BALTIMORE – Initial presentations of Dravet syndrome often differ from the prototypical phenotype, researchers said at the annual meeting of the American Epilepsy Society. About half of patients have an afebrile seizure as their first seizure, and it is common for patients to present with seizures before age 5 months. Patients also may have seizure onset after age 18 months, said Wenhui Li, a researcher affiliated with Children’s Hospital of Fudan University in Shanghai and University of Melbourne, and colleagues.

“Subtle differences in Dravet syndrome phenotypes lead to delayed diagnosis,” the researchers said. “Understanding key features within the phenotypic spectrum will assist clinicians in evaluating whether a child has Dravet syndrome, facilitating early diagnosis for precision therapies.”

Typically, Dravet syndrome is thought to begin with prolonged febrile hemiclonic or generalized tonic-clonic seizures at about age 6 months in normally developing infants. Multiple seizure types occur during subsequent years, including focal impaired awareness, bilateral tonic-clonic, absence, and myoclonic seizures.

Patients often do not receive a diagnosis of Dravet syndrome until they are older than 3 years, after “developmental plateau or regression occurs in the second year,” the investigators said. “Earlier diagnosis is critical for optimal management.”

To outline the range of phenotypes, researchers analyzed the clinical histories of 188 patients with Dravet syndrome and pathogenic SCN1A variants. They excluded from their analysis patients with SCN1A-positive genetic epilepsy with febrile seizures plus (GEFS+).

In all, 53% of the patients were female, and 2% had developmental delay prior to the onset of seizures. Age at seizure onset ranged from 1.5 months to 21 months (median, 5.75 months). Three patients had seizure onset after age 12 months, the authors noted.

In cases where the first seizure type could be classified, 52% had generalized tonic-clonic seizures at onset, 37% had hemiclonic seizures, 4% myoclonic seizures, 4% focal impaired awareness seizures, and 0.5% absence seizures. In addition, 1% had hemiclonic and myoclonic seizures, and 2% had tonic-clonic and myoclonic seizures.

Fifty-four percent of patients were febrile during their first seizure, and 46% were afebrile.

Status epilepticus as the first seizure occurred in about 44% of cases, while 35% of patients had a first seizure duration of 5 minutes or less.

The researchers had no disclosures.

[email protected]

SOURCE: Li W et al. AES 2019. Abstract 2.116.

BALTIMORE – Initial presentations of Dravet syndrome often differ from the prototypical phenotype, researchers said at the annual meeting of the American Epilepsy Society. About half of patients have an afebrile seizure as their first seizure, and it is common for patients to present with seizures before age 5 months. Patients also may have seizure onset after age 18 months, said Wenhui Li, a researcher affiliated with Children’s Hospital of Fudan University in Shanghai and University of Melbourne, and colleagues.

“Subtle differences in Dravet syndrome phenotypes lead to delayed diagnosis,” the researchers said. “Understanding key features within the phenotypic spectrum will assist clinicians in evaluating whether a child has Dravet syndrome, facilitating early diagnosis for precision therapies.”

Typically, Dravet syndrome is thought to begin with prolonged febrile hemiclonic or generalized tonic-clonic seizures at about age 6 months in normally developing infants. Multiple seizure types occur during subsequent years, including focal impaired awareness, bilateral tonic-clonic, absence, and myoclonic seizures.

Patients often do not receive a diagnosis of Dravet syndrome until they are older than 3 years, after “developmental plateau or regression occurs in the second year,” the investigators said. “Earlier diagnosis is critical for optimal management.”

To outline the range of phenotypes, researchers analyzed the clinical histories of 188 patients with Dravet syndrome and pathogenic SCN1A variants. They excluded from their analysis patients with SCN1A-positive genetic epilepsy with febrile seizures plus (GEFS+).

In all, 53% of the patients were female, and 2% had developmental delay prior to the onset of seizures. Age at seizure onset ranged from 1.5 months to 21 months (median, 5.75 months). Three patients had seizure onset after age 12 months, the authors noted.

In cases where the first seizure type could be classified, 52% had generalized tonic-clonic seizures at onset, 37% had hemiclonic seizures, 4% myoclonic seizures, 4% focal impaired awareness seizures, and 0.5% absence seizures. In addition, 1% had hemiclonic and myoclonic seizures, and 2% had tonic-clonic and myoclonic seizures.

Fifty-four percent of patients were febrile during their first seizure, and 46% were afebrile.

Status epilepticus as the first seizure occurred in about 44% of cases, while 35% of patients had a first seizure duration of 5 minutes or less.

The researchers had no disclosures.

[email protected]

SOURCE: Li W et al. AES 2019. Abstract 2.116.

BALTIMORE – Initial presentations of Dravet syndrome often differ from the prototypical phenotype, researchers said at the annual meeting of the American Epilepsy Society. About half of patients have an afebrile seizure as their first seizure, and it is common for patients to present with seizures before age 5 months. Patients also may have seizure onset after age 18 months, said Wenhui Li, a researcher affiliated with Children’s Hospital of Fudan University in Shanghai and University of Melbourne, and colleagues.

“Subtle differences in Dravet syndrome phenotypes lead to delayed diagnosis,” the researchers said. “Understanding key features within the phenotypic spectrum will assist clinicians in evaluating whether a child has Dravet syndrome, facilitating early diagnosis for precision therapies.”

