturation of 94%, an oxygen nadir of 84% with a total of 7 minutes with oxygen < 90%. On a 6-minute walk test, the patient had a max heart rate of 116 and oxygen nadir of 93%. Chest CT with and without contrast showed no evidence of pulmonary emboli but noted mild emphysematous changes. A V/Q revealed no evidence of acute or chronic pulmonary thromboembolic disease. Coronary catheterization showed normal coronary anatomy without significant CAD. A right heart catheterization showed findings consistent with severe PH with normal left-sided filling pressures (Table 3).

The patient returned a normal antinuclear antibody, C-reactive protein, HIV, and liver function panel. Based on these findings, a presumptive diagnosis of group 1 PH (idiopathic PAH) was made. Given the severity of his right heart dysfunction, he was transferred to the cardiac care unit and initiated on epoprostenol.

Dr. Maron, can you review the different treatment options for idiopathic PAH and explain why epoprostenol was chosen for this patient?
 

►Dr. Maron: There are 14 US Food and Drug Administration-approved drug therapies for patients with PAH, which all target either nitric oxide signaling, endothelin receptors, or the prostacyclin pathway. In the current era, treatment-naïve patients with PAH are generally initiated on calcium channel antagonist therapy if there is evidence of vasoreactivity during right heart catheterization (following nitric oxide administration), dual therapy most often with an endothelin receptor antagonist and phosphodiesterase inhibitor, or parenteral prostacyclin therapy. Since < 5% of patients will demonstrate vasoreactivity, the decision at point of care in incident patients with PAH often focuses on dual oral therapy or initiation of parenteral prostacyclin therapy. In this case, the patient reported presyncope with minimal physical activity (eg, bending over or walking up stairs) and severely decreased functional status (ie, New York Heart Association Functional [NYHA] Class III – IV), and he had a cardiac index within the range of cardiogenic shock (< 2.0 L/min/m²). Collectively, this clinical profile is considered particularly high risk, therefore, a recommendation for parenteral continuous prostacyclin therapy was made.

► Dr. Clark: The patient tolerated epoprostenol and reported improvement in his symptoms. He had a tunneled line catheter placed for continuous epoprostenol infusion. He was discharged home and scheduled for outpatient follow-up in a PH clinic. At 4 months following discharge, he was reporting steady clinical and functional improvement as well as improvement in his dyspnea. A second therapy (oral phosphodiesterase type-V inhibitor) was initiated and tolerated well. Overall, he reported resolution of presyncope, NYHA Functional Class II symptoms, and the absence of important drug effects.

The novel coronavirus SARS-CoV-2 and resulting viral syndrome (COVID-19) was first reported in China during December 2019 and within weeks emerged in the US.¹ Since it is a rapidly evolving situation, clinicians must remain current on best practices—a challenging institutional responsibility. According to LitCovid, a curated literature hub for tracking scientific information on COVID-19, there are > 54,000 articles on the subject in PubMed. Among these include venous thromboembolism (VTE) prophylaxis guidance from 4 respected thrombosis organizations/societies and the US National Institutes of Health.^1-5

Observations

COVID-19 predisposes patients with and without a history of cardiovascular disease to thrombotic complications, occurring in either the venous or arterial circulation system.^2,6 Early observational studies suggest that thrombotic rates may be in excess of 20 to 30%; however, the use of prophylactic anticoagulation was inconsistent among studies that were rushed to publication.⁶

Autopsy data have demonstrated the presence of fibrin thrombi within distended small vessels and capillaries and extensive extracellular fibrin deposition.⁶ Investigators compared the characteristics of acute pulmonary embolism in 23 cases with COVID-19 but with no clinical signs of deep vein thrombosis with 100 controls without COVID-19.⁷ They observed that thrombotic lesions had a greater distribution in peripheral lung segments (ie, peripheral arteries) and were less extensive for those with COVID-19 vs without COVID-19 infection. Thus, experts currently hypothesize that COVID-19 has a distinct “pathomechanism.” As a unique phenotype, thrombotic events represent a combination of thromboembolic disease influenced by components of the Virchow triad (eg, acute illness and immobility) and in situ immunothrombosis, a local inflammatory response.^6,7

Well-established surgical and nonsurgical VTE thromboprophylaxis guidelines serve as the foundation for current COVID-19 thromboprophylaxis guidance.^8,9 Condition specific guidance is extrapolated from small, retrospective observational studies or based on expert opinion, representing levels 2 and 3 evidence, respectively.^1-5 Table 1 captures similarities and differences among COVID-19 VTE thromboprophylaxis recommendations which vary by time to publication and by society member expertise gained from practice in the field.

