Stress cardiomyopathy (SCM), also known as takotsubo cardiomyopathy, is a nonischemic cardiomyopathy initially identified in Japan in 1990. In 2006, SCM gained an International Classification of Diseases code at the 9^th Clinical Modification (ICD-9 CM). Subsequently, several epidemiological studies have used ICD codes to evaluate trends in the diagnosis of SCM;^1-8 however, to our knowledge, no previous studies have validated ICD-9 or -10 codes using chart review. We aimed to determine the positive predictive value (PPV) and the limitations of these ICD codes among hospitalized patients.

We performed a retrospective cohort study at a single tertiary care center, identifying all adults aged ≥18 years from 2010 to 2016 who were hospitalized with a first known diagnosis of SCM in our Electronic Health Records (EHR) system (Cerner, Stoltenberg Consulting, Inc., Bethel Park, Pennsylvania), which includes both inpatient and outpatient records. We included patients hospitalized with a principal or secondary ICD-9 discharge diagnosis code of 429.83 (for those hospitalized before October 2015) or an ICD-10 discharge diagnosis code of I51.81 (for those hospitalized from October 1, 2015 through December 2016). We excluded hospital readmissions and patients with recurrent SCM, but we could not administratively remove patients who carried a prior diagnosis of SCM made previously at other institutions. One investigator (KW) then reviewed our EHR for a documentation of SCM anywhere in the chart by performing a systematic review of discharge, admission, consultation, daily progress notes, as well as biomarkers, electrocardiograms, echocardiograms, and coronary angiograms. If the first reviewer did not find documentation of SCM anywhere in the EHR, this finding was confirmed by a second chart review by a cardiologist (QP).

Principal and secondary discharge diagnoses were entered into our administrative database by hospital coders using standard coding practices. Because ICD codes also record comorbidities that were present prior to admission, we determined whether each patient had a new diagnosis of SCM during the hospitalization. If not, we considered their ICD code as a preexisting comorbidity and labeled these as chronic cases.

We recorded age, sex, race, ethnicity, and frequency of echocardiogram and cardiac catheterization among all patients. To determine the burden of other comorbidities, we used the Charlson Comorbidity Index and the Elixhauser Comorbidity Index,^9,10 but limited our reporting to comorbidities with >5% prevalence.

Our primary aim was to measure the PPV of these ICD codes to determine a diagnosis of SCM. This was done by dividing the total number of cases with a clinical documentation of SCM by the total number of patients with an ICD diagnosis of SCM. As secondary aims, we noted the percentage of new and chronic SCM, the proportion of patients who underwent echocardiography and/or cardiac catheterization and recorded the annual number of total cases of confirmed SCM from 2010 to 2016. Trends were evaluated using the Cochran-Armitage test. To better understand the difference between patients given a principal and secondary code for SCM, we compared these two groups using summary statistics using t tests and chi-squared tests as appropriate, noted the PPV, and determined the 95% confidence intervals of ICD codes in these subgroups. This study was approved by the institutional review board of Baystate Medical Center (#1109756-4). Statistical analysis was done using JMP version12.0.1 (SAS Institute, Cary, North Carolina, 2015).

During 2010-2016, a total of 592 patients with a first known ICD code in our EHR for SCM were hospitalized, comprising 242 (41.0%) with a principal diagnosis code. Upon chart review, we were unable to confirm a clinical diagnosis of SCM among 12 (2.0%) patients. In addition, 38 (6.4%) were chronic cases of SCM, without evidence of active disease at the time of hospitalization. In general, chronic cases typically carried an SCM diagnosis from a hospitalization at a non-Baystate hospital (outside our EHR), or from an outpatient setting. Occasionally, we also found cases where the diagnosis of SCM was mentioned but testing was not pursued, and the patient had no symptoms that were attributed to SCM. Overall use of echocardiogram and cardiac angiography was 91.5% and 66.8%, respectively, and was lower in chronic than in new cases of SCM.

Compared with patients with a secondary diagnosis code, patients with a principal diagnosis of SCM underwent more cardiac angiography and echocardiography (Table 1). When comparing the difference between those with principal and secondary ICD codes, we found that 237 (98%) vs 305 (87%) were new cases of SCM, respectively, and all 12 patients without any clinical diagnosis of SCM had been given a secondary ICD code. Between 2010 and 2016, we noted a significant increase in the number of cases of SCM (Cochrane–Armitage, P < .0001).

In this study, we found a strong relationship between the receipt of an ICD code for SCM and the clinical documentation of a diagnosis of SCM, with an overall PPV of 98%. The PPV was higher when the sample was limited to those assigned a principal ICD code for SCM, but it was lower when considering that some ICD codes represented chronic SCM from prior hospitalizations, despite our attempts to exclude these cases administratively prior to chart review. Furthermore, cardiac catheterization and echocardiography were used inconsistently and were less frequent among secondary compared with a principal diagnosis of SCM. Thus, although a principal ICD diagnosis code for SCM appears to accurately reflect a diagnosis of SCM, a secondary code for SCM appears less reliable. These findings suggest that future epidemiological studies can rely on principal diagnosis codes for use in research studies, but that they should use caution when including patients with secondary codes for SCM.

Our study makes an important contribution to the literature because it quantitates the reliability of ICD codes to identify patients with SCM. This finding is important because multiple studies have used this code to study trends in the incidence of this disease,^1-8 and futures studies will almost certainly continue to do so. Our results also showed similar demographics and trends in the incidence of SCM compared with those of prior studies^1-3,11 but additionally revealed that these codes also have some important limitations.

A key factor to remember is that neither a clinical diagnosis nor an ICD code at the time of hospital discharge is based upon formal diagnostic criteria for SCM. Importantly, all currently proposed diagnostic criteria require resolution of typical regional wall motion abnormalities before finalizing a research-grade diagnosis of SCM (Table 2).^12,13 However, because the median time to recovery of ejection fraction in SCM is between three and four weeks after hospital discharge (with some recovery extending much longer),⁶ it is almost impossible to make a research-grade diagnosis of SCM after a three- to four-day hospitalization. Moreover, 33% of our patients did not undergo cardiac catheterization, 8.5% did not undergo echocardiography, and it is our experience that testing for pheochromocytoma and myocarditis is rarely done. Thus, we emphasize that ICD codes for SCM assigned at the time of hospital discharge represent a clinical diagnosis of SCM and not research-grade criteria for this disease. This is a significant limitation of prior epidemiologic studies that consider only the short time frame of hospitalization.

Stress cardiomyopathy (SCM), also known as takotsubo cardiomyopathy, is a nonischemic cardiomyopathy initially identified in Japan in 1990. In 2006, SCM gained an International Classification of Diseases code at the 9^th Clinical Modification (ICD-9 CM). Subsequently, several epidemiological studies have used ICD codes to evaluate trends in the diagnosis of SCM;^1-8 however, to our knowledge, no previous studies have validated ICD-9 or -10 codes using chart review. We aimed to determine the positive predictive value (PPV) and the limitations of these ICD codes among hospitalized patients.

We performed a retrospective cohort study at a single tertiary care center, identifying all adults aged ≥18 years from 2010 to 2016 who were hospitalized with a first known diagnosis of SCM in our Electronic Health Records (EHR) system (Cerner, Stoltenberg Consulting, Inc., Bethel Park, Pennsylvania), which includes both inpatient and outpatient records. We included patients hospitalized with a principal or secondary ICD-9 discharge diagnosis code of 429.83 (for those hospitalized before October 2015) or an ICD-10 discharge diagnosis code of I51.81 (for those hospitalized from October 1, 2015 through December 2016). We excluded hospital readmissions and patients with recurrent SCM, but we could not administratively remove patients who carried a prior diagnosis of SCM made previously at other institutions. One investigator (KW) then reviewed our EHR for a documentation of SCM anywhere in the chart by performing a systematic review of discharge, admission, consultation, daily progress notes, as well as biomarkers, electrocardiograms, echocardiograms, and coronary angiograms. If the first reviewer did not find documentation of SCM anywhere in the EHR, this finding was confirmed by a second chart review by a cardiologist (QP).

Principal and secondary discharge diagnoses were entered into our administrative database by hospital coders using standard coding practices. Because ICD codes also record comorbidities that were present prior to admission, we determined whether each patient had a new diagnosis of SCM during the hospitalization. If not, we considered their ICD code as a preexisting comorbidity and labeled these as chronic cases.

We recorded age, sex, race, ethnicity, and frequency of echocardiogram and cardiac catheterization among all patients. To determine the burden of other comorbidities, we used the Charlson Comorbidity Index and the Elixhauser Comorbidity Index,^9,10 but limited our reporting to comorbidities with >5% prevalence.

Our primary aim was to measure the PPV of these ICD codes to determine a diagnosis of SCM. This was done by dividing the total number of cases with a clinical documentation of SCM by the total number of patients with an ICD diagnosis of SCM. As secondary aims, we noted the percentage of new and chronic SCM, the proportion of patients who underwent echocardiography and/or cardiac catheterization and recorded the annual number of total cases of confirmed SCM from 2010 to 2016. Trends were evaluated using the Cochran-Armitage test. To better understand the difference between patients given a principal and secondary code for SCM, we compared these two groups using summary statistics using t tests and chi-squared tests as appropriate, noted the PPV, and determined the 95% confidence intervals of ICD codes in these subgroups. This study was approved by the institutional review board of Baystate Medical Center (#1109756-4). Statistical analysis was done using JMP version12.0.1 (SAS Institute, Cary, North Carolina, 2015).

During 2010-2016, a total of 592 patients with a first known ICD code in our EHR for SCM were hospitalized, comprising 242 (41.0%) with a principal diagnosis code. Upon chart review, we were unable to confirm a clinical diagnosis of SCM among 12 (2.0%) patients. In addition, 38 (6.4%) were chronic cases of SCM, without evidence of active disease at the time of hospitalization. In general, chronic cases typically carried an SCM diagnosis from a hospitalization at a non-Baystate hospital (outside our EHR), or from an outpatient setting. Occasionally, we also found cases where the diagnosis of SCM was mentioned but testing was not pursued, and the patient had no symptoms that were attributed to SCM. Overall use of echocardiogram and cardiac angiography was 91.5% and 66.8%, respectively, and was lower in chronic than in new cases of SCM.

Compared with patients with a secondary diagnosis code, patients with a principal diagnosis of SCM underwent more cardiac angiography and echocardiography (Table 1). When comparing the difference between those with principal and secondary ICD codes, we found that 237 (98%) vs 305 (87%) were new cases of SCM, respectively, and all 12 patients without any clinical diagnosis of SCM had been given a secondary ICD code. Between 2010 and 2016, we noted a significant increase in the number of cases of SCM (Cochrane–Armitage, P < .0001).

In this study, we found a strong relationship between the receipt of an ICD code for SCM and the clinical documentation of a diagnosis of SCM, with an overall PPV of 98%. The PPV was higher when the sample was limited to those assigned a principal ICD code for SCM, but it was lower when considering that some ICD codes represented chronic SCM from prior hospitalizations, despite our attempts to exclude these cases administratively prior to chart review. Furthermore, cardiac catheterization and echocardiography were used inconsistently and were less frequent among secondary compared with a principal diagnosis of SCM. Thus, although a principal ICD diagnosis code for SCM appears to accurately reflect a diagnosis of SCM, a secondary code for SCM appears less reliable. These findings suggest that future epidemiological studies can rely on principal diagnosis codes for use in research studies, but that they should use caution when including patients with secondary codes for SCM.

Our study makes an important contribution to the literature because it quantitates the reliability of ICD codes to identify patients with SCM. This finding is important because multiple studies have used this code to study trends in the incidence of this disease,^1-8 and futures studies will almost certainly continue to do so. Our results also showed similar demographics and trends in the incidence of SCM compared with those of prior studies^1-3,11 but additionally revealed that these codes also have some important limitations.