Typically, Dravet syndrome is thought to begin with prolonged febrile hemiclonic or generalized tonic-clonic seizures at about age 6 months in normally developing infants. Multiple seizure types occur during subsequent years, including focal impaired awareness, bilateral tonic-clonic, absence, and myoclonic seizures.

Patients often do not receive a diagnosis of Dravet syndrome until they are older than 3 years, after “developmental plateau or regression occurs in the second year,” the investigators said. “Earlier diagnosis is critical for optimal management.”

To outline the range of phenotypes, researchers analyzed the clinical histories of 188 patients with Dravet syndrome and pathogenic SCN1A variants. They excluded from their analysis patients with SCN1A-positive genetic epilepsy with febrile seizures plus (GEFS+).

In all, 53% of the patients were female, and 2% had developmental delay prior to the onset of seizures. Age at seizure onset ranged from 1.5 months to 21 months (median, 5.75 months). Three patients had seizure onset after age 12 months, the authors noted.

In cases where the first seizure type could be classified, 52% had generalized tonic-clonic seizures at onset, 37% had hemiclonic seizures, 4% myoclonic seizures, 4% focal impaired awareness seizures, and 0.5% absence seizures. In addition, 1% had hemiclonic and myoclonic seizures, and 2% had tonic-clonic and myoclonic seizures.

Fifty-four percent of patients were febrile during their first seizure, and 46% were afebrile.

Status epilepticus as the first seizure occurred in about 44% of cases, while 35% of patients had a first seizure duration of 5 minutes or less.

The researchers had no disclosures.

[email protected]

SOURCE: Li W et al. AES 2019. Abstract 2.116.

PHILADELPHIA – Obese people living in the United Kingdom who underwent bariatric surgery had a two-thirds lower rate of major cerebrovascular events than that of a matched group of obese residents who did not undergo bariatric surgery, in a retrospective study of 8,424 people followed for a mean of just over 11 years.

Mitchel L. Zoler/MDedge News

Although the cut in cerebrovascular events that linked with bariatric surgery shown by the analysis was mostly driven by a reduced rate of transient ischemic attacks, a potentially unreliable diagnosis, the results showed consistent reductions in the rates of acute ischemic strokes as well as in acute, nontraumatic intracranial hemorrhages, two other components of the combined primary endpoint, Maddalena Ardissino, MBBS, said at the American Heart Association scientific sessions.

This finding of an apparent benefit from bariatric surgery in obese patients in a large U.K. database confirms other findings from a “fast-growing” evidence base showing benefits from bariatric surgery for reducing other types of cardiovascular disease events, said Dr. Ardissino, a researcher at Imperial College, London. However, the impact of bariatric surgery specifically on cerebrovascular events had not received much attention in published studies, she noted.

Her study used data collected by the Clinical Practice Research Datalink, which has primary and secondary care health records for about 42 million U.K. residents. The researchers focused on more than 251,000 obese U.K. adults (body mass index of 30 kg/m² or greater) without a history of a cerebrovascular event who had at least 1 year of follow-up, a data file that included 4,212 adults who had undergone bariatric surgery. Their analysis matched these surgical patients with an equal number of obese adults who did not have surgery, pairing the cases and controls based on age, sex, and BMI. The resulting matched cohorts each averaged 50 years old, with a mean BMI of 40.5 kg/m².

During just over 11 years of average follow-up, the incidence of acute ischemic stroke, acute intracranial hemorrhage, subarachnoid hemorrhage, or transient ischemic attack was about 1.3% in those without bariatric surgery and about 0.4% in those who had surgery, an absolute risk reduction of 0.9 linked with surgery and a relative risk reduction of 65% that was statistically significant, Dr. Ardissino reported. All-cause mortality was about 70% lower in the group that underwent bariatric surgery compared with those who did not have surgery, a finding that confirmed prior reports. She cautioned that the analysis was limited by a relatively low number of total events, and by the small number of criteria used for cohort matching that might have left unadjusted certain potential confounders such as the level of engagement people had with their medical care.

[email protected]

SOURCE: Ardissino M. AHA 2019, Abstract 335.

PHILADELPHIA – Obese people living in the United Kingdom who underwent bariatric surgery had a two-thirds lower rate of major cerebrovascular events than that of a matched group of obese residents who did not undergo bariatric surgery, in a retrospective study of 8,424 people followed for a mean of just over 11 years.

Mitchel L. Zoler/MDedge News

Although the cut in cerebrovascular events that linked with bariatric surgery shown by the analysis was mostly driven by a reduced rate of transient ischemic attacks, a potentially unreliable diagnosis, the results showed consistent reductions in the rates of acute ischemic strokes as well as in acute, nontraumatic intracranial hemorrhages, two other components of the combined primary endpoint, Maddalena Ardissino, MBBS, said at the American Heart Association scientific sessions.

This finding of an apparent benefit from bariatric surgery in obese patients in a large U.K. database confirms other findings from a “fast-growing” evidence base showing benefits from bariatric surgery for reducing other types of cardiovascular disease events, said Dr. Ardissino, a researcher at Imperial College, London. However, the impact of bariatric surgery specifically on cerebrovascular events had not received much attention in published studies, she noted.