Conclusions

The COVID-19 pandemic has resulted in arguably the most challenging medical climate in the evidence-based medicine era. Until high-quality randomized controlled trials are published, the medical community is, in a sense, operating within a crucible of crisis having to navigate therapeutic policy with little certainty. This principle holds true for thromboprophylaxis in patients with COVID-19 despite the numerous advancements in this field over the past decade.

A review of societal guidance shows there is universal agreement with regards to supporting standard doses of pharmacologicalprophylaxis in acutely ill patients either when universally applied or guided by a RAM as well as the use of universal thromboprophylaxis in critically ill patients. All societies discourage the use of antiplatelet therapy for arterial thrombosis prevention and advocate for mechanical compression in patients with contraindications to pharmacologic anticoagulation. Beyond this, divergence between guidance statements begins to appear. For example, societies do not currently agree on the role and approach for extended pharmacologic prophylaxis postdischarge. The differences between societal guidance speaks to the degree of uncertainty among leading experts, which is considered to be the logical outworking of the current level of evidence. Regardless, these guidance documents should be considered the best resource currently available.

The medical community is fortunate to have robust societies that have published guidance on thromboprophylaxis in patients with COVID-19. The novelty of COVID-19 precludes these societal guidance publications from being based on high-quality evidence, but at the very least, they provide insight into how leading experts in the field of thrombosis and hemostasis are currently navigating the therapeutic landscape.

While this paper provides a summary of the current guidance, evidence is evolving at an unprecedented pace. Facilities and anticoagulation leads should be actively and frequently evaluating literature and guidance to ensure their practices and policies remain current.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville/Murfreesboro.

The novel coronavirus SARS-CoV-2 and resulting viral syndrome (COVID-19) was first reported in China during December 2019 and within weeks emerged in the US.¹ Since it is a rapidly evolving situation, clinicians must remain current on best practices—a challenging institutional responsibility. According to LitCovid, a curated literature hub for tracking scientific information on COVID-19, there are > 54,000 articles on the subject in PubMed. Among these include venous thromboembolism (VTE) prophylaxis guidance from 4 respected thrombosis organizations/societies and the US National Institutes of Health.^1-5

Observations

COVID-19 predisposes patients with and without a history of cardiovascular disease to thrombotic complications, occurring in either the venous or arterial circulation system.^2,6 Early observational studies suggest that thrombotic rates may be in excess of 20 to 30%; however, the use of prophylactic anticoagulation was inconsistent among studies that were rushed to publication.⁶

Autopsy data have demonstrated the presence of fibrin thrombi within distended small vessels and capillaries and extensive extracellular fibrin deposition.⁶ Investigators compared the characteristics of acute pulmonary embolism in 23 cases with COVID-19 but with no clinical signs of deep vein thrombosis with 100 controls without COVID-19.⁷ They observed that thrombotic lesions had a greater distribution in peripheral lung segments (ie, peripheral arteries) and were less extensive for those with COVID-19 vs without COVID-19 infection. Thus, experts currently hypothesize that COVID-19 has a distinct “pathomechanism.” As a unique phenotype, thrombotic events represent a combination of thromboembolic disease influenced by components of the Virchow triad (eg, acute illness and immobility) and in situ immunothrombosis, a local inflammatory response.^6,7

Well-established surgical and nonsurgical VTE thromboprophylaxis guidelines serve as the foundation for current COVID-19 thromboprophylaxis guidance.^8,9 Condition specific guidance is extrapolated from small, retrospective observational studies or based on expert opinion, representing levels 2 and 3 evidence, respectively.^1-5 Table 1 captures similarities and differences among COVID-19 VTE thromboprophylaxis recommendations which vary by time to publication and by society member expertise gained from practice in the field.