A key factor to remember is that neither a clinical diagnosis nor an ICD code at the time of hospital discharge is based upon formal diagnostic criteria for SCM. Importantly, all currently proposed diagnostic criteria require resolution of typical regional wall motion abnormalities before finalizing a research-grade diagnosis of SCM (Table 2).^12,13 However, because the median time to recovery of ejection fraction in SCM is between three and four weeks after hospital discharge (with some recovery extending much longer),⁶ it is almost impossible to make a research-grade diagnosis of SCM after a three- to four-day hospitalization. Moreover, 33% of our patients did not undergo cardiac catheterization, 8.5% did not undergo echocardiography, and it is our experience that testing for pheochromocytoma and myocarditis is rarely done. Thus, we emphasize that ICD codes for SCM assigned at the time of hospital discharge represent a clinical diagnosis of SCM and not research-grade criteria for this disease. This is a significant limitation of prior epidemiologic studies that consider only the short time frame of hospitalization.

Stress cardiomyopathy (SCM), also known as takotsubo cardiomyopathy, is a nonischemic cardiomyopathy initially identified in Japan in 1990. In 2006, SCM gained an International Classification of Diseases code at the 9^th Clinical Modification (ICD-9 CM). Subsequently, several epidemiological studies have used ICD codes to evaluate trends in the diagnosis of SCM;^1-8 however, to our knowledge, no previous studies have validated ICD-9 or -10 codes using chart review. We aimed to determine the positive predictive value (PPV) and the limitations of these ICD codes among hospitalized patients.

We performed a retrospective cohort study at a single tertiary care center, identifying all adults aged ≥18 years from 2010 to 2016 who were hospitalized with a first known diagnosis of SCM in our Electronic Health Records (EHR) system (Cerner, Stoltenberg Consulting, Inc., Bethel Park, Pennsylvania), which includes both inpatient and outpatient records. We included patients hospitalized with a principal or secondary ICD-9 discharge diagnosis code of 429.83 (for those hospitalized before October 2015) or an ICD-10 discharge diagnosis code of I51.81 (for those hospitalized from October 1, 2015 through December 2016). We excluded hospital readmissions and patients with recurrent SCM, but we could not administratively remove patients who carried a prior diagnosis of SCM made previously at other institutions. One investigator (KW) then reviewed our EHR for a documentation of SCM anywhere in the chart by performing a systematic review of discharge, admission, consultation, daily progress notes, as well as biomarkers, electrocardiograms, echocardiograms, and coronary angiograms. If the first reviewer did not find documentation of SCM anywhere in the EHR, this finding was confirmed by a second chart review by a cardiologist (QP).

Principal and secondary discharge diagnoses were entered into our administrative database by hospital coders using standard coding practices. Because ICD codes also record comorbidities that were present prior to admission, we determined whether each patient had a new diagnosis of SCM during the hospitalization. If not, we considered their ICD code as a preexisting comorbidity and labeled these as chronic cases.

We recorded age, sex, race, ethnicity, and frequency of echocardiogram and cardiac catheterization among all patients. To determine the burden of other comorbidities, we used the Charlson Comorbidity Index and the Elixhauser Comorbidity Index,^9,10 but limited our reporting to comorbidities with >5% prevalence.

Our primary aim was to measure the PPV of these ICD codes to determine a diagnosis of SCM. This was done by dividing the total number of cases with a clinical documentation of SCM by the total number of patients with an ICD diagnosis of SCM. As secondary aims, we noted the percentage of new and chronic SCM, the proportion of patients who underwent echocardiography and/or cardiac catheterization and recorded the annual number of total cases of confirmed SCM from 2010 to 2016. Trends were evaluated using the Cochran-Armitage test. To better understand the difference between patients given a principal and secondary code for SCM, we compared these two groups using summary statistics using t tests and chi-squared tests as appropriate, noted the PPV, and determined the 95% confidence intervals of ICD codes in these subgroups. This study was approved by the institutional review board of Baystate Medical Center (#1109756-4). Statistical analysis was done using JMP version12.0.1 (SAS Institute, Cary, North Carolina, 2015).

During 2010-2016, a total of 592 patients with a first known ICD code in our EHR for SCM were hospitalized, comprising 242 (41.0%) with a principal diagnosis code. Upon chart review, we were unable to confirm a clinical diagnosis of SCM among 12 (2.0%) patients. In addition, 38 (6.4%) were chronic cases of SCM, without evidence of active disease at the time of hospitalization. In general, chronic cases typically carried an SCM diagnosis from a hospitalization at a non-Baystate hospital (outside our EHR), or from an outpatient setting. Occasionally, we also found cases where the diagnosis of SCM was mentioned but testing was not pursued, and the patient had no symptoms that were attributed to SCM. Overall use of echocardiogram and cardiac angiography was 91.5% and 66.8%, respectively, and was lower in chronic than in new cases of SCM.

Compared with patients with a secondary diagnosis code, patients with a principal diagnosis of SCM underwent more cardiac angiography and echocardiography (Table 1). When comparing the difference between those with principal and secondary ICD codes, we found that 237 (98%) vs 305 (87%) were new cases of SCM, respectively, and all 12 patients without any clinical diagnosis of SCM had been given a secondary ICD code. Between 2010 and 2016, we noted a significant increase in the number of cases of SCM (Cochrane–Armitage, P < .0001).

In this study, we found a strong relationship between the receipt of an ICD code for SCM and the clinical documentation of a diagnosis of SCM, with an overall PPV of 98%. The PPV was higher when the sample was limited to those assigned a principal ICD code for SCM, but it was lower when considering that some ICD codes represented chronic SCM from prior hospitalizations, despite our attempts to exclude these cases administratively prior to chart review. Furthermore, cardiac catheterization and echocardiography were used inconsistently and were less frequent among secondary compared with a principal diagnosis of SCM. Thus, although a principal ICD diagnosis code for SCM appears to accurately reflect a diagnosis of SCM, a secondary code for SCM appears less reliable. These findings suggest that future epidemiological studies can rely on principal diagnosis codes for use in research studies, but that they should use caution when including patients with secondary codes for SCM.

Our study makes an important contribution to the literature because it quantitates the reliability of ICD codes to identify patients with SCM. This finding is important because multiple studies have used this code to study trends in the incidence of this disease,^1-8 and futures studies will almost certainly continue to do so. Our results also showed similar demographics and trends in the incidence of SCM compared with those of prior studies^1-3,11 but additionally revealed that these codes also have some important limitations.

A key factor to remember is that neither a clinical diagnosis nor an ICD code at the time of hospital discharge is based upon formal diagnostic criteria for SCM. Importantly, all currently proposed diagnostic criteria require resolution of typical regional wall motion abnormalities before finalizing a research-grade diagnosis of SCM (Table 2).^12,13 However, because the median time to recovery of ejection fraction in SCM is between three and four weeks after hospital discharge (with some recovery extending much longer),⁶ it is almost impossible to make a research-grade diagnosis of SCM after a three- to four-day hospitalization. Moreover, 33% of our patients did not undergo cardiac catheterization, 8.5% did not undergo echocardiography, and it is our experience that testing for pheochromocytoma and myocarditis is rarely done. Thus, we emphasize that ICD codes for SCM assigned at the time of hospital discharge represent a clinical diagnosis of SCM and not research-grade criteria for this disease. This is a significant limitation of prior epidemiologic studies that consider only the short time frame of hospitalization.

The loss of mobility during hospitalization is common and is an important reason why more than 40% of hospitalized Medicare patients require placement in a postacute facility.^1,2 Discharge planning may be delayed when the medical team focuses on managing acute medical issues without recognizing a patient’s rehabilitation needs until near the time of discharge.³ For patients who require rehabilitation in a postacute facility, delays in discharge can exacerbate hospital-acquired mobility loss and prolong functional recovery.^2,4 In addition, even small increases in length of stay have substantial financial impact.⁵ Increased efficiency in the discharge process has the potential to reduce healthcare costs, facilitate patient recovery, and reduce delays for new admissions awaiting beds.⁶ For effective discharge planning, a proactive, patient-centered, interdisciplinary approach that considers patient mobility status is needed.³

Systematic measurement of patient mobility that extends beyond evaluations by physical therapists is not common practice, but has the potential to facilitate early discharge planning.^7,8 At our hospital, mobility assessment is performed routinely using a reliable and valid interdisciplinary assessment of mobility throughout the patient’s entire hospitalization.⁹ We recently showed that nurse-recorded mobility status within the first 24 hours of hospitalization was associated with discharge disposition,⁷ but a prediction tool to help aid clinicians in the discharge planning process would be more useful. In this study, we evaluated the predictive ability of a patient’s mobility score, obtained within 48 hours of hospital admission, to identify the need for postacute care in a diverse patient population.

After receiving approval from the Johns Hopkins Institutional Review Board, we conducted analyses on a retrospective cohort of 821 admissions (777 unique patients admitted between January 1, 2017 and August 25, 2017) who were hospitalized for ≥72 hours on two inpatient units (medical and neurological/neurosurgical) at The Johns Hopkins Hospital (JHH). These units were chosen to reduce the potential for both selection and measurement bias. First, these units manage a diverse patient population that is likely to generalize to a general hospital population. Second, the nursing staff on these units has the most accurate and consistent documentation compliance for our predictor variable.

Mobility Measure

The Activity Measure for Post Acute Care Inpatient Mobility Short Form (AM-PAC IMSF) is a measure of functional capacity. This short form is widely used and is nicknamed “6 clicks.” It has questions for six mobility tasks, and each question is scored on a four-point Likert scale.⁹ Patients do not have to attempt the tasks to be scored. Clinicians can score items using clinical judgement based on observation or discussion with the patient, family, or other clinicians. The interrater reliability is very good (Intraclass Correlation Coefficient = .85-.99)⁹ and construct validity has been demonstrated for the inpatient hospital population (AM-PAC IMSF correlations with: functional independence measure [FIM] = .65; Katz activities of daily living [ADL] = .80; 2-minute walk = .73; 5-times sit-to-stand = −.69).⁹ At JHH, the AM-PAC IMSF is scored at admission by nursing staff (>90% documentation compliance on the units in this study); these admission scores were used.

Outcome and Predictors

Discharge location (postacute care facility vs home) was the primary outcome in this study, as recorded in a discrete field in the electronic medical record (EMR). To ensure the validity of this measure, we performed manual chart audits on a sample of patients (n = 300). It was confirmed that the measure entered in the discrete field in the EMR correctly identified the disposition (home vs postacute care facility) in all cases. The primary predictor was the lowest AM-PAC IMSF score obtained within 48 hours after hospital admission, reflecting the patient’s capability to mobilize after hospital admission. Raw scores were converted to scale scores (0-100) for analysis.⁹ Additional predictors considered included: age, sex, race, and primary diagnosis, all of which were readily available from the EMR at the time of hospital admission. We then grouped the primary diagnosis into the following categories using ICD-10 codes upon admission: Oncologic, Progressive Neurological, Sudden Onset Neurological, and Medical/Other.

Statistical Analysis

We constructed a classification tree, a machine learning approach,¹⁰ to predict discharge placement (postacute facility vs home) based on the patients’ hospital admission characteristics and AM-PAC IMSF score. The prediction model was developed using the classification tree approach, as opposed to a logistic regression model. This approach allows for the inclusion of higher-order interactions (ie, interactions of more than two predictors) which would need to be explicitly specified otherwise and a priori we did not have strong evidence from prior studies to guide the model construction. The classification tree was constructed and evaluated by dividing our sample into a 70% training set and a 30% validation set using random sampling within key strata defined by age (<65 vs ≥65 years), gender, and quartile of the AM-PAC IMSF score. The classification tree was developed using the training set. Next, measures of predictive accuracy (ie, the proportion of correctly classified patients with placement in a postacute facility [sensitivity]) and the proportion of correctly classified patients not discharged to postacute care (ie, to home, specificity), were estimated by applying the validation set to the classification tree. The R statistical package rpart¹¹ with procedure rpart was used to construct the classification tree using standard criteria for growing (Gini index¹⁰) and pruning (misclassification error estimated by leave-1-out cross-validation¹²) the tree.