Her study used data collected by the Clinical Practice Research Datalink, which has primary and secondary care health records for about 42 million U.K. residents. The researchers focused on more than 251,000 obese U.K. adults (body mass index of 30 kg/m² or greater) without a history of a cerebrovascular event who had at least 1 year of follow-up, a data file that included 4,212 adults who had undergone bariatric surgery. Their analysis matched these surgical patients with an equal number of obese adults who did not have surgery, pairing the cases and controls based on age, sex, and BMI. The resulting matched cohorts each averaged 50 years old, with a mean BMI of 40.5 kg/m².

During just over 11 years of average follow-up, the incidence of acute ischemic stroke, acute intracranial hemorrhage, subarachnoid hemorrhage, or transient ischemic attack was about 1.3% in those without bariatric surgery and about 0.4% in those who had surgery, an absolute risk reduction of 0.9 linked with surgery and a relative risk reduction of 65% that was statistically significant, Dr. Ardissino reported. All-cause mortality was about 70% lower in the group that underwent bariatric surgery compared with those who did not have surgery, a finding that confirmed prior reports. She cautioned that the analysis was limited by a relatively low number of total events, and by the small number of criteria used for cohort matching that might have left unadjusted certain potential confounders such as the level of engagement people had with their medical care.

[email protected]

SOURCE: Ardissino M. AHA 2019, Abstract 335.

PHILADELPHIA – Obese people living in the United Kingdom who underwent bariatric surgery had a two-thirds lower rate of major cerebrovascular events than that of a matched group of obese residents who did not undergo bariatric surgery, in a retrospective study of 8,424 people followed for a mean of just over 11 years.

Mitchel L. Zoler/MDedge News

Although the cut in cerebrovascular events that linked with bariatric surgery shown by the analysis was mostly driven by a reduced rate of transient ischemic attacks, a potentially unreliable diagnosis, the results showed consistent reductions in the rates of acute ischemic strokes as well as in acute, nontraumatic intracranial hemorrhages, two other components of the combined primary endpoint, Maddalena Ardissino, MBBS, said at the American Heart Association scientific sessions.

This finding of an apparent benefit from bariatric surgery in obese patients in a large U.K. database confirms other findings from a “fast-growing” evidence base showing benefits from bariatric surgery for reducing other types of cardiovascular disease events, said Dr. Ardissino, a researcher at Imperial College, London. However, the impact of bariatric surgery specifically on cerebrovascular events had not received much attention in published studies, she noted.

Her study used data collected by the Clinical Practice Research Datalink, which has primary and secondary care health records for about 42 million U.K. residents. The researchers focused on more than 251,000 obese U.K. adults (body mass index of 30 kg/m² or greater) without a history of a cerebrovascular event who had at least 1 year of follow-up, a data file that included 4,212 adults who had undergone bariatric surgery. Their analysis matched these surgical patients with an equal number of obese adults who did not have surgery, pairing the cases and controls based on age, sex, and BMI. The resulting matched cohorts each averaged 50 years old, with a mean BMI of 40.5 kg/m².

During just over 11 years of average follow-up, the incidence of acute ischemic stroke, acute intracranial hemorrhage, subarachnoid hemorrhage, or transient ischemic attack was about 1.3% in those without bariatric surgery and about 0.4% in those who had surgery, an absolute risk reduction of 0.9 linked with surgery and a relative risk reduction of 65% that was statistically significant, Dr. Ardissino reported. All-cause mortality was about 70% lower in the group that underwent bariatric surgery compared with those who did not have surgery, a finding that confirmed prior reports. She cautioned that the analysis was limited by a relatively low number of total events, and by the small number of criteria used for cohort matching that might have left unadjusted certain potential confounders such as the level of engagement people had with their medical care.

[email protected]

SOURCE: Ardissino M. AHA 2019, Abstract 335.

Currently available fibrosis scoring systems appear to have only a modest predictive ability for development of severe liver disease in the general population, according to authors of a large, retrospective cohort study.

Of five noninvasive scoring systems evaluated, all did have high negative predictive value in the general population, according to authors of the study, which included data on more than 800,000 individuals in Sweden. However, their sensitivities were low, with most of the individuals who developed severe liver disease over a 10-year follow-up period initially classified as being at low risk for advanced fibrosis, according to the study authors, led by Hannes Hagström, MD, PhD, of the division of hepatology, Karolinska University Hospital, Stockholm.

The scoring systems tended to perform better in patients at higher risk for nonalcoholic fatty liver disease (NAFLD) at baseline, suggesting the best use of the tools is in patients at increased risk or who have liver disease indications, Dr. Hagström and coauthors wrote in a report on the study.

“Although useful in populations with a high prevalence of advanced fibrosis, current scores lack precision for usage in the general population for which the prevalence of advanced fibrosis is much lower,” Dr. Hagström and colleagues said.

The scoring systems were derived from high-risk cohorts with liver diseases, the authors noted, stating that the disease prevalence in any given population will affect the performance of a test that’s intended to diagnose that specific disease.

“New and improved” scoring systems should be developed to more effectively pinpoint patients with NAFLD who are at higher risk of a severe liver event, they added in the report, which appears in Gastroenterology.

The population-based cohort study by Dr. Hagström and colleagues was based on data from 812,073 patients enrolled in the Swedish Apolipoprotein Mortality Risk (AMORIS) cohort between 1985 and 1996. Investigators said they excluded patients under 35 and over 79 years of age, patients with severe liver disease at baseline, and those with a prior diagnosis of alcohol or drug abuse.