Conclusions

The COVID-19 pandemic has resulted in arguably the most challenging medical climate in the evidence-based medicine era. Until high-quality randomized controlled trials are published, the medical community is, in a sense, operating within a crucible of crisis having to navigate therapeutic policy with little certainty. This principle holds true for thromboprophylaxis in patients with COVID-19 despite the numerous advancements in this field over the past decade.

A review of societal guidance shows there is universal agreement with regards to supporting standard doses of pharmacologicalprophylaxis in acutely ill patients either when universally applied or guided by a RAM as well as the use of universal thromboprophylaxis in critically ill patients. All societies discourage the use of antiplatelet therapy for arterial thrombosis prevention and advocate for mechanical compression in patients with contraindications to pharmacologic anticoagulation. Beyond this, divergence between guidance statements begins to appear. For example, societies do not currently agree on the role and approach for extended pharmacologic prophylaxis postdischarge. The differences between societal guidance speaks to the degree of uncertainty among leading experts, which is considered to be the logical outworking of the current level of evidence. Regardless, these guidance documents should be considered the best resource currently available.

The medical community is fortunate to have robust societies that have published guidance on thromboprophylaxis in patients with COVID-19. The novelty of COVID-19 precludes these societal guidance publications from being based on high-quality evidence, but at the very least, they provide insight into how leading experts in the field of thrombosis and hemostasis are currently navigating the therapeutic landscape.

While this paper provides a summary of the current guidance, evidence is evolving at an unprecedented pace. Facilities and anticoagulation leads should be actively and frequently evaluating literature and guidance to ensure their practices and policies remain current.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville/Murfreesboro.

The novel coronavirus SARS-CoV-2 and resulting viral syndrome (COVID-19) was first reported in China during December 2019 and within weeks emerged in the US.¹ Since it is a rapidly evolving situation, clinicians must remain current on best practices—a challenging institutional responsibility. According to LitCovid, a curated literature hub for tracking scientific information on COVID-19, there are > 54,000 articles on the subject in PubMed. Among these include venous thromboembolism (VTE) prophylaxis guidance from 4 respected thrombosis organizations/societies and the US National Institutes of Health.^1-5

Observations

COVID-19 predisposes patients with and without a history of cardiovascular disease to thrombotic complications, occurring in either the venous or arterial circulation system.^2,6 Early observational studies suggest that thrombotic rates may be in excess of 20 to 30%; however, the use of prophylactic anticoagulation was inconsistent among studies that were rushed to publication.⁶

Autopsy data have demonstrated the presence of fibrin thrombi within distended small vessels and capillaries and extensive extracellular fibrin deposition.⁶ Investigators compared the characteristics of acute pulmonary embolism in 23 cases with COVID-19 but with no clinical signs of deep vein thrombosis with 100 controls without COVID-19.⁷ They observed that thrombotic lesions had a greater distribution in peripheral lung segments (ie, peripheral arteries) and were less extensive for those with COVID-19 vs without COVID-19 infection. Thus, experts currently hypothesize that COVID-19 has a distinct “pathomechanism.” As a unique phenotype, thrombotic events represent a combination of thromboembolic disease influenced by components of the Virchow triad (eg, acute illness and immobility) and in situ immunothrombosis, a local inflammatory response.^6,7

Well-established surgical and nonsurgical VTE thromboprophylaxis guidelines serve as the foundation for current COVID-19 thromboprophylaxis guidance.^8,9 Condition specific guidance is extrapolated from small, retrospective observational studies or based on expert opinion, representing levels 2 and 3 evidence, respectively.^1-5 Table 1 captures similarities and differences among COVID-19 VTE thromboprophylaxis recommendations which vary by time to publication and by society member expertise gained from practice in the field.

Conclusions

The COVID-19 pandemic has resulted in arguably the most challenging medical climate in the evidence-based medicine era. Until high-quality randomized controlled trials are published, the medical community is, in a sense, operating within a crucible of crisis having to navigate therapeutic policy with little certainty. This principle holds true for thromboprophylaxis in patients with COVID-19 despite the numerous advancements in this field over the past decade.