Improving the efficiency of hospital discharge planning is of great interest to hospital-based clinicians and administrators. Identifying patients early who are likely to need placement in a postacute facility is an important first step. Using a reliable and valid nursing assessment tool of patient mobility to help with discharge planning is an attractive and feasible approach. The literature on predicting disposition is very limited and has focused primarily on patients with stroke or joint replacement.^13,14 Previously, we used the same measure of mobility within 24 hours of admission to show an association with discharge disposition.⁷ Here, we expanded upon that prior research to include mobility assessment within a 48-hour window from admission in a diverse patient population. Using a machine learning approach, we were able to predict 73% of hospital discharges correctly using only the patient’s mobility score and age. Having tools such as this simple decision tree to identify discharge locations early in a patient’s hospitalization has the potential to increase efficiency in the discharge planning process.

Despite being able to classify the discharge disposition correctly for most patients, our sensitivity for predicting postacute care need was low. There are likely other patient and system factors that could be collected near the time of hospital admission, such as the patient’s prior level of function, the difference between function at baseline and admission, their prior living situation (eg, long term care, home environment), social support, and hospital relationships with postacute care facilities that may help to improve the prediction of postacute care placement.¹⁵ We recommend that future research consider these and other potentially important predictors. However, the specificity was high enough that all patients who score positive merit evaluation for possible postacute care. While our patient sample was diverse, it did not focus on some patients who may be more likely to be discharged to a postacute facility, such as the geriatric population. This may be a potential limitation to our study and will require this tool to be tested in more patient groups. A final limitation is the grouping of all potential types of postacute care into one category since important differences exist between the care provided at skilled nursing facilities with or without rehabilitation and inpatient acute rehabilitation. Despite these limitations, this study emphasizes the value of a systematic mobility assessment and provides a simple decision tree to help providers begin early discharge planning by anticipating patient rehabilitation needs.

Acknowledgments

The authors thank Christina Lin, MD and Sophia Andrews, PT, DPT for their assistance with data validation.

The loss of mobility during hospitalization is common and is an important reason why more than 40% of hospitalized Medicare patients require placement in a postacute facility.^1,2 Discharge planning may be delayed when the medical team focuses on managing acute medical issues without recognizing a patient’s rehabilitation needs until near the time of discharge.³ For patients who require rehabilitation in a postacute facility, delays in discharge can exacerbate hospital-acquired mobility loss and prolong functional recovery.^2,4 In addition, even small increases in length of stay have substantial financial impact.⁵ Increased efficiency in the discharge process has the potential to reduce healthcare costs, facilitate patient recovery, and reduce delays for new admissions awaiting beds.⁶ For effective discharge planning, a proactive, patient-centered, interdisciplinary approach that considers patient mobility status is needed.³

Systematic measurement of patient mobility that extends beyond evaluations by physical therapists is not common practice, but has the potential to facilitate early discharge planning.^7,8 At our hospital, mobility assessment is performed routinely using a reliable and valid interdisciplinary assessment of mobility throughout the patient’s entire hospitalization.⁹ We recently showed that nurse-recorded mobility status within the first 24 hours of hospitalization was associated with discharge disposition,⁷ but a prediction tool to help aid clinicians in the discharge planning process would be more useful. In this study, we evaluated the predictive ability of a patient’s mobility score, obtained within 48 hours of hospital admission, to identify the need for postacute care in a diverse patient population.

After receiving approval from the Johns Hopkins Institutional Review Board, we conducted analyses on a retrospective cohort of 821 admissions (777 unique patients admitted between January 1, 2017 and August 25, 2017) who were hospitalized for ≥72 hours on two inpatient units (medical and neurological/neurosurgical) at The Johns Hopkins Hospital (JHH). These units were chosen to reduce the potential for both selection and measurement bias. First, these units manage a diverse patient population that is likely to generalize to a general hospital population. Second, the nursing staff on these units has the most accurate and consistent documentation compliance for our predictor variable.

Mobility Measure

The Activity Measure for Post Acute Care Inpatient Mobility Short Form (AM-PAC IMSF) is a measure of functional capacity. This short form is widely used and is nicknamed “6 clicks.” It has questions for six mobility tasks, and each question is scored on a four-point Likert scale.⁹ Patients do not have to attempt the tasks to be scored. Clinicians can score items using clinical judgement based on observation or discussion with the patient, family, or other clinicians. The interrater reliability is very good (Intraclass Correlation Coefficient = .85-.99)⁹ and construct validity has been demonstrated for the inpatient hospital population (AM-PAC IMSF correlations with: functional independence measure [FIM] = .65; Katz activities of daily living [ADL] = .80; 2-minute walk = .73; 5-times sit-to-stand = −.69).⁹ At JHH, the AM-PAC IMSF is scored at admission by nursing staff (>90% documentation compliance on the units in this study); these admission scores were used.

Outcome and Predictors

Discharge location (postacute care facility vs home) was the primary outcome in this study, as recorded in a discrete field in the electronic medical record (EMR). To ensure the validity of this measure, we performed manual chart audits on a sample of patients (n = 300). It was confirmed that the measure entered in the discrete field in the EMR correctly identified the disposition (home vs postacute care facility) in all cases. The primary predictor was the lowest AM-PAC IMSF score obtained within 48 hours after hospital admission, reflecting the patient’s capability to mobilize after hospital admission. Raw scores were converted to scale scores (0-100) for analysis.⁹ Additional predictors considered included: age, sex, race, and primary diagnosis, all of which were readily available from the EMR at the time of hospital admission. We then grouped the primary diagnosis into the following categories using ICD-10 codes upon admission: Oncologic, Progressive Neurological, Sudden Onset Neurological, and Medical/Other.

Statistical Analysis

We constructed a classification tree, a machine learning approach,¹⁰ to predict discharge placement (postacute facility vs home) based on the patients’ hospital admission characteristics and AM-PAC IMSF score. The prediction model was developed using the classification tree approach, as opposed to a logistic regression model. This approach allows for the inclusion of higher-order interactions (ie, interactions of more than two predictors) which would need to be explicitly specified otherwise and a priori we did not have strong evidence from prior studies to guide the model construction. The classification tree was constructed and evaluated by dividing our sample into a 70% training set and a 30% validation set using random sampling within key strata defined by age (<65 vs ≥65 years), gender, and quartile of the AM-PAC IMSF score. The classification tree was developed using the training set. Next, measures of predictive accuracy (ie, the proportion of correctly classified patients with placement in a postacute facility [sensitivity]) and the proportion of correctly classified patients not discharged to postacute care (ie, to home, specificity), were estimated by applying the validation set to the classification tree. The R statistical package rpart¹¹ with procedure rpart was used to construct the classification tree using standard criteria for growing (Gini index¹⁰) and pruning (misclassification error estimated by leave-1-out cross-validation¹²) the tree.

Improving the efficiency of hospital discharge planning is of great interest to hospital-based clinicians and administrators. Identifying patients early who are likely to need placement in a postacute facility is an important first step. Using a reliable and valid nursing assessment tool of patient mobility to help with discharge planning is an attractive and feasible approach. The literature on predicting disposition is very limited and has focused primarily on patients with stroke or joint replacement.^13,14 Previously, we used the same measure of mobility within 24 hours of admission to show an association with discharge disposition.⁷ Here, we expanded upon that prior research to include mobility assessment within a 48-hour window from admission in a diverse patient population. Using a machine learning approach, we were able to predict 73% of hospital discharges correctly using only the patient’s mobility score and age. Having tools such as this simple decision tree to identify discharge locations early in a patient’s hospitalization has the potential to increase efficiency in the discharge planning process.

Despite being able to classify the discharge disposition correctly for most patients, our sensitivity for predicting postacute care need was low. There are likely other patient and system factors that could be collected near the time of hospital admission, such as the patient’s prior level of function, the difference between function at baseline and admission, their prior living situation (eg, long term care, home environment), social support, and hospital relationships with postacute care facilities that may help to improve the prediction of postacute care placement.¹⁵ We recommend that future research consider these and other potentially important predictors. However, the specificity was high enough that all patients who score positive merit evaluation for possible postacute care. While our patient sample was diverse, it did not focus on some patients who may be more likely to be discharged to a postacute facility, such as the geriatric population. This may be a potential limitation to our study and will require this tool to be tested in more patient groups. A final limitation is the grouping of all potential types of postacute care into one category since important differences exist between the care provided at skilled nursing facilities with or without rehabilitation and inpatient acute rehabilitation. Despite these limitations, this study emphasizes the value of a systematic mobility assessment and provides a simple decision tree to help providers begin early discharge planning by anticipating patient rehabilitation needs.

Acknowledgments

The authors thank Christina Lin, MD and Sophia Andrews, PT, DPT for their assistance with data validation.

The loss of mobility during hospitalization is common and is an important reason why more than 40% of hospitalized Medicare patients require placement in a postacute facility.^1,2 Discharge planning may be delayed when the medical team focuses on managing acute medical issues without recognizing a patient’s rehabilitation needs until near the time of discharge.³ For patients who require rehabilitation in a postacute facility, delays in discharge can exacerbate hospital-acquired mobility loss and prolong functional recovery.^2,4 In addition, even small increases in length of stay have substantial financial impact.⁵ Increased efficiency in the discharge process has the potential to reduce healthcare costs, facilitate patient recovery, and reduce delays for new admissions awaiting beds.⁶ For effective discharge planning, a proactive, patient-centered, interdisciplinary approach that considers patient mobility status is needed.³

Systematic measurement of patient mobility that extends beyond evaluations by physical therapists is not common practice, but has the potential to facilitate early discharge planning.^7,8 At our hospital, mobility assessment is performed routinely using a reliable and valid interdisciplinary assessment of mobility throughout the patient’s entire hospitalization.⁹ We recently showed that nurse-recorded mobility status within the first 24 hours of hospitalization was associated with discharge disposition,⁷ but a prediction tool to help aid clinicians in the discharge planning process would be more useful. In this study, we evaluated the predictive ability of a patient’s mobility score, obtained within 48 hours of hospital admission, to identify the need for postacute care in a diverse patient population.

After receiving approval from the Johns Hopkins Institutional Review Board, we conducted analyses on a retrospective cohort of 821 admissions (777 unique patients admitted between January 1, 2017 and August 25, 2017) who were hospitalized for ≥72 hours on two inpatient units (medical and neurological/neurosurgical) at The Johns Hopkins Hospital (JHH). These units were chosen to reduce the potential for both selection and measurement bias. First, these units manage a diverse patient population that is likely to generalize to a general hospital population. Second, the nursing staff on these units has the most accurate and consistent documentation compliance for our predictor variable.

Mobility Measure

The Activity Measure for Post Acute Care Inpatient Mobility Short Form (AM-PAC IMSF) is a measure of functional capacity. This short form is widely used and is nicknamed “6 clicks.” It has questions for six mobility tasks, and each question is scored on a four-point Likert scale.⁹ Patients do not have to attempt the tasks to be scored. Clinicians can score items using clinical judgement based on observation or discussion with the patient, family, or other clinicians. The interrater reliability is very good (Intraclass Correlation Coefficient = .85-.99)⁹ and construct validity has been demonstrated for the inpatient hospital population (AM-PAC IMSF correlations with: functional independence measure [FIM] = .65; Katz activities of daily living [ADL] = .80; 2-minute walk = .73; 5-times sit-to-stand = −.69).⁹ At JHH, the AM-PAC IMSF is scored at admission by nursing staff (>90% documentation compliance on the units in this study); these admission scores were used.