Investigators used available data to calculate five scores, including the AST to Platelet Ratio Index (APRI); the body mass index, AST/ALT ratio, and diabetes (BARD) score; the Fibrosis-4 (FIB-4) score; Forns Index; and NAFLD Fibrosis Score (NFS).

At baseline, 0.5%-8.0% of patients were considered to be at high risk for advanced fibrosis, depending on the test used, investigators said. With up to 10 years of follow-up, the proportion of individuals who developed severe liver diseases (cirrhosis, liver failure, hepatocellular carcinoma, liver transplantation, or decompensated liver disease) was 0.3%-0.6%, and with the maximum 27 years of follow-up, the incidence ranged from 1.0% to 1.4%.

There was a “strong association” between baseline risk of fibrosis and development of severe liver diseases; however, the majority of cases occurred in patients deemed low risk at baseline, Dr. Hagström and colleagues noted in their report.

For example, 12.4% of individuals classified as high risk by APRI developed severe liver diseases over 10 years, compared to just 0.4% of the low-risk group, yet out of 723 cases, 502 (69%) occurred in the low-risk patients, the data show.

Hazard ratios did increase with risk level, and at the high-risk level, adjusted hazard ratios ranged from 1.7 (95% confidence interval [CI], 1.1-2.5) for the high-risk BARD patients to 45.9 (95% CI, 36.1-58.3) for the high-risk APRI patients, investigators reported.

Taken together, results of this study demonstrate that the performance of all scores was low in an unselected population, according to investigators.

Of all tests, APRI was least likely to falsely classify patients who never developed severe liver diseases and had an intermediate-risk group of 4%, the lowest of any test, which are findings that may have implications for routine primary care, according to investigators.

“APRI could be the currently best score to exclude a high risk of liver-related events in the near future, and thereby reduce unnecessary testing in a general population,” they said in a discussion of their results.

The study was supported by an independent grant from AstraZeneca. Dr. Hagström reported disclosures related to that company, as well as Novo Nordisk, Gilead Sciences, IQVIA, Intercept, and Bristol Myers-Squibb.

SOURCE: Hagström H et al. Gastroenterology. 2019 Sep 26. doi: 10.1053/j.gastro.2019.09.008.

Currently available fibrosis scoring systems appear to have only a modest predictive ability for development of severe liver disease in the general population, according to authors of a large, retrospective cohort study.

Of five noninvasive scoring systems evaluated, all did have high negative predictive value in the general population, according to authors of the study, which included data on more than 800,000 individuals in Sweden. However, their sensitivities were low, with most of the individuals who developed severe liver disease over a 10-year follow-up period initially classified as being at low risk for advanced fibrosis, according to the study authors, led by Hannes Hagström, MD, PhD, of the division of hepatology, Karolinska University Hospital, Stockholm.

The scoring systems tended to perform better in patients at higher risk for nonalcoholic fatty liver disease (NAFLD) at baseline, suggesting the best use of the tools is in patients at increased risk or who have liver disease indications, Dr. Hagström and coauthors wrote in a report on the study.

“Although useful in populations with a high prevalence of advanced fibrosis, current scores lack precision for usage in the general population for which the prevalence of advanced fibrosis is much lower,” Dr. Hagström and colleagues said.

The scoring systems were derived from high-risk cohorts with liver diseases, the authors noted, stating that the disease prevalence in any given population will affect the performance of a test that’s intended to diagnose that specific disease.

“New and improved” scoring systems should be developed to more effectively pinpoint patients with NAFLD who are at higher risk of a severe liver event, they added in the report, which appears in Gastroenterology.

The population-based cohort study by Dr. Hagström and colleagues was based on data from 812,073 patients enrolled in the Swedish Apolipoprotein Mortality Risk (AMORIS) cohort between 1985 and 1996. Investigators said they excluded patients under 35 and over 79 years of age, patients with severe liver disease at baseline, and those with a prior diagnosis of alcohol or drug abuse.

Investigators used available data to calculate five scores, including the AST to Platelet Ratio Index (APRI); the body mass index, AST/ALT ratio, and diabetes (BARD) score; the Fibrosis-4 (FIB-4) score; Forns Index; and NAFLD Fibrosis Score (NFS).

At baseline, 0.5%-8.0% of patients were considered to be at high risk for advanced fibrosis, depending on the test used, investigators said. With up to 10 years of follow-up, the proportion of individuals who developed severe liver diseases (cirrhosis, liver failure, hepatocellular carcinoma, liver transplantation, or decompensated liver disease) was 0.3%-0.6%, and with the maximum 27 years of follow-up, the incidence ranged from 1.0% to 1.4%.

There was a “strong association” between baseline risk of fibrosis and development of severe liver diseases; however, the majority of cases occurred in patients deemed low risk at baseline, Dr. Hagström and colleagues noted in their report.

For example, 12.4% of individuals classified as high risk by APRI developed severe liver diseases over 10 years, compared to just 0.4% of the low-risk group, yet out of 723 cases, 502 (69%) occurred in the low-risk patients, the data show.