A review of societal guidance shows there is universal agreement with regards to supporting standard doses of pharmacologicalprophylaxis in acutely ill patients either when universally applied or guided by a RAM as well as the use of universal thromboprophylaxis in critically ill patients. All societies discourage the use of antiplatelet therapy for arterial thrombosis prevention and advocate for mechanical compression in patients with contraindications to pharmacologic anticoagulation. Beyond this, divergence between guidance statements begins to appear. For example, societies do not currently agree on the role and approach for extended pharmacologic prophylaxis postdischarge. The differences between societal guidance speaks to the degree of uncertainty among leading experts, which is considered to be the logical outworking of the current level of evidence. Regardless, these guidance documents should be considered the best resource currently available.

The medical community is fortunate to have robust societies that have published guidance on thromboprophylaxis in patients with COVID-19. The novelty of COVID-19 precludes these societal guidance publications from being based on high-quality evidence, but at the very least, they provide insight into how leading experts in the field of thrombosis and hemostasis are currently navigating the therapeutic landscape.

While this paper provides a summary of the current guidance, evidence is evolving at an unprecedented pace. Facilities and anticoagulation leads should be actively and frequently evaluating literature and guidance to ensure their practices and policies remain current.

Acknowledgments
This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville/Murfreesboro.

In the Veterans Health Administration (VHA), there are frequent e-mails and requests for employees to accept a detail or short-term assignment across a wide range of positions from administrative to executive leadership. These opportunities afford an employee and the service line valuable benefits and growth opportunities; however, there are reasons why some may be reluctant to pursue these opportunities. In this article, we discuss the barriers to applying for and accepting detail positions and the benefits for the employee and the service lines during periods of standard operations as well as during emergencies requiring alternative staffing strategies.

Details are short-term assignments used to fill a vacant position while hiring for the permanent position or to fill a short-term need (eg, during a pandemic). Details usually last 30 to 120 days, though they may be extended, depending on the position, the number of people willing to serve in the detailed role, and the time to select a candidate for the permanent position. Details can be created for any skill level or type of position to meet an identified need, but they are most often needed for supervisory or leadership roles.

The COVID-19 pandemic has shed light on the importance of individuals’ flexibility and adaptability both within and between roles. Many US Department of Veterans Affairs (VA) facilities stood up Incident Command structures to support the changes required to adapt to the needs created by the pandemic. Establishing an Incident Command means that people within the organization must take on new responsibilities, and in many cases, they are detailed to new positions that were not needed or prioritized before the pandemic.

Barriers

An employee may be reluctant to apply for or accept a detail because he or she has little to no experience; feels uncomfortable stepping into an unfamiliar role; is concerned about making a leap from a clinical to administrative role; has uncertainty whether the job is a good professional fit; dislikes the lack of a pay increase during the detail period even if the new role has more responsibility; and has concern that serving in the detail may make them ineligible to apply for the permanent position due to a perception of being preselected. Additionally, the employee may recognize the added stress on colleagues because the same amount of work must be completed.

Benefits

Although leaving a position for a period of months can be stressful, serving in a detail position provides significant opportunities for professional growth. An employee can gain knowledge and experience in an unfamiliar role before applying for or committing to a permanent position. Those serving in temporary details are often given more support as colleagues and supervisors understand that the role was accepted on short notice with little time to prepare. Other benefits include expanding professional contacts, gaining perspective on a different part of the VHA, and working on skills, such as flexibility, time management, and perseverance. By succeeding in a detail, employees build professional acumen. After taking on additional challenges they become more competitive for future jobs. The VHA Executive Candidate Development Program requires a 120-day detail, serving as either assistant or associate director, chief of staff, or associate director for patient care services/nurse executive as part of the program.¹

Temporarily leaving a service line to detail in a different service line has an impact on the home service because of the restrictions imposed. These restrictions guarantee that the employee can return to the original position at the end of a detail, thus providing a sense of job security; however, the home service line is down an employee.

Given these considerations, the following are key points to establish before undertaking the detail: (1) length of assignment; (2) once started, potential for the assignment to be extended; (3) will the employee be doing any of their prior job or just the new job or a blend of both; (4) possible changes in hours and site of work of the employee; (5) who will supervise the employee; (6) who will write the employee’s review; (7) training or skills needed prior to starting; (8) necessary paperwork; (9) how will the new assignment be communicated to others; (10) what happens if the detail ends sooner than planned; and (11) approval and support of all involved parties.