Outcome and Predictors

Discharge location (postacute care facility vs home) was the primary outcome in this study, as recorded in a discrete field in the electronic medical record (EMR). To ensure the validity of this measure, we performed manual chart audits on a sample of patients (n = 300). It was confirmed that the measure entered in the discrete field in the EMR correctly identified the disposition (home vs postacute care facility) in all cases. The primary predictor was the lowest AM-PAC IMSF score obtained within 48 hours after hospital admission, reflecting the patient’s capability to mobilize after hospital admission. Raw scores were converted to scale scores (0-100) for analysis.⁹ Additional predictors considered included: age, sex, race, and primary diagnosis, all of which were readily available from the EMR at the time of hospital admission. We then grouped the primary diagnosis into the following categories using ICD-10 codes upon admission: Oncologic, Progressive Neurological, Sudden Onset Neurological, and Medical/Other.

Statistical Analysis

We constructed a classification tree, a machine learning approach,¹⁰ to predict discharge placement (postacute facility vs home) based on the patients’ hospital admission characteristics and AM-PAC IMSF score. The prediction model was developed using the classification tree approach, as opposed to a logistic regression model. This approach allows for the inclusion of higher-order interactions (ie, interactions of more than two predictors) which would need to be explicitly specified otherwise and a priori we did not have strong evidence from prior studies to guide the model construction. The classification tree was constructed and evaluated by dividing our sample into a 70% training set and a 30% validation set using random sampling within key strata defined by age (<65 vs ≥65 years), gender, and quartile of the AM-PAC IMSF score. The classification tree was developed using the training set. Next, measures of predictive accuracy (ie, the proportion of correctly classified patients with placement in a postacute facility [sensitivity]) and the proportion of correctly classified patients not discharged to postacute care (ie, to home, specificity), were estimated by applying the validation set to the classification tree. The R statistical package rpart¹¹ with procedure rpart was used to construct the classification tree using standard criteria for growing (Gini index¹⁰) and pruning (misclassification error estimated by leave-1-out cross-validation¹²) the tree.

Improving the efficiency of hospital discharge planning is of great interest to hospital-based clinicians and administrators. Identifying patients early who are likely to need placement in a postacute facility is an important first step. Using a reliable and valid nursing assessment tool of patient mobility to help with discharge planning is an attractive and feasible approach. The literature on predicting disposition is very limited and has focused primarily on patients with stroke or joint replacement.^13,14 Previously, we used the same measure of mobility within 24 hours of admission to show an association with discharge disposition.⁷ Here, we expanded upon that prior research to include mobility assessment within a 48-hour window from admission in a diverse patient population. Using a machine learning approach, we were able to predict 73% of hospital discharges correctly using only the patient’s mobility score and age. Having tools such as this simple decision tree to identify discharge locations early in a patient’s hospitalization has the potential to increase efficiency in the discharge planning process.

Despite being able to classify the discharge disposition correctly for most patients, our sensitivity for predicting postacute care need was low. There are likely other patient and system factors that could be collected near the time of hospital admission, such as the patient’s prior level of function, the difference between function at baseline and admission, their prior living situation (eg, long term care, home environment), social support, and hospital relationships with postacute care facilities that may help to improve the prediction of postacute care placement.¹⁵ We recommend that future research consider these and other potentially important predictors. However, the specificity was high enough that all patients who score positive merit evaluation for possible postacute care. While our patient sample was diverse, it did not focus on some patients who may be more likely to be discharged to a postacute facility, such as the geriatric population. This may be a potential limitation to our study and will require this tool to be tested in more patient groups. A final limitation is the grouping of all potential types of postacute care into one category since important differences exist between the care provided at skilled nursing facilities with or without rehabilitation and inpatient acute rehabilitation. Despite these limitations, this study emphasizes the value of a systematic mobility assessment and provides a simple decision tree to help providers begin early discharge planning by anticipating patient rehabilitation needs.

Acknowledgments

The authors thank Christina Lin, MD and Sophia Andrews, PT, DPT for their assistance with data validation.

Suboptimal dosing of renin-angiotensin-aldosterone system (RAAS) inhibitors to reduce the risk of hyperkalemia could increase the risk of major adverse cardiac events (MACE) and all-cause mortality in patients with chronic kidney disease (CKD) or heart failure.

HYWARDS/Thinkstock

Researchers reported the outcomes of an observational study that explored the real-world associations between RAAS inhibitor dose, hyperkalemia, and clinical outcomes.

RAAS inhibitors – such as ACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists – are known to reduce potassium excretion and therefore increase the risk of high potassium levels.

Dr. Cecilia Linde, from the Karolinska University Hospital and Karolinska Institutet in Stockholm, and coauthors wrote that management of serum potassium levels often requires reducing the dosage of RAAS inhibitors or stopping them altogether. However, this is also associated with risks in patients with heart failure or CKD.

In this study, researchers looked at data from 100,572 people with nondialysis CKD and 13,113 with new-onset heart failure who were prescribed RAAS inhibitors during 2006-2015.

Overall, 58% of patients with CKD and 63% of patients with heart failure spent the majority of follow-up on prescribed optimal doses of RAAS inhibitors – defined as at least 50% of the guidelines-recommended dose.

Patients with hyperkalemia were more likely to have down-titrations or discontinue their RAAS inhibitors, and this increased with increasing hyperkalemia severity.

The study found consistently lower mortality rates among patients who spent most of their follow-up time on at least 50% of the guideline-recommended dose of RAAS inhibitors.

In patients with CKD, mortality rates were 7.2 deaths per 1,000 patient-years in those taking at least 50% of the recommended dose, compared with 57.7 deaths per 1,000 patient-years for those on suboptimal doses. The rates of MACE were 73 and 130 per 1,000 patient-years, respectively.

The differences were even more pronounced in patients with heart failure. Those taking at least 50% of the recommended dose had mortality rates of 12.5 per 1000 patient-years, compared with 141.7 among those on suboptimal doses. The rates of MACE were 148.5 and 290.4, respectively.

“The results highlight the potential negative impact of suboptimal RAASi dosing, indicate the generalizability of [European Society of Cardiology–recommended] RAASi doses in HF to CKD patients, and emphasize the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation,” the authors wrote.

The study was funded by AstraZeneca. One author was an employee and stockholder of AstraZeneca, and five authors declared funding and support from the pharmaceutical sector, including AstraZeneca.

SOURCE: Linde C et al. J Am Heart Assoc. 2019 Nov 12. doi: 10.1161/JAHA.119.012655.

Suboptimal dosing of renin-angiotensin-aldosterone system (RAAS) inhibitors to reduce the risk of hyperkalemia could increase the risk of major adverse cardiac events (MACE) and all-cause mortality in patients with chronic kidney disease (CKD) or heart failure.

HYWARDS/Thinkstock

Researchers reported the outcomes of an observational study that explored the real-world associations between RAAS inhibitor dose, hyperkalemia, and clinical outcomes.

RAAS inhibitors – such as ACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists – are known to reduce potassium excretion and therefore increase the risk of high potassium levels.

Dr. Cecilia Linde, from the Karolinska University Hospital and Karolinska Institutet in Stockholm, and coauthors wrote that management of serum potassium levels often requires reducing the dosage of RAAS inhibitors or stopping them altogether. However, this is also associated with risks in patients with heart failure or CKD.

In this study, researchers looked at data from 100,572 people with nondialysis CKD and 13,113 with new-onset heart failure who were prescribed RAAS inhibitors during 2006-2015.

Overall, 58% of patients with CKD and 63% of patients with heart failure spent the majority of follow-up on prescribed optimal doses of RAAS inhibitors – defined as at least 50% of the guidelines-recommended dose.

Patients with hyperkalemia were more likely to have down-titrations or discontinue their RAAS inhibitors, and this increased with increasing hyperkalemia severity.

The study found consistently lower mortality rates among patients who spent most of their follow-up time on at least 50% of the guideline-recommended dose of RAAS inhibitors.

In patients with CKD, mortality rates were 7.2 deaths per 1,000 patient-years in those taking at least 50% of the recommended dose, compared with 57.7 deaths per 1,000 patient-years for those on suboptimal doses. The rates of MACE were 73 and 130 per 1,000 patient-years, respectively.

The differences were even more pronounced in patients with heart failure. Those taking at least 50% of the recommended dose had mortality rates of 12.5 per 1000 patient-years, compared with 141.7 among those on suboptimal doses. The rates of MACE were 148.5 and 290.4, respectively.

“The results highlight the potential negative impact of suboptimal RAASi dosing, indicate the generalizability of [European Society of Cardiology–recommended] RAASi doses in HF to CKD patients, and emphasize the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation,” the authors wrote.

The study was funded by AstraZeneca. One author was an employee and stockholder of AstraZeneca, and five authors declared funding and support from the pharmaceutical sector, including AstraZeneca.

SOURCE: Linde C et al. J Am Heart Assoc. 2019 Nov 12. doi: 10.1161/JAHA.119.012655.

Suboptimal dosing of renin-angiotensin-aldosterone system (RAAS) inhibitors to reduce the risk of hyperkalemia could increase the risk of major adverse cardiac events (MACE) and all-cause mortality in patients with chronic kidney disease (CKD) or heart failure.

HYWARDS/Thinkstock

Researchers reported the outcomes of an observational study that explored the real-world associations between RAAS inhibitor dose, hyperkalemia, and clinical outcomes.

RAAS inhibitors – such as ACE inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists – are known to reduce potassium excretion and therefore increase the risk of high potassium levels.

Dr. Cecilia Linde, from the Karolinska University Hospital and Karolinska Institutet in Stockholm, and coauthors wrote that management of serum potassium levels often requires reducing the dosage of RAAS inhibitors or stopping them altogether. However, this is also associated with risks in patients with heart failure or CKD.

In this study, researchers looked at data from 100,572 people with nondialysis CKD and 13,113 with new-onset heart failure who were prescribed RAAS inhibitors during 2006-2015.

Overall, 58% of patients with CKD and 63% of patients with heart failure spent the majority of follow-up on prescribed optimal doses of RAAS inhibitors – defined as at least 50% of the guidelines-recommended dose.

Patients with hyperkalemia were more likely to have down-titrations or discontinue their RAAS inhibitors, and this increased with increasing hyperkalemia severity.

The study found consistently lower mortality rates among patients who spent most of their follow-up time on at least 50% of the guideline-recommended dose of RAAS inhibitors.

In patients with CKD, mortality rates were 7.2 deaths per 1,000 patient-years in those taking at least 50% of the recommended dose, compared with 57.7 deaths per 1,000 patient-years for those on suboptimal doses. The rates of MACE were 73 and 130 per 1,000 patient-years, respectively.

The differences were even more pronounced in patients with heart failure. Those taking at least 50% of the recommended dose had mortality rates of 12.5 per 1000 patient-years, compared with 141.7 among those on suboptimal doses. The rates of MACE were 148.5 and 290.4, respectively.

“The results highlight the potential negative impact of suboptimal RAASi dosing, indicate the generalizability of [European Society of Cardiology–recommended] RAASi doses in HF to CKD patients, and emphasize the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation,” the authors wrote.

The study was funded by AstraZeneca. One author was an employee and stockholder of AstraZeneca, and five authors declared funding and support from the pharmaceutical sector, including AstraZeneca.

SOURCE: Linde C et al. J Am Heart Assoc. 2019 Nov 12. doi: 10.1161/JAHA.119.012655.

ORLANDO – A large, retrospective study suggests several factors are associated with an increased risk of intracranial hemorrhage in patients with immune thrombocytopenia.

Jennifer Smith/MDedge News

Data on more than 300,000 immune thrombocytopenia (ITP) hospitalizations indicated that older age, male sex, not having private insurance, having a gastrointestinal or “other” bleed, and receiving treatment at a hospital in the western United States, a medium- or large-sized hospital, or an urban teaching hospital were all associated with an increased risk of intracranial hemorrhage (ICH).