Hazard ratios did increase with risk level, and at the high-risk level, adjusted hazard ratios ranged from 1.7 (95% confidence interval [CI], 1.1-2.5) for the high-risk BARD patients to 45.9 (95% CI, 36.1-58.3) for the high-risk APRI patients, investigators reported.

Taken together, results of this study demonstrate that the performance of all scores was low in an unselected population, according to investigators.

Of all tests, APRI was least likely to falsely classify patients who never developed severe liver diseases and had an intermediate-risk group of 4%, the lowest of any test, which are findings that may have implications for routine primary care, according to investigators.

“APRI could be the currently best score to exclude a high risk of liver-related events in the near future, and thereby reduce unnecessary testing in a general population,” they said in a discussion of their results.

The study was supported by an independent grant from AstraZeneca. Dr. Hagström reported disclosures related to that company, as well as Novo Nordisk, Gilead Sciences, IQVIA, Intercept, and Bristol Myers-Squibb.

SOURCE: Hagström H et al. Gastroenterology. 2019 Sep 26. doi: 10.1053/j.gastro.2019.09.008.

Currently available fibrosis scoring systems appear to have only a modest predictive ability for development of severe liver disease in the general population, according to authors of a large, retrospective cohort study.

Of five noninvasive scoring systems evaluated, all did have high negative predictive value in the general population, according to authors of the study, which included data on more than 800,000 individuals in Sweden. However, their sensitivities were low, with most of the individuals who developed severe liver disease over a 10-year follow-up period initially classified as being at low risk for advanced fibrosis, according to the study authors, led by Hannes Hagström, MD, PhD, of the division of hepatology, Karolinska University Hospital, Stockholm.

The scoring systems tended to perform better in patients at higher risk for nonalcoholic fatty liver disease (NAFLD) at baseline, suggesting the best use of the tools is in patients at increased risk or who have liver disease indications, Dr. Hagström and coauthors wrote in a report on the study.

“Although useful in populations with a high prevalence of advanced fibrosis, current scores lack precision for usage in the general population for which the prevalence of advanced fibrosis is much lower,” Dr. Hagström and colleagues said.

The scoring systems were derived from high-risk cohorts with liver diseases, the authors noted, stating that the disease prevalence in any given population will affect the performance of a test that’s intended to diagnose that specific disease.

“New and improved” scoring systems should be developed to more effectively pinpoint patients with NAFLD who are at higher risk of a severe liver event, they added in the report, which appears in Gastroenterology.

The population-based cohort study by Dr. Hagström and colleagues was based on data from 812,073 patients enrolled in the Swedish Apolipoprotein Mortality Risk (AMORIS) cohort between 1985 and 1996. Investigators said they excluded patients under 35 and over 79 years of age, patients with severe liver disease at baseline, and those with a prior diagnosis of alcohol or drug abuse.

Investigators used available data to calculate five scores, including the AST to Platelet Ratio Index (APRI); the body mass index, AST/ALT ratio, and diabetes (BARD) score; the Fibrosis-4 (FIB-4) score; Forns Index; and NAFLD Fibrosis Score (NFS).

At baseline, 0.5%-8.0% of patients were considered to be at high risk for advanced fibrosis, depending on the test used, investigators said. With up to 10 years of follow-up, the proportion of individuals who developed severe liver diseases (cirrhosis, liver failure, hepatocellular carcinoma, liver transplantation, or decompensated liver disease) was 0.3%-0.6%, and with the maximum 27 years of follow-up, the incidence ranged from 1.0% to 1.4%.

There was a “strong association” between baseline risk of fibrosis and development of severe liver diseases; however, the majority of cases occurred in patients deemed low risk at baseline, Dr. Hagström and colleagues noted in their report.

For example, 12.4% of individuals classified as high risk by APRI developed severe liver diseases over 10 years, compared to just 0.4% of the low-risk group, yet out of 723 cases, 502 (69%) occurred in the low-risk patients, the data show.

Hazard ratios did increase with risk level, and at the high-risk level, adjusted hazard ratios ranged from 1.7 (95% confidence interval [CI], 1.1-2.5) for the high-risk BARD patients to 45.9 (95% CI, 36.1-58.3) for the high-risk APRI patients, investigators reported.

Taken together, results of this study demonstrate that the performance of all scores was low in an unselected population, according to investigators.

Of all tests, APRI was least likely to falsely classify patients who never developed severe liver diseases and had an intermediate-risk group of 4%, the lowest of any test, which are findings that may have implications for routine primary care, according to investigators.

“APRI could be the currently best score to exclude a high risk of liver-related events in the near future, and thereby reduce unnecessary testing in a general population,” they said in a discussion of their results.

The study was supported by an independent grant from AstraZeneca. Dr. Hagström reported disclosures related to that company, as well as Novo Nordisk, Gilead Sciences, IQVIA, Intercept, and Bristol Myers-Squibb.

SOURCE: Hagström H et al. Gastroenterology. 2019 Sep 26. doi: 10.1053/j.gastro.2019.09.008.

ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.

Andrew D. Bowser/MDedge News

If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.

If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.

“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”

The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.

All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.

“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.

While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.

“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.

Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.

“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.

They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.

In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.

PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.

However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.

Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”

Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.

SOURCE: Mato AR et al. ASH 2019, Abstract 502.

ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.

Andrew D. Bowser/MDedge News

If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.

If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.

“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”

The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.

All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.

“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.