The employee’s home service may need a temporary plan to cover the employee’s workload, especially if the employee will be detailed to a different service line. The temporary plan may require creativity and flexibility and can be a way to trial the contingency plans for staffing the home service. One benefit to the home service is that the employee will have additional skills on returning that may benefit the home service, and the service will gain a potential leader.

When an employee goes to a different service, that service gains an employee who may bring a new perspective to help solve existing conflicts or problems. This can serve as a time to reset expectations or set new goals prior to the arrival of new leadership. If the detail is a good fit, then there is the chance that the employee may return in the future or refer others to it as a professional opportunity.

Conclusions

A detail can benefit the employee and the home and host services if planned in advance, and all parties support the process. A short-term leadership or administrative assignment can help an employee gain valuable experience for the future.

In the Veterans Health Administration (VHA), there are frequent e-mails and requests for employees to accept a detail or short-term assignment across a wide range of positions from administrative to executive leadership. These opportunities afford an employee and the service line valuable benefits and growth opportunities; however, there are reasons why some may be reluctant to pursue these opportunities. In this article, we discuss the barriers to applying for and accepting detail positions and the benefits for the employee and the service lines during periods of standard operations as well as during emergencies requiring alternative staffing strategies.

Details are short-term assignments used to fill a vacant position while hiring for the permanent position or to fill a short-term need (eg, during a pandemic). Details usually last 30 to 120 days, though they may be extended, depending on the position, the number of people willing to serve in the detailed role, and the time to select a candidate for the permanent position. Details can be created for any skill level or type of position to meet an identified need, but they are most often needed for supervisory or leadership roles.

The COVID-19 pandemic has shed light on the importance of individuals’ flexibility and adaptability both within and between roles. Many US Department of Veterans Affairs (VA) facilities stood up Incident Command structures to support the changes required to adapt to the needs created by the pandemic. Establishing an Incident Command means that people within the organization must take on new responsibilities, and in many cases, they are detailed to new positions that were not needed or prioritized before the pandemic.

Barriers

An employee may be reluctant to apply for or accept a detail because he or she has little to no experience; feels uncomfortable stepping into an unfamiliar role; is concerned about making a leap from a clinical to administrative role; has uncertainty whether the job is a good professional fit; dislikes the lack of a pay increase during the detail period even if the new role has more responsibility; and has concern that serving in the detail may make them ineligible to apply for the permanent position due to a perception of being preselected. Additionally, the employee may recognize the added stress on colleagues because the same amount of work must be completed.

Benefits

Although leaving a position for a period of months can be stressful, serving in a detail position provides significant opportunities for professional growth. An employee can gain knowledge and experience in an unfamiliar role before applying for or committing to a permanent position. Those serving in temporary details are often given more support as colleagues and supervisors understand that the role was accepted on short notice with little time to prepare. Other benefits include expanding professional contacts, gaining perspective on a different part of the VHA, and working on skills, such as flexibility, time management, and perseverance. By succeeding in a detail, employees build professional acumen. After taking on additional challenges they become more competitive for future jobs. The VHA Executive Candidate Development Program requires a 120-day detail, serving as either assistant or associate director, chief of staff, or associate director for patient care services/nurse executive as part of the program.¹

Temporarily leaving a service line to detail in a different service line has an impact on the home service because of the restrictions imposed. These restrictions guarantee that the employee can return to the original position at the end of a detail, thus providing a sense of job security; however, the home service line is down an employee.

Given these considerations, the following are key points to establish before undertaking the detail: (1) length of assignment; (2) once started, potential for the assignment to be extended; (3) will the employee be doing any of their prior job or just the new job or a blend of both; (4) possible changes in hours and site of work of the employee; (5) who will supervise the employee; (6) who will write the employee’s review; (7) training or skills needed prior to starting; (8) necessary paperwork; (9) how will the new assignment be communicated to others; (10) what happens if the detail ends sooner than planned; and (11) approval and support of all involved parties.

The employee’s home service may need a temporary plan to cover the employee’s workload, especially if the employee will be detailed to a different service line. The temporary plan may require creativity and flexibility and can be a way to trial the contingency plans for staffing the home service. One benefit to the home service is that the employee will have additional skills on returning that may benefit the home service, and the service will gain a potential leader.