Mayank Sharma, of the University of Miami, detailed these findings at the annual meeting of the American Society of Hematology.

Mr. Sharma and colleagues analyzed data from the National Inpatient Sample database from 2007 to 2016. Of the 348,906 ITP hospitalizations included, there were 3,408 (0.98%) cases of ICH.

The overall incidence of ICH was low and remained stable over time, “which is reassuring,” Mr. Sharma said. However, the mortality rate was higher among patients with ICH than among those without it – 26.7% and 3.2%, respectively.

A multivariate analysis showed that female patients had a decreased likelihood of ICH, with an odds ratio of 0.81 (95% confidence interval, 0.68-0.97). Patients with private insurance had a decreased likelihood of ICH as well, with an OR of 0.81 (95% CI, 0.61-1.08).

Conversely, older patients had an increased likelihood of ICH. The OR was 2.23 (95% CI, 1.51-3.31) for patients aged 25-64 years, and the OR was 3.69 (95% CI, 2.34-5.84) for patients aged 65 years and older.

Patients with a gastrointestinal bleed or an other bleed (not including hematuria or epistaxis) had an increased likelihood of ICH. The ORs were 1.60 (95% CI, 1.18-2.16) and 1.69 (95% CI, 1.19-2.42), respectively.

Patients hospitalized in the western United States (OR, 1.62; 95% CI, 1.26-2.08), at a medium-sized hospital (OR, 1.64; 95% CI, 1.08-2.47), at a large hospital (OR, 2.42; 95% CI, 1.65-3.55), or at an urban teaching hospital (OR, 2.73; 95% CI, 1.80-4.13) all had an increased likelihood of ICH.

“Our second objective was to study the factors associated with mortality in ITP patients with ICH,” Mr. Sharma said. “We found female gender and Medicaid, private, or self-pay as primary payers to be associated with a lower mortality in ITP with ICH.

“[A]ge of 25-64 and 65 years and above, coexistence of a GI bleed or other bleed, and admission to a large or urban teaching hospital were associated with a higher mortality,” he added.

Mr. Sharma said the study’s strengths are that it is the most recent study on trends in ITP/ICH hospitalizations, and that it’s a longitudinal assessment of data from a nationally representative database.

The study’s limitations include its retrospective nature and the use of ICD codes, which could lead to inaccuracies. Data on prior therapies and long-term outcomes were not available, and the researchers were unable to differentiate between acute and chronic ITP.

Mr. Sharma said he had no relevant conflicts of interest.
 

[email protected]

SOURCE: Sharma M et al. ASH 2019, Abstract 55.

ORLANDO – A large, retrospective study suggests several factors are associated with an increased risk of intracranial hemorrhage in patients with immune thrombocytopenia.

Jennifer Smith/MDedge News

Data on more than 300,000 immune thrombocytopenia (ITP) hospitalizations indicated that older age, male sex, not having private insurance, having a gastrointestinal or “other” bleed, and receiving treatment at a hospital in the western United States, a medium- or large-sized hospital, or an urban teaching hospital were all associated with an increased risk of intracranial hemorrhage (ICH).

Mayank Sharma, of the University of Miami, detailed these findings at the annual meeting of the American Society of Hematology.

Mr. Sharma and colleagues analyzed data from the National Inpatient Sample database from 2007 to 2016. Of the 348,906 ITP hospitalizations included, there were 3,408 (0.98%) cases of ICH.

The overall incidence of ICH was low and remained stable over time, “which is reassuring,” Mr. Sharma said. However, the mortality rate was higher among patients with ICH than among those without it – 26.7% and 3.2%, respectively.

A multivariate analysis showed that female patients had a decreased likelihood of ICH, with an odds ratio of 0.81 (95% confidence interval, 0.68-0.97). Patients with private insurance had a decreased likelihood of ICH as well, with an OR of 0.81 (95% CI, 0.61-1.08).

Conversely, older patients had an increased likelihood of ICH. The OR was 2.23 (95% CI, 1.51-3.31) for patients aged 25-64 years, and the OR was 3.69 (95% CI, 2.34-5.84) for patients aged 65 years and older.

Patients with a gastrointestinal bleed or an other bleed (not including hematuria or epistaxis) had an increased likelihood of ICH. The ORs were 1.60 (95% CI, 1.18-2.16) and 1.69 (95% CI, 1.19-2.42), respectively.

Patients hospitalized in the western United States (OR, 1.62; 95% CI, 1.26-2.08), at a medium-sized hospital (OR, 1.64; 95% CI, 1.08-2.47), at a large hospital (OR, 2.42; 95% CI, 1.65-3.55), or at an urban teaching hospital (OR, 2.73; 95% CI, 1.80-4.13) all had an increased likelihood of ICH.

“Our second objective was to study the factors associated with mortality in ITP patients with ICH,” Mr. Sharma said. “We found female gender and Medicaid, private, or self-pay as primary payers to be associated with a lower mortality in ITP with ICH.

“[A]ge of 25-64 and 65 years and above, coexistence of a GI bleed or other bleed, and admission to a large or urban teaching hospital were associated with a higher mortality,” he added.

Mr. Sharma said the study’s strengths are that it is the most recent study on trends in ITP/ICH hospitalizations, and that it’s a longitudinal assessment of data from a nationally representative database.

The study’s limitations include its retrospective nature and the use of ICD codes, which could lead to inaccuracies. Data on prior therapies and long-term outcomes were not available, and the researchers were unable to differentiate between acute and chronic ITP.

Mr. Sharma said he had no relevant conflicts of interest.
 

[email protected]

SOURCE: Sharma M et al. ASH 2019, Abstract 55.

ORLANDO – A large, retrospective study suggests several factors are associated with an increased risk of intracranial hemorrhage in patients with immune thrombocytopenia.

Jennifer Smith/MDedge News

Data on more than 300,000 immune thrombocytopenia (ITP) hospitalizations indicated that older age, male sex, not having private insurance, having a gastrointestinal or “other” bleed, and receiving treatment at a hospital in the western United States, a medium- or large-sized hospital, or an urban teaching hospital were all associated with an increased risk of intracranial hemorrhage (ICH).

Mayank Sharma, of the University of Miami, detailed these findings at the annual meeting of the American Society of Hematology.

Mr. Sharma and colleagues analyzed data from the National Inpatient Sample database from 2007 to 2016. Of the 348,906 ITP hospitalizations included, there were 3,408 (0.98%) cases of ICH.

The overall incidence of ICH was low and remained stable over time, “which is reassuring,” Mr. Sharma said. However, the mortality rate was higher among patients with ICH than among those without it – 26.7% and 3.2%, respectively.

A multivariate analysis showed that female patients had a decreased likelihood of ICH, with an odds ratio of 0.81 (95% confidence interval, 0.68-0.97). Patients with private insurance had a decreased likelihood of ICH as well, with an OR of 0.81 (95% CI, 0.61-1.08).

Conversely, older patients had an increased likelihood of ICH. The OR was 2.23 (95% CI, 1.51-3.31) for patients aged 25-64 years, and the OR was 3.69 (95% CI, 2.34-5.84) for patients aged 65 years and older.

Patients with a gastrointestinal bleed or an other bleed (not including hematuria or epistaxis) had an increased likelihood of ICH. The ORs were 1.60 (95% CI, 1.18-2.16) and 1.69 (95% CI, 1.19-2.42), respectively.

Patients hospitalized in the western United States (OR, 1.62; 95% CI, 1.26-2.08), at a medium-sized hospital (OR, 1.64; 95% CI, 1.08-2.47), at a large hospital (OR, 2.42; 95% CI, 1.65-3.55), or at an urban teaching hospital (OR, 2.73; 95% CI, 1.80-4.13) all had an increased likelihood of ICH.

“Our second objective was to study the factors associated with mortality in ITP patients with ICH,” Mr. Sharma said. “We found female gender and Medicaid, private, or self-pay as primary payers to be associated with a lower mortality in ITP with ICH.

“[A]ge of 25-64 and 65 years and above, coexistence of a GI bleed or other bleed, and admission to a large or urban teaching hospital were associated with a higher mortality,” he added.

Mr. Sharma said the study’s strengths are that it is the most recent study on trends in ITP/ICH hospitalizations, and that it’s a longitudinal assessment of data from a nationally representative database.

The study’s limitations include its retrospective nature and the use of ICD codes, which could lead to inaccuracies. Data on prior therapies and long-term outcomes were not available, and the researchers were unable to differentiate between acute and chronic ITP.

Mr. Sharma said he had no relevant conflicts of interest.
 

[email protected]

SOURCE: Sharma M et al. ASH 2019, Abstract 55.

CHICAGO – The investigational monoclonal antibody iscalimab reduced levels of thyroid hormone and thyroid-stimulating hormone–receptor antibodies (TSHR-Ab) in some patients with Graves disease in a small study.

Of 15 patients with Graves disease, 7 patients, or 47%, saw their thyroid hormone levels normalize, and levels of TSHR-Ab normalized in 4 patients, or 27% of the cohort. In addition, mean levels of a chemokine associated with Graves disease activity dropped.

“These results suggest that iscalimab may be an effective and attractive immunomodulation strategy for Graves disease,” said George Kahaly, MD, PhD, in his presentation of the phase 2 results at the annual meeting of the American Thyroid Association (J Clin Endocrinol Metab. 2019 Sep 12. doi: 10.1210/clinem/dgz013).

Overall, patients who responded had lower levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSHR-Ab and lower thyroid volume at baseline.

Iscalimab is a fully human monoclonal antibody that is active against the costimulatory protein CD40 that is present on the surface of antigen-presenting cells. Dr. Kahaly, professor of endocrinology at Johannes Gutenberg University Medical Center, Mainz, Germany, explained that in primate studies, iscalimab inhibits the T cell–dependent antibody response to an antigen, without depletion of B cells. However, iscalimab would be expected to block B-cell activation and differentiation, “leading to reduced de novo TSHR antibody production,” said Dr. Kahaly. Inhibition of T cell–dependent antibody response was seen when iscalimab was given at a dose of 3 mg/kg in healthy human study participants.

The study results presented by Dr. Kahaly were drawn from a single-arm, proof-of-concept study that enrolled 15 patients with Graves disease to 12 weeks of treatment with iscalimab. The participants were followed for an additional 24 weeks after receiving intravenous iscalimab at 10 mg/kg on study days 1, 15, 29, 57, and 85.

All participants were receiving beta blockers at enrollment; four patients had new-onset Graves disease, and the rest were experiencing a treatment relapse.

The participants were a median 49 years old, and all but two were female. One patient was Asian, and the remainder were white. They were mostly normal weight, with a mean body mass index of about 23 kg/m².

A group of seven patients who were clear responders to iscalimab saw normalization of FT4 levels; of the eight patients considered to be nonresponders, six required rescue medication with antithyroid drugs.

For responders, the initial mean FT4 level was 33.5 pmol/L, whereas for nonresponders, it was 51.3 pmol/L (P less than .05). Similarly, mean FT3 levels were 13.6 pmol/L in responders, compared with 22 pmol/L in nonresponders (P less than .05).

Mean thyroid volume was 14.5 ml in responders, compared with 26 ml in nonresponders (P less than .005).

A subgroup of four patients within the responder group became TSHR-Ab negative, with sustained low antibody levels seen during the follow-up period. All but one of the eight nonresponders had initial TSHR-Ab levels of more than 20 U/L, whereas the seven responders began with TSHR-Ab levels of about 10 U/L or less. Mean TSHR-Ab levels at baseline were 5.6 IU/L for responders, compared with 27.3 IU/L for nonresponders (P less than .001).

Most responders also had lower initial levels of antithyroid peroxidase IgG antibodies, compared with the nonresponder group.

Levels of chemokine (motif C-X-C) ligand 13 (CXCL13) fell throughout the study period. Higher CXCL13 levels are associated with lymphocytic infiltrates seen in autoimmune thyroiditis.