While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.

“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.

Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.

“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.

They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.

In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.

PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.

However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.

Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”

Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.

SOURCE: Mato AR et al. ASH 2019, Abstract 502.

ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.

Andrew D. Bowser/MDedge News

If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.

If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.

“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”

The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.

All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.

“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.

While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.

“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.

Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.

“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.

They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.

In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.

PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.

However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.

Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”

Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.

SOURCE: Mato AR et al. ASH 2019, Abstract 502.

Adults aged 18-64 years were more likely to see or talk to a health care professional in 2017-2018 than they were in 2012-2013, according to the Centers for Disease Control and Prevention.

The percentage of American adults who had seen or talked to a health care professional in the past 12 months rose from 79.3% in 2012-2013 to 82.1% in 2017-2018, Michael E. Martinez, MPH, and Tainya C. Clarke, PhD, reported in the Morbidity and Mortality Weekly Report.

Analysis by race/ethnicity showed that Hispanic adults were still the least likely to have seen or talked to a health care professional in 2017-2018, even though they had the largest increase – more than six percentage points – between the two time periods, the CDC investigators reported.

White adults were the most likely to have seen or talked to a health care provider in both 2012-2013 and 2017-2018 but their 2.1-percentage-point increase over the course of the analysis was the smallest of the four groups included, based on data from the National Health Interview Survey.

[email protected]

SOURCE: Martinez ME, Clarke TC. MMWR. 2019 Dec 6;68(48):1124.

Adults aged 18-64 years were more likely to see or talk to a health care professional in 2017-2018 than they were in 2012-2013, according to the Centers for Disease Control and Prevention.

The percentage of American adults who had seen or talked to a health care professional in the past 12 months rose from 79.3% in 2012-2013 to 82.1% in 2017-2018, Michael E. Martinez, MPH, and Tainya C. Clarke, PhD, reported in the Morbidity and Mortality Weekly Report.

Analysis by race/ethnicity showed that Hispanic adults were still the least likely to have seen or talked to a health care professional in 2017-2018, even though they had the largest increase – more than six percentage points – between the two time periods, the CDC investigators reported.

White adults were the most likely to have seen or talked to a health care provider in both 2012-2013 and 2017-2018 but their 2.1-percentage-point increase over the course of the analysis was the smallest of the four groups included, based on data from the National Health Interview Survey.

[email protected]

SOURCE: Martinez ME, Clarke TC. MMWR. 2019 Dec 6;68(48):1124.

Adults aged 18-64 years were more likely to see or talk to a health care professional in 2017-2018 than they were in 2012-2013, according to the Centers for Disease Control and Prevention.

The percentage of American adults who had seen or talked to a health care professional in the past 12 months rose from 79.3% in 2012-2013 to 82.1% in 2017-2018, Michael E. Martinez, MPH, and Tainya C. Clarke, PhD, reported in the Morbidity and Mortality Weekly Report.

Analysis by race/ethnicity showed that Hispanic adults were still the least likely to have seen or talked to a health care professional in 2017-2018, even though they had the largest increase – more than six percentage points – between the two time periods, the CDC investigators reported.

White adults were the most likely to have seen or talked to a health care provider in both 2012-2013 and 2017-2018 but their 2.1-percentage-point increase over the course of the analysis was the smallest of the four groups included, based on data from the National Health Interview Survey.

[email protected]

SOURCE: Martinez ME, Clarke TC. MMWR. 2019 Dec 6;68(48):1124.

Men aged 65-75 years with a history of smoking should undergo one-time screening for abdominal aortic aneurysms (AAA), but clinicians can selectively screen men in this age group who don’t smoke, according to updated recommendations from the U.S. Preventive Services Task Force published in JAMA.

The task force issued a B recommendation for screening men aged 65-75 years with a smoking history and a C recommendation for selectively screening male never smokers in this age group in an update to the previous recommendations issued in 2014.

The task force also recommended against screening for AAA in women with no history of smoking (D recommendation) and cited insufficient evidence to make recommendations about AAA screening for women with a history of smoking or a family history of AAA (I statement).

The current prevalence of AAA in the United States is unclear because of the low rate of screening, but data from countries including the United Kingdom, Sweden, Denmark, and New Zealand have shown a decline in AAA among screened men aged 65 years and older, according to the USPSTF report.

Risk factors for AAA include smoking, male gender, older age, and having a first-degree relative with AAA, the task force noted.

In an evidence review accompanying the recommendations, Janelle M. Guirguis-Blake, MD, of the University of Washington, Tacoma, and colleagues analyzed data from 33 studies. They found a significant reduction in AAA-related mortality over 12-15 years’ follow-up among men aged 65 years and older who underwent AAA screening, compared with unscreened controls (odds ratio, 0.65). In addition, the risk of ruptures related to AAA was significantly lower over 12-15 years among men who underwent screening, compared with unscreened controls (OR, 0.62). However, no significant difference was noted in all-cause mortality over 12-15 years between screened and unscreened groups (relative risk, 0.99; 95% confidence interval, 0.98-1.00).

Data from four studies of early surgery to treat small aneurysms showed no significant difference in AAA-related mortality or all-cause mortality.