When an employee goes to a different service, that service gains an employee who may bring a new perspective to help solve existing conflicts or problems. This can serve as a time to reset expectations or set new goals prior to the arrival of new leadership. If the detail is a good fit, then there is the chance that the employee may return in the future or refer others to it as a professional opportunity.

Conclusions

A detail can benefit the employee and the home and host services if planned in advance, and all parties support the process. A short-term leadership or administrative assignment can help an employee gain valuable experience for the future.

In the Veterans Health Administration (VHA), there are frequent e-mails and requests for employees to accept a detail or short-term assignment across a wide range of positions from administrative to executive leadership. These opportunities afford an employee and the service line valuable benefits and growth opportunities; however, there are reasons why some may be reluctant to pursue these opportunities. In this article, we discuss the barriers to applying for and accepting detail positions and the benefits for the employee and the service lines during periods of standard operations as well as during emergencies requiring alternative staffing strategies.

Details are short-term assignments used to fill a vacant position while hiring for the permanent position or to fill a short-term need (eg, during a pandemic). Details usually last 30 to 120 days, though they may be extended, depending on the position, the number of people willing to serve in the detailed role, and the time to select a candidate for the permanent position. Details can be created for any skill level or type of position to meet an identified need, but they are most often needed for supervisory or leadership roles.

The COVID-19 pandemic has shed light on the importance of individuals’ flexibility and adaptability both within and between roles. Many US Department of Veterans Affairs (VA) facilities stood up Incident Command structures to support the changes required to adapt to the needs created by the pandemic. Establishing an Incident Command means that people within the organization must take on new responsibilities, and in many cases, they are detailed to new positions that were not needed or prioritized before the pandemic.

Barriers

An employee may be reluctant to apply for or accept a detail because he or she has little to no experience; feels uncomfortable stepping into an unfamiliar role; is concerned about making a leap from a clinical to administrative role; has uncertainty whether the job is a good professional fit; dislikes the lack of a pay increase during the detail period even if the new role has more responsibility; and has concern that serving in the detail may make them ineligible to apply for the permanent position due to a perception of being preselected. Additionally, the employee may recognize the added stress on colleagues because the same amount of work must be completed.

Benefits

Although leaving a position for a period of months can be stressful, serving in a detail position provides significant opportunities for professional growth. An employee can gain knowledge and experience in an unfamiliar role before applying for or committing to a permanent position. Those serving in temporary details are often given more support as colleagues and supervisors understand that the role was accepted on short notice with little time to prepare. Other benefits include expanding professional contacts, gaining perspective on a different part of the VHA, and working on skills, such as flexibility, time management, and perseverance. By succeeding in a detail, employees build professional acumen. After taking on additional challenges they become more competitive for future jobs. The VHA Executive Candidate Development Program requires a 120-day detail, serving as either assistant or associate director, chief of staff, or associate director for patient care services/nurse executive as part of the program.¹

Temporarily leaving a service line to detail in a different service line has an impact on the home service because of the restrictions imposed. These restrictions guarantee that the employee can return to the original position at the end of a detail, thus providing a sense of job security; however, the home service line is down an employee.

Given these considerations, the following are key points to establish before undertaking the detail: (1) length of assignment; (2) once started, potential for the assignment to be extended; (3) will the employee be doing any of their prior job or just the new job or a blend of both; (4) possible changes in hours and site of work of the employee; (5) who will supervise the employee; (6) who will write the employee’s review; (7) training or skills needed prior to starting; (8) necessary paperwork; (9) how will the new assignment be communicated to others; (10) what happens if the detail ends sooner than planned; and (11) approval and support of all involved parties.

The employee’s home service may need a temporary plan to cover the employee’s workload, especially if the employee will be detailed to a different service line. The temporary plan may require creativity and flexibility and can be a way to trial the contingency plans for staffing the home service. One benefit to the home service is that the employee will have additional skills on returning that may benefit the home service, and the service will gain a potential leader.

When an employee goes to a different service, that service gains an employee who may bring a new perspective to help solve existing conflicts or problems. This can serve as a time to reset expectations or set new goals prior to the arrival of new leadership. If the detail is a good fit, then there is the chance that the employee may return in the future or refer others to it as a professional opportunity.

Conclusions

A detail can benefit the employee and the home and host services if planned in advance, and all parties support the process. A short-term leadership or administrative assignment can help an employee gain valuable experience for the future.