Occupancy of CD40 was initially measured at week 4 of the study and it remained high until week 16, when free CD40 receptors rose rapidly for several participants in both the responder and nonresponder groups. “The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks,” wrote Dr. Kahaly and colleagues in the abstract accompanying the presentation.

In assessing CD40 target engagement, the investigators found that total soluble CD40 levels climbed during the treatment period, reaching peaks as high as 400-500 ng/mL, and then plummeted back to zero by study’s end for all participants.

A pharmacokinetic analysis revealed expected peaks of serum iscalimab after treatments, with levels dropping sharply at the end of the study period and falling to levels approaching zero by week 24 for most participants.

In terms of safety, 12 patients experienced at least one adverse event, with 3 participants reporting an episode of cystitis during the study. Fatigue, headache, insomnia, nausea, and viral upper respiratory infection were each reported by 2 patients. No injection site reactions were seen. All adverse events were mild or moderate, did not result in study withdrawal, and resolved by the end of the study period, Dr. Kahaly noted.

“These encouraging results suggest that iscalimab should be tested further to understand better its potential therapeutic benefit,” the investigators wrote.

The study was funded by Novartis, which is developing iscalimab for Graves disease, other autoimmune disorders, and as an antirejection drug for patients with kidney transplants.

[email protected]

CHICAGO – The investigational monoclonal antibody iscalimab reduced levels of thyroid hormone and thyroid-stimulating hormone–receptor antibodies (TSHR-Ab) in some patients with Graves disease in a small study.

Of 15 patients with Graves disease, 7 patients, or 47%, saw their thyroid hormone levels normalize, and levels of TSHR-Ab normalized in 4 patients, or 27% of the cohort. In addition, mean levels of a chemokine associated with Graves disease activity dropped.

“These results suggest that iscalimab may be an effective and attractive immunomodulation strategy for Graves disease,” said George Kahaly, MD, PhD, in his presentation of the phase 2 results at the annual meeting of the American Thyroid Association (J Clin Endocrinol Metab. 2019 Sep 12. doi: 10.1210/clinem/dgz013).

Overall, patients who responded had lower levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSHR-Ab and lower thyroid volume at baseline.

Iscalimab is a fully human monoclonal antibody that is active against the costimulatory protein CD40 that is present on the surface of antigen-presenting cells. Dr. Kahaly, professor of endocrinology at Johannes Gutenberg University Medical Center, Mainz, Germany, explained that in primate studies, iscalimab inhibits the T cell–dependent antibody response to an antigen, without depletion of B cells. However, iscalimab would be expected to block B-cell activation and differentiation, “leading to reduced de novo TSHR antibody production,” said Dr. Kahaly. Inhibition of T cell–dependent antibody response was seen when iscalimab was given at a dose of 3 mg/kg in healthy human study participants.

The study results presented by Dr. Kahaly were drawn from a single-arm, proof-of-concept study that enrolled 15 patients with Graves disease to 12 weeks of treatment with iscalimab. The participants were followed for an additional 24 weeks after receiving intravenous iscalimab at 10 mg/kg on study days 1, 15, 29, 57, and 85.

All participants were receiving beta blockers at enrollment; four patients had new-onset Graves disease, and the rest were experiencing a treatment relapse.

The participants were a median 49 years old, and all but two were female. One patient was Asian, and the remainder were white. They were mostly normal weight, with a mean body mass index of about 23 kg/m².

A group of seven patients who were clear responders to iscalimab saw normalization of FT4 levels; of the eight patients considered to be nonresponders, six required rescue medication with antithyroid drugs.

For responders, the initial mean FT4 level was 33.5 pmol/L, whereas for nonresponders, it was 51.3 pmol/L (P less than .05). Similarly, mean FT3 levels were 13.6 pmol/L in responders, compared with 22 pmol/L in nonresponders (P less than .05).

Mean thyroid volume was 14.5 ml in responders, compared with 26 ml in nonresponders (P less than .005).

A subgroup of four patients within the responder group became TSHR-Ab negative, with sustained low antibody levels seen during the follow-up period. All but one of the eight nonresponders had initial TSHR-Ab levels of more than 20 U/L, whereas the seven responders began with TSHR-Ab levels of about 10 U/L or less. Mean TSHR-Ab levels at baseline were 5.6 IU/L for responders, compared with 27.3 IU/L for nonresponders (P less than .001).

Most responders also had lower initial levels of antithyroid peroxidase IgG antibodies, compared with the nonresponder group.

Levels of chemokine (motif C-X-C) ligand 13 (CXCL13) fell throughout the study period. Higher CXCL13 levels are associated with lymphocytic infiltrates seen in autoimmune thyroiditis.

Occupancy of CD40 was initially measured at week 4 of the study and it remained high until week 16, when free CD40 receptors rose rapidly for several participants in both the responder and nonresponder groups. “The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks,” wrote Dr. Kahaly and colleagues in the abstract accompanying the presentation.

In assessing CD40 target engagement, the investigators found that total soluble CD40 levels climbed during the treatment period, reaching peaks as high as 400-500 ng/mL, and then plummeted back to zero by study’s end for all participants.

A pharmacokinetic analysis revealed expected peaks of serum iscalimab after treatments, with levels dropping sharply at the end of the study period and falling to levels approaching zero by week 24 for most participants.

In terms of safety, 12 patients experienced at least one adverse event, with 3 participants reporting an episode of cystitis during the study. Fatigue, headache, insomnia, nausea, and viral upper respiratory infection were each reported by 2 patients. No injection site reactions were seen. All adverse events were mild or moderate, did not result in study withdrawal, and resolved by the end of the study period, Dr. Kahaly noted.

“These encouraging results suggest that iscalimab should be tested further to understand better its potential therapeutic benefit,” the investigators wrote.

The study was funded by Novartis, which is developing iscalimab for Graves disease, other autoimmune disorders, and as an antirejection drug for patients with kidney transplants.

[email protected]

CHICAGO – The investigational monoclonal antibody iscalimab reduced levels of thyroid hormone and thyroid-stimulating hormone–receptor antibodies (TSHR-Ab) in some patients with Graves disease in a small study.

Of 15 patients with Graves disease, 7 patients, or 47%, saw their thyroid hormone levels normalize, and levels of TSHR-Ab normalized in 4 patients, or 27% of the cohort. In addition, mean levels of a chemokine associated with Graves disease activity dropped.

“These results suggest that iscalimab may be an effective and attractive immunomodulation strategy for Graves disease,” said George Kahaly, MD, PhD, in his presentation of the phase 2 results at the annual meeting of the American Thyroid Association (J Clin Endocrinol Metab. 2019 Sep 12. doi: 10.1210/clinem/dgz013).

Overall, patients who responded had lower levels of free triiodothyronine (FT3), free thyroxine (FT4), and TSHR-Ab and lower thyroid volume at baseline.

Iscalimab is a fully human monoclonal antibody that is active against the costimulatory protein CD40 that is present on the surface of antigen-presenting cells. Dr. Kahaly, professor of endocrinology at Johannes Gutenberg University Medical Center, Mainz, Germany, explained that in primate studies, iscalimab inhibits the T cell–dependent antibody response to an antigen, without depletion of B cells. However, iscalimab would be expected to block B-cell activation and differentiation, “leading to reduced de novo TSHR antibody production,” said Dr. Kahaly. Inhibition of T cell–dependent antibody response was seen when iscalimab was given at a dose of 3 mg/kg in healthy human study participants.

The study results presented by Dr. Kahaly were drawn from a single-arm, proof-of-concept study that enrolled 15 patients with Graves disease to 12 weeks of treatment with iscalimab. The participants were followed for an additional 24 weeks after receiving intravenous iscalimab at 10 mg/kg on study days 1, 15, 29, 57, and 85.

All participants were receiving beta blockers at enrollment; four patients had new-onset Graves disease, and the rest were experiencing a treatment relapse.

The participants were a median 49 years old, and all but two were female. One patient was Asian, and the remainder were white. They were mostly normal weight, with a mean body mass index of about 23 kg/m².

A group of seven patients who were clear responders to iscalimab saw normalization of FT4 levels; of the eight patients considered to be nonresponders, six required rescue medication with antithyroid drugs.

For responders, the initial mean FT4 level was 33.5 pmol/L, whereas for nonresponders, it was 51.3 pmol/L (P less than .05). Similarly, mean FT3 levels were 13.6 pmol/L in responders, compared with 22 pmol/L in nonresponders (P less than .05).

Mean thyroid volume was 14.5 ml in responders, compared with 26 ml in nonresponders (P less than .005).

A subgroup of four patients within the responder group became TSHR-Ab negative, with sustained low antibody levels seen during the follow-up period. All but one of the eight nonresponders had initial TSHR-Ab levels of more than 20 U/L, whereas the seven responders began with TSHR-Ab levels of about 10 U/L or less. Mean TSHR-Ab levels at baseline were 5.6 IU/L for responders, compared with 27.3 IU/L for nonresponders (P less than .001).

Most responders also had lower initial levels of antithyroid peroxidase IgG antibodies, compared with the nonresponder group.

Levels of chemokine (motif C-X-C) ligand 13 (CXCL13) fell throughout the study period. Higher CXCL13 levels are associated with lymphocytic infiltrates seen in autoimmune thyroiditis.

Occupancy of CD40 was initially measured at week 4 of the study and it remained high until week 16, when free CD40 receptors rose rapidly for several participants in both the responder and nonresponder groups. “The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks,” wrote Dr. Kahaly and colleagues in the abstract accompanying the presentation.

In assessing CD40 target engagement, the investigators found that total soluble CD40 levels climbed during the treatment period, reaching peaks as high as 400-500 ng/mL, and then plummeted back to zero by study’s end for all participants.

A pharmacokinetic analysis revealed expected peaks of serum iscalimab after treatments, with levels dropping sharply at the end of the study period and falling to levels approaching zero by week 24 for most participants.

In terms of safety, 12 patients experienced at least one adverse event, with 3 participants reporting an episode of cystitis during the study. Fatigue, headache, insomnia, nausea, and viral upper respiratory infection were each reported by 2 patients. No injection site reactions were seen. All adverse events were mild or moderate, did not result in study withdrawal, and resolved by the end of the study period, Dr. Kahaly noted.

“These encouraging results suggest that iscalimab should be tested further to understand better its potential therapeutic benefit,” the investigators wrote.

The study was funded by Novartis, which is developing iscalimab for Graves disease, other autoimmune disorders, and as an antirejection drug for patients with kidney transplants.

[email protected]

ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.

M. Alexander Otto/MDedge News

Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.

About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.

The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.

Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.

The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.

There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.

Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.

In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.

Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.

Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.

The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.

The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”

The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.

Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.

The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.

The National Institutes of Health funded the work. The investigators had no relevant disclosures.

[email protected]

SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.

ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.

M. Alexander Otto/MDedge News

Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.

About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.

The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.

Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.

The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.

There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.

Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.

In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.

Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.

Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.

The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.

The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”

The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.

Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.

The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.

The National Institutes of Health funded the work. The investigators had no relevant disclosures.

[email protected]

SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.

ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.

M. Alexander Otto/MDedge News

Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.

About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.

The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.

Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.

The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.

There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.

Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.

In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.

Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.

Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.

The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.

The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”

The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.

Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.

The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.

The National Institutes of Health funded the work. The investigators had no relevant disclosures.

[email protected]

SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.

To solve our most pressing national health issues, we must start locally, according to a Health Affairs blog post.

“For example, in [Mecklenburg County] North Carolina, African Americans face rates of cardiovascular disease 22% higher than their white counterparts do. To fight this, an organization called Village HeartBEAT joined forces with more than 60 faith-based groups to reach more than 20,000 people – connecting them with health resources to reduce their cardiovascular risk. As a direct result, rates of smoking decreased from 17.4% to 13.9%, and obesity rates fell from 70% to 64.7%.”