“Screening for AAA entails a simple, noninvasive, and focused ultrasonography examination that costs roughly $50. The only potential harms are the psychologic burden of knowing of the presence of an aneurysm and the risk of elective surgery,” wrote Marc Schermerhorn, MD, of Beth Israel Deaconess Medical Center, Boston, in an accompanying editorial published in JAMA Surgery (doi: 10.1001/jamasurg.2019.5234).

“The latter can be calculated for each patient, weighed against the risk of rupture, and together with the estimated life expectancy, should be factored into the decision to screen and the decision to operate. We as a country can do better to detect and treat this disease cost effectively for all appropriate patients including women and elderly individuals,” he said.

Dr. Schermerhorn noted that overall the recommendations are reasonable, but he expressed concern for three populations excluded from the guidelines that warrant additional consideration: nonsmokers with equivalent risk factors, patients older than 75 years, and women. “In the meantime, we should work to ensure that patients determined appropriate by the USPSTF are actually screened,” he said.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers had no financial conflicts to disclose. Dr. Schermerhorn disclosed relationships with Abbott, Cook Medical, Endologix, Medtronic, and Philips.

SOURCE: Guirguis-Blake JM et al. JAMA. 2019. doi: 10.1001/jama.2019.17021.
 

Men aged 65-75 years with a history of smoking should undergo one-time screening for abdominal aortic aneurysms (AAA), but clinicians can selectively screen men in this age group who don’t smoke, according to updated recommendations from the U.S. Preventive Services Task Force published in JAMA.

The task force issued a B recommendation for screening men aged 65-75 years with a smoking history and a C recommendation for selectively screening male never smokers in this age group in an update to the previous recommendations issued in 2014.

The task force also recommended against screening for AAA in women with no history of smoking (D recommendation) and cited insufficient evidence to make recommendations about AAA screening for women with a history of smoking or a family history of AAA (I statement).

The current prevalence of AAA in the United States is unclear because of the low rate of screening, but data from countries including the United Kingdom, Sweden, Denmark, and New Zealand have shown a decline in AAA among screened men aged 65 years and older, according to the USPSTF report.

Risk factors for AAA include smoking, male gender, older age, and having a first-degree relative with AAA, the task force noted.

In an evidence review accompanying the recommendations, Janelle M. Guirguis-Blake, MD, of the University of Washington, Tacoma, and colleagues analyzed data from 33 studies. They found a significant reduction in AAA-related mortality over 12-15 years’ follow-up among men aged 65 years and older who underwent AAA screening, compared with unscreened controls (odds ratio, 0.65). In addition, the risk of ruptures related to AAA was significantly lower over 12-15 years among men who underwent screening, compared with unscreened controls (OR, 0.62). However, no significant difference was noted in all-cause mortality over 12-15 years between screened and unscreened groups (relative risk, 0.99; 95% confidence interval, 0.98-1.00).

Data from four studies of early surgery to treat small aneurysms showed no significant difference in AAA-related mortality or all-cause mortality.

“Screening for AAA entails a simple, noninvasive, and focused ultrasonography examination that costs roughly $50. The only potential harms are the psychologic burden of knowing of the presence of an aneurysm and the risk of elective surgery,” wrote Marc Schermerhorn, MD, of Beth Israel Deaconess Medical Center, Boston, in an accompanying editorial published in JAMA Surgery (doi: 10.1001/jamasurg.2019.5234).

“The latter can be calculated for each patient, weighed against the risk of rupture, and together with the estimated life expectancy, should be factored into the decision to screen and the decision to operate. We as a country can do better to detect and treat this disease cost effectively for all appropriate patients including women and elderly individuals,” he said.

Dr. Schermerhorn noted that overall the recommendations are reasonable, but he expressed concern for three populations excluded from the guidelines that warrant additional consideration: nonsmokers with equivalent risk factors, patients older than 75 years, and women. “In the meantime, we should work to ensure that patients determined appropriate by the USPSTF are actually screened,” he said.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers had no financial conflicts to disclose. Dr. Schermerhorn disclosed relationships with Abbott, Cook Medical, Endologix, Medtronic, and Philips.

SOURCE: Guirguis-Blake JM et al. JAMA. 2019. doi: 10.1001/jama.2019.17021.
 

Men aged 65-75 years with a history of smoking should undergo one-time screening for abdominal aortic aneurysms (AAA), but clinicians can selectively screen men in this age group who don’t smoke, according to updated recommendations from the U.S. Preventive Services Task Force published in JAMA.

The task force issued a B recommendation for screening men aged 65-75 years with a smoking history and a C recommendation for selectively screening male never smokers in this age group in an update to the previous recommendations issued in 2014.

The task force also recommended against screening for AAA in women with no history of smoking (D recommendation) and cited insufficient evidence to make recommendations about AAA screening for women with a history of smoking or a family history of AAA (I statement).

The current prevalence of AAA in the United States is unclear because of the low rate of screening, but data from countries including the United Kingdom, Sweden, Denmark, and New Zealand have shown a decline in AAA among screened men aged 65 years and older, according to the USPSTF report.

Risk factors for AAA include smoking, male gender, older age, and having a first-degree relative with AAA, the task force noted.

In an evidence review accompanying the recommendations, Janelle M. Guirguis-Blake, MD, of the University of Washington, Tacoma, and colleagues analyzed data from 33 studies. They found a significant reduction in AAA-related mortality over 12-15 years’ follow-up among men aged 65 years and older who underwent AAA screening, compared with unscreened controls (odds ratio, 0.65). In addition, the risk of ruptures related to AAA was significantly lower over 12-15 years among men who underwent screening, compared with unscreened controls (OR, 0.62). However, no significant difference was noted in all-cause mortality over 12-15 years between screened and unscreened groups (relative risk, 0.99; 95% confidence interval, 0.98-1.00).

Data from four studies of early surgery to treat small aneurysms showed no significant difference in AAA-related mortality or all-cause mortality.

“Screening for AAA entails a simple, noninvasive, and focused ultrasonography examination that costs roughly $50. The only potential harms are the psychologic burden of knowing of the presence of an aneurysm and the risk of elective surgery,” wrote Marc Schermerhorn, MD, of Beth Israel Deaconess Medical Center, Boston, in an accompanying editorial published in JAMA Surgery (doi: 10.1001/jamasurg.2019.5234).

“The latter can be calculated for each patient, weighed against the risk of rupture, and together with the estimated life expectancy, should be factored into the decision to screen and the decision to operate. We as a country can do better to detect and treat this disease cost effectively for all appropriate patients including women and elderly individuals,” he said.

Dr. Schermerhorn noted that overall the recommendations are reasonable, but he expressed concern for three populations excluded from the guidelines that warrant additional consideration: nonsmokers with equivalent risk factors, patients older than 75 years, and women. “In the meantime, we should work to ensure that patients determined appropriate by the USPSTF are actually screened,” he said.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers had no financial conflicts to disclose. Dr. Schermerhorn disclosed relationships with Abbott, Cook Medical, Endologix, Medtronic, and Philips.

SOURCE: Guirguis-Blake JM et al. JAMA. 2019. doi: 10.1001/jama.2019.17021.
 

BALTIMORE – Decrease in the frequency of convulsive seizures is significantly associated with improvement in executive function among patients with Dravet syndrome, according to data presented at the annual meeting of the American Epilepsy Society. Large reductions in convulsive seizure frequency for prolonged periods may improve everyday deficits in executive function in these patients, according to the investigators.

Dravet syndrome often entails cognitive impairment, including deficits in executive function. The frequency and severity of convulsive seizures are believed to worsen cognitive impairment over time, but few researchers have conducted long-term studies to test this hypothesis. Adjunctive fenfluramine significantly reduced the frequency of convulsive seizures and improved executive function after 14 weeks in a phase 3 study of patients with Dravet syndrome.
 

An open-label extension of a phase 3 study

In an open-label extension of this study, Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco, Benioff Children’s Hospital, and colleagues analyzed the relationship between changes in convulsive seizure frequency and executive function. The investigators also examined the effect of reducing convulsive seizure frequency by comparing patients with profound reductions (greater than 75%) versus patients with minimal reductions (less than 25%).

Patients aged 2-18 years entered the open-label study and received adjunctive fenfluramine for 1 year. At the beginning of the open-label phase, the dose was titrated to effect. The dose ranged from 0.2 mg/kg per day to 0.7 mg/kg per day and was administered as 2.5 mg/mL of fenfluramine. The maximum dose was 17 mg with stiripentol or 26 mg without.

The investigators calculated the percent difference in convulsive seizure frequency per 28 days from baseline to the end of the open-label study. They evaluated executive function using the Behavior Rating Inventory of Executive Function (BRIEF), which caregivers completed at baseline and year 1 for patients aged 5-18 years. Scores on the BRIEF were updated to the newer version: BRIEF2. Dr. Sullivan and colleagues calculated Spearman’s rho correlation coefficients to evaluate the association between BRIEF2 Behavior Regulation Index, Emotion Regulation Index, Cognitive Regulation Index, and Global Executive Composite scores. Lower scores on the BRIEF2 indexes and composite indicate better executive functioning. In addition, the researchers compared clinically meaningful change in BRIEF2 indexes and composite scores from baseline to year 1 between patients with minimal and profound reductions in convulsive seizure frequency using Fisher’s exact test. They defined a clinically meaningful change as an improvement in the Reliable Change Index of greater than 95%.
 

Profound reduction in seizure frequency was common

At the time of analysis, 53 patients had completed at least 1 year of open-label fenfluramine and had baseline and year 1 BRIEF2 data. Patients’ median age was 10 years, and 57% of patients were male. The median reduction from prerandomization baseline in convulsive seizure frequency was 71%. The reduction ranged from 99.7% to 55.0%.

Twenty-four (45%) patients had a reduction in convulsive seizure frequency of greater than 75%, and 11 (21%) had a reduction of less than 25%. Change in convulsive seizure frequency correlated significantly with Emotion Regulation Index and Global Executive Composite. Change in seizure frequency tended to correlate with Cognitive Regulation Index, but the result was not statistically significant. Change in convulsive seizure frequency was not significantly associated with Behavior Regulation Index. A significantly higher percentage of patients in the profound responder group had significant, clinically meaningful improvements on Emotion Regulation Index and Global Executive Composite, compared with minimal responders.

Zogenix, the company that is developing fenfluramine as a treatment for Dravet syndrome, funded the study. Several investigators are employees of Zogenix.

[email protected]

SOURCE: Bishop KI et al. AES 2019, Abstract 2.438.

BALTIMORE – Decrease in the frequency of convulsive seizures