Mecklenburg County is a winner of the Healthiest Cities & Counties Challenge, a collaboration between the Aetna Foundation, the American Public Health Association, and the National Association of Counties, which has awarded more than $1.5 million in grants and prizes over the last 2 years.

Reference

1. Graham G, Benjamin G. “Winning Local Solutions to Our Most Pressing Public Health Needs.” Health Affairs. https://www.healthaffairs.org/do/10.1377/hblog20190423.202497/full/. Published April 25, 2019.

To solve our most pressing national health issues, we must start locally, according to a Health Affairs blog post.

“For example, in [Mecklenburg County] North Carolina, African Americans face rates of cardiovascular disease 22% higher than their white counterparts do. To fight this, an organization called Village HeartBEAT joined forces with more than 60 faith-based groups to reach more than 20,000 people – connecting them with health resources to reduce their cardiovascular risk. As a direct result, rates of smoking decreased from 17.4% to 13.9%, and obesity rates fell from 70% to 64.7%.”

Mecklenburg County is a winner of the Healthiest Cities & Counties Challenge, a collaboration between the Aetna Foundation, the American Public Health Association, and the National Association of Counties, which has awarded more than $1.5 million in grants and prizes over the last 2 years.

Reference

1. Graham G, Benjamin G. “Winning Local Solutions to Our Most Pressing Public Health Needs.” Health Affairs. https://www.healthaffairs.org/do/10.1377/hblog20190423.202497/full/. Published April 25, 2019.

To solve our most pressing national health issues, we must start locally, according to a Health Affairs blog post.

“For example, in [Mecklenburg County] North Carolina, African Americans face rates of cardiovascular disease 22% higher than their white counterparts do. To fight this, an organization called Village HeartBEAT joined forces with more than 60 faith-based groups to reach more than 20,000 people – connecting them with health resources to reduce their cardiovascular risk. As a direct result, rates of smoking decreased from 17.4% to 13.9%, and obesity rates fell from 70% to 64.7%.”

Mecklenburg County is a winner of the Healthiest Cities & Counties Challenge, a collaboration between the Aetna Foundation, the American Public Health Association, and the National Association of Counties, which has awarded more than $1.5 million in grants and prizes over the last 2 years.

Reference

1. Graham G, Benjamin G. “Winning Local Solutions to Our Most Pressing Public Health Needs.” Health Affairs. https://www.healthaffairs.org/do/10.1377/hblog20190423.202497/full/. Published April 25, 2019.

The American College of Rheumatology and the European League Against Rheumatism have released the first classification criteria for IgG4-related disease.

Although it was first recognized as a distinct disease in 2003, investigators have since learned that IgG4-related disease (IgG4-RD) is not particularly rare. Specialists across many different fields of medicine now treat IgG4-RD, which affects multiple organ systems, and the pancreas, kidneys, and orbits are most commonly affected by severe disease.

“IgG4-RD has proven to be a remarkable window into human immunology, and the insights investigators have made from studying this disease have already led to important discoveries in other rheumatic diseases, such as scleroderma,” John H. Stone, MD, professor of medicine at Harvard Medical School and director of clinical rheumatology at Massachusetts General Hospital, both in Boston, said in an interview.

To develop the classification criteria, 86 experts from five continents across various subspecialties including rheumatology, internal medicine, ophthalmology, pathology, gastroenterology, allergology, pulmonology, radiology, neurology, nephrology, and others met as a working group in 2016, achieving consensus on 79 criteria. They then narrowed down the number of items to 8 domains and 29 items within a set of inclusion and exclusion criteria for the draft classification criteria. For the final classification criteria, the working group applied weighting to each inclusion criteria item within a domain on a Likert scale (–5 to 5 range), removing items that were not significantly attributable to IgG4-RD classification (those with –2 to 2 scores).

The final IgG4-RD criteria are divided into three classification steps: entry criteria, exclusion criteria, and inclusion criteria. Patients who meet the entry criteria should have clinical or radiologic involvement of one or more organs consistent with IgG4-RD, such as the pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland. Patients could alternatively meet the entry criteria by having “pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs,” the authors wrote.

If a patient meets the entry criteria, their case is examined against 32 clinical, serologic, radiologic, and pathologic items and specific disease inclusions. Any exclusion criteria present in a case means the patient does not meet the criteria for IgG4-RD classification.

The third step is to evaluate whether a patient meets inclusion criteria consisting of clinical findings, serologic results, radiology assessments, and pathology interpretations across eight domains: immunostaining, head and neck gland involvement, chest, pancreas and biliary tree, kidney, and the retroperitoneum. Each criterion has a weight, and if a patient has a score of 20 or higher, they meet the classification criteria for IgG4-RD.

“The final criteria set is easy to use and lends itself well to adaptation in an electronic format, which we have already instituted at my hospital,” said Dr. Stone, who is also director of the international panel of experts who created the criteria.

Two cohorts were used to validate the IgG4-RD classification criteria. In the first cohort, investigators used 771 patients (85% of the total cohort) in whom they were “confident” or “very confident” of a diagnosis of IgG4-RD or a mimicker to assess the test performance with a classification threshold of 20 points. The researchers found the criteria had a specificity of 99.2% (95% confidence interval, 97.2%-99.8%) and a sensitivity of 85.5% (95% CI, 81.9%-88.5%). The experts used a second validation cohort of 402 additional patients (83% of the total cohort) with suspected IgG4-RD or a mimicker using the same confident and very confident metric. The panel assembled this cohort because of minor definition changes in inclusion and exclusion criteria that had been made after the derivation set of patients had been collected, but the definitions of inclusion and exclusion criteria used in the two validation cohorts were exactly the same. Overall, the specificity of the criteria was 97.8% (95% CI, 93.7%-99.2%) and the sensitivity was 82.0% (95% CI, 77.0%-86.1%) for IgG4-RD classification in this second group.

Dr. Stone said that more investigations, including multicenter clinical trials, are being organized for patients with IgG4-RD, and these classification criteria will help to identify which patients to include in these studies.

“These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” Dr. Stone said. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”

The authors reported no relevant conflicts of interest.

SOURCE: Wallace ZS et al. Arthritis Rheumatol. 2019 Dec 2. doi: 10.1002/art.41120.

The American College of Rheumatology and the European League Against Rheumatism have released the first classification criteria for IgG4-related disease.

Although it was first recognized as a distinct disease in 2003, investigators have since learned that IgG4-related disease (IgG4-RD) is not particularly rare. Specialists across many different fields of medicine now treat IgG4-RD, which affects multiple organ systems, and the pancreas, kidneys, and orbits are most commonly affected by severe disease.

“IgG4-RD has proven to be a remarkable window into human immunology, and the insights investigators have made from studying this disease have already led to important discoveries in other rheumatic diseases, such as scleroderma,” John H. Stone, MD, professor of medicine at Harvard Medical School and director of clinical rheumatology at Massachusetts General Hospital, both in Boston, said in an interview.

To develop the classification criteria, 86 experts from five continents across various subspecialties including rheumatology, internal medicine, ophthalmology, pathology, gastroenterology, allergology, pulmonology, radiology, neurology, nephrology, and others met as a working group in 2016, achieving consensus on 79 criteria. They then narrowed down the number of items to 8 domains and 29 items within a set of inclusion and exclusion criteria for the draft classification criteria. For the final classification criteria, the working group applied weighting to each inclusion criteria item within a domain on a Likert scale (–5 to 5 range), removing items that were not significantly attributable to IgG4-RD classification (those with –2 to 2 scores).

The final IgG4-RD criteria are divided into three classification steps: entry criteria, exclusion criteria, and inclusion criteria. Patients who meet the entry criteria should have clinical or radiologic involvement of one or more organs consistent with IgG4-RD, such as the pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland. Patients could alternatively meet the entry criteria by having “pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs,” the authors wrote.

If a patient meets the entry criteria, their case is examined against 32 clinical, serologic, radiologic, and pathologic items and specific disease inclusions. Any exclusion criteria present in a case means the patient does not meet the criteria for IgG4-RD classification.

The third step is to evaluate whether a patient meets inclusion criteria consisting of clinical findings, serologic results, radiology assessments, and pathology interpretations across eight domains: immunostaining, head and neck gland involvement, chest, pancreas and biliary tree, kidney, and the retroperitoneum. Each criterion has a weight, and if a patient has a score of 20 or higher, they meet the classification criteria for IgG4-RD.

“The final criteria set is easy to use and lends itself well to adaptation in an electronic format, which we have already instituted at my hospital,” said Dr. Stone, who is also director of the international panel of experts who created the criteria.

Two cohorts were used to validate the IgG4-RD classification criteria. In the first cohort, investigators used 771 patients (85% of the total cohort) in whom they were “confident” or “very confident” of a diagnosis of IgG4-RD or a mimicker to assess the test performance with a classification threshold of 20 points. The researchers found the criteria had a specificity of 99.2% (95% confidence interval, 97.2%-99.8%) and a sensitivity of 85.5% (95% CI, 81.9%-88.5%). The experts used a second validation cohort of 402 additional patients (83% of the total cohort) with suspected IgG4-RD or a mimicker using the same confident and very confident metric. The panel assembled this cohort because of minor definition changes in inclusion and exclusion criteria that had been made after the derivation set of patients had been collected, but the definitions of inclusion and exclusion criteria used in the two validation cohorts were exactly the same. Overall, the specificity of the criteria was 97.8% (95% CI, 93.7%-99.2%) and the sensitivity was 82.0% (95% CI, 77.0%-86.1%) for IgG4-RD classification in this second group.

Dr. Stone said that more investigations, including multicenter clinical trials, are being organized for patients with IgG4-RD, and these classification criteria will help to identify which patients to include in these studies.

“These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” Dr. Stone said. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”

The authors reported no relevant conflicts of interest.

SOURCE: Wallace ZS et al. Arthritis Rheumatol. 2019 Dec 2. doi: 10.1002/art.41120.

The American College of Rheumatology and the European League Against Rheumatism have released the first classification criteria for IgG4-related disease.

Although it was first recognized as a distinct disease in 2003, investigators have since learned that IgG4-related disease (IgG4-RD) is not particularly rare. Specialists across many different fields of medicine now treat IgG4-RD, which affects multiple organ systems, and the pancreas, kidneys, and orbits are most commonly affected by severe disease.

“IgG4-RD has proven to be a remarkable window into human immunology, and the insights investigators have made from studying this disease have already led to important discoveries in other rheumatic diseases, such as scleroderma,” John H. Stone, MD, professor of medicine at Harvard Medical School and director of clinical rheumatology at Massachusetts General Hospital, both in Boston, said in an interview.

To develop the classification criteria, 86 experts from five continents across various subspecialties including rheumatology, internal medicine, ophthalmology, pathology, gastroenterology, allergology, pulmonology, radiology, neurology, nephrology, and others met as a working group in 2016, achieving consensus on 79 criteria. They then narrowed down the number of items to 8 domains and 29 items within a set of inclusion and exclusion criteria for the draft classification criteria. For the final classification criteria, the working group applied weighting to each inclusion criteria item within a domain on a Likert scale (–5 to 5 range), removing items that were not significantly attributable to IgG4-RD classification (those with –2 to 2 scores).

The final IgG4-RD criteria are divided into three classification steps: entry criteria, exclusion criteria, and inclusion criteria. Patients who meet the entry criteria should have clinical or radiologic involvement of one or more organs consistent with IgG4-RD, such as the pancreas, salivary glands, bile ducts, orbits, kidney, lung, aorta, retroperitoneum, pachymeninges, or thyroid gland. Patients could alternatively meet the entry criteria by having “pathologic evidence of an inflammatory process accompanied by a lymphoplasmacytic infiltrate of uncertain etiology in one of these same organs,” the authors wrote.

If a patient meets the entry criteria, their case is examined against 32 clinical, serologic, radiologic, and pathologic items and specific disease inclusions. Any exclusion criteria present in a case means the patient does not meet the criteria for IgG4-RD classification.

The third step is to evaluate whether a patient meets inclusion criteria consisting of clinical findings, serologic results, radiology assessments, and pathology interpretations across eight domains: immunostaining, head and neck gland involvement, chest, pancreas and biliary tree, kidney, and the retroperitoneum. Each criterion has a weight, and if a patient has a score of 20 or higher, they meet the classification criteria for IgG4-RD.

“The final criteria set is easy to use and lends itself well to adaptation in an electronic format, which we have already instituted at my hospital,” said Dr. Stone, who is also director of the international panel of experts who created the criteria.

Two cohorts were used to validate the IgG4-RD classification criteria. In the first cohort, investigators used 771 patients (85% of the total cohort) in whom they were “confident” or “very confident” of a diagnosis of IgG4-RD or a mimicker to assess the test performance with a classification threshold of 20 points. The researchers found the criteria had a specificity of 99.2% (95% confidence interval, 97.2%-99.8%) and a sensitivity of 85.5% (95% CI, 81.9%-88.5%). The experts used a second validation cohort of 402 additional patients (83% of the total cohort) with suspected IgG4-RD or a mimicker using the same confident and very confident metric. The panel assembled this cohort because of minor definition changes in inclusion and exclusion criteria that had been made after the derivation set of patients had been collected, but the definitions of inclusion and exclusion criteria used in the two validation cohorts were exactly the same. Overall, the specificity of the criteria was 97.8% (95% CI, 93.7%-99.2%) and the sensitivity was 82.0% (95% CI, 77.0%-86.1%) for IgG4-RD classification in this second group.

Dr. Stone said that more investigations, including multicenter clinical trials, are being organized for patients with IgG4-RD, and these classification criteria will help to identify which patients to include in these studies.

“These rigorous ACR/EULAR classification criteria will help guide us through some of the most important challenges of studying this disease well,” Dr. Stone said. “I’m anticipating major advances in this field in the years to come, triggered in part by the strength of having sound classification criteria.”

The authors reported no relevant conflicts of interest.

SOURCE: Wallace ZS et al. Arthritis Rheumatol. 2019 Dec 2. doi: 10.1002/art.41120.

ORLANDO – While the benefit of daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) continues to improve with longer follow-up of the GRIFFIN trial, even early adopters may want to wait for additional data before declaring the combination a first-line standard for transplant-eligible multiple myeloma, according to an investigator on the trial.

Andrew D. Bowser/MDedge News

D-RVd has significantly improved both response rates and depth of response, compared with RVd alone, Peter M. Voorhees, MD, of Levine Cancer Institute, Atrium Health, Charlotte, N.C., reported at the annual meeting of the American Society of Hematology.

Additionally, rates of response and minimal residual disease (MRD) negativity with D-RVd have increased with longer follow-up beyond posttransplant consolidation, in the ongoing randomized phase 2 trial, Dr. Voorhees said.

“Those of you that are early adopters have good ammunition based on this result, but I would argue that we do need to confirm that the increased MRD-negative rate that we’re seeing translates into a sustained improvement in MRD negativity,” said Dr. Voorhees while presenting the updated results.

Most importantly, it needs to be confirmed that improved depth of response with D-RVd translates into an improvement in progression-free survival, not only in GRIFFIN, he said, but in PERSEUS, a large, randomized European phase 3 trial of subcutaneous daratumumab plus RVd versus RVd alone.

In the GRIFFIN trial, a total of 207 patients with transplant-eligible newly diagnosed multiple myeloma were randomized to intravenous daratumumab plus RVd versus RVd alone, with a primary endpoint of stringent complete response (sCR) by the end of consolidation.

Primary findings, presented in September at the 17th International Myeloma Workshop (IMW) meeting in Boston, indicated an sCR of 42.4% for D-RVd versus 32.0% for RVd at a median follow-up of 13.5 months, a difference that Dr. Voorhees said was statistically significant as defined by the protocol (1-sided P = .068), with an odds ratio of 1.57 (95% confidence interval, 0.87-2.82) in favor of the D-RVd arm.

With longer follow-up data, which Dr. Voorhees reported at ASH, the responses have “deepened over time” in both arms of the study, though he said the daratumumab arm continues to perform better. The sCR with 22.1 months of follow-up was 62.6% for D-RVd versus 45.4% for RVd.

The rates of MRD negativity at this clinical cutoff were 51.0% versus 20.4% for the D-RVd and RVd arms, respectively (P less than .0001), while the 24-month PFS rates were 95.8% for D-RVd and 89.8% for RVd. “Suffice it to say that both groups of patients are doing incredibly well at 2 years,” Dr. Voorhees said.

Rates of grade 3 and 4 neutropenia and thrombocytopenia were higher in the D-RVd arm, and there were more infections, though this was largely driven by an increased incidence of grade 1 or 2 upper respiratory tract infections, according to Dr. Voorhees.

Daratumumab did not impact time to engraftment, with a median CD34+ cell yield of 8.2 x 10⁶ cells/kg for D-RVd and 9.4 x 10⁶ cells/kg for RVd, a difference that Dr. Voorhees said was “not of clinical significance.”

Dr. Voorhees reported disclosures related to Takeda, Oncopeptides, Novartis, GSK, Janssen, Celgene, BMS, Adaptive Biotechnologies, Amgen, and TeneBio.

SOURCE: Voorhees PM et al. ASH 2019, Abstract 691.

ORLANDO – While the benefit of daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) continues to improve with longer follow-up of the GRIFFIN trial, even early adopters may want to wait for additional data before declaring the combination a first-line standard for transplant-eligible multiple myeloma, according to an investigator on the trial.

Andrew D. Bowser/MDedge News

D-RVd has significantly improved both response rates and depth of response, compared with RVd alone, Peter M. Voorhees, MD, of Levine Cancer Institute, Atrium Health, Charlotte, N.C., reported at the annual meeting of the American Society of Hematology.

Additionally, rates of response and minimal residual disease (MRD) negativity with D-RVd have increased with longer follow-up beyond posttransplant consolidation, in the ongoing randomized phase 2 trial, Dr. Voorhees said.

“Those of you that are early adopters have good ammunition based on this result, but I would argue that we do need to confirm that the increased MRD-negative rate that we’re seeing translates into a sustained improvement in MRD negativity,” said Dr. Voorhees while presenting the updated results.

Most importantly, it needs to be confirmed that improved depth of response with D-RVd translates into an improvement in progression-free survival, not only in GRIFFIN, he said, but in PERSEUS, a large, randomized European phase 3 trial of subcutaneous daratumumab plus RVd versus RVd alone.

In the GRIFFIN trial, a total of 207 patients with transplant-eligible newly diagnosed multiple myeloma were randomized to intravenous daratumumab plus RVd versus RVd alone, with a primary endpoint of stringent complete response (sCR) by the end of consolidation.

Primary findings, presented in September at the 17th International Myeloma Workshop (IMW) meeting in Boston, indicated an sCR of 42.4% for D-RVd versus 32.0% for RVd at a median follow-up of 13.5 months, a difference that Dr. Voorhees said was statistically significant as defined by the protocol (1-sided P = .068), with an odds ratio of 1.57 (95% confidence interval, 0.87-2.82) in favor of the D-RVd arm.

With longer follow-up data, which Dr. Voorhees reported at ASH, the responses have “deepened over time” in both arms of the study, though he said the daratumumab arm continues to perform better. The sCR with 22.1 months of follow-up was 62.6% for D-RVd versus 45.4% for RVd.

The rates of MRD negativity at this clinical cutoff were 51.0% versus 20.4% for the D-RVd and RVd arms, respectively (P less than .0001), while the 24-month PFS rates were 95.8% for D-RVd and 89.8% for RVd. “Suffice it to say that both groups of patients are doing incredibly well at 2 years,” Dr. Voorhees said.

Rates of grade 3 and 4 neutropenia and thrombocytopenia were higher in the D-RVd arm, and there were more infections, though this was largely driven by an increased incidence of grade 1 or 2 upper respiratory tract infections, according to Dr. Voorhees.

Daratumumab did not impact time to engraftment, with a median CD34+ cell yield of 8.2 x 10⁶ cells/kg for D-RVd and 9.4 x 10⁶ cells/kg for RVd, a difference that Dr. Voorhees said was “not of clinical significance.”

Dr. Voorhees reported disclosures related to Takeda, Oncopeptides, Novartis, GSK, Janssen, Celgene, BMS, Adaptive Biotechnologies, Amgen, and TeneBio.

SOURCE: Voorhees PM et al. ASH 2019, Abstract 691.

ORLANDO – While the benefit of daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) continues to improve with longer follow-up of the GRIFFIN trial, even early adopters may want to wait for additional data before declaring the combination a first-line standard for transplant-eligible multiple myeloma, according to an investigator on the trial.

Andrew D. Bowser/MDedge News

D-RVd has significantly improved both response rates and depth of response, compared with RVd alone, Peter M. Voorhees, MD, of Levine Cancer Institute, Atrium Health, Charlotte, N.C., reported at the annual meeting of the American Society of Hematology.

Additionally, rates of response and minimal residual disease (MRD) negativity with D-RVd have increased with longer follow-up beyond posttransplant consolidation, in the ongoing randomized phase 2 trial, Dr. Voorhees said.

“Those of you that are early adopters have good ammunition based on this result, but I would argue that we do need to confirm that the increased MRD-negative rate that we’re seeing translates into a sustained improvement in MRD negativity,” said Dr. Voorhees while presenting the updated results.

Most importantly, it needs to be confirmed that improved depth of response with D-RVd translates into an improvement in progression-free survival, not only in GRIFFIN, he said, but in PERSEUS, a large, randomized European phase 3 trial of subcutaneous daratumumab plus RVd versus RVd alone.

In the GRIFFIN trial, a total of 207 patients with transplant-eligible newly diagnosed multiple myeloma were randomized to intravenous daratumumab plus RVd versus RVd alone, with a primary endpoint of stringent complete response (sCR) by the end of consolidation.

Primary findings, presented in September at the 17th International Myeloma Workshop (IMW) meeting in Boston, indicated an sCR of 42.4% for D-RVd versus 32.0% for RVd at a median follow-up of 13.5 months, a difference that Dr. Voorhees said was statistically significant as defined by the protocol (1-sided P = .068), with an odds ratio of 1.57 (95% confidence interval, 0.87-2.82) in favor of the D-RVd arm.

With longer follow-up data, which Dr. Voorhees reported at ASH, the responses have “deepened over time” in both arms of the study, though he said the daratumumab arm continues to perform better. The sCR with 22.1 months of follow-up was 62.6% for D-RVd versus 45.4% for RVd.

The rates of MRD negativity at this clinical cutoff were 51.0% versus 20.4% for the D-RVd and RVd arms, respectively (P less than .0001), while the 24-month PFS rates were 95.8% for D-RVd and 89.8% for RVd. “Suffice it to say that both groups of patients are doing incredibly well at 2 years,” Dr. Voorhees said.

Rates of grade 3 and 4 neutropenia and thrombocytopenia were higher in the D-RVd arm, and there were more infections, though this was largely driven by an increased incidence of grade 1 or 2 upper respiratory tract infections, according to Dr. Voorhees.

Daratumumab did not impact time to engraftment, with a median CD34+ cell yield of 8.2 x 10⁶ cells/kg for D-RVd and 9.4 x 10⁶ cells/kg for RVd, a difference that Dr. Voorhees said was “not of clinical significance.”

Dr. Voorhees reported disclosures related to Takeda, Oncopeptides, Novartis, GSK, Janssen, Celgene, BMS, Adaptive Biotechnologies, Amgen, and TeneBio.

SOURCE: Voorhees PM et al. ASH 2019, Abstract 691.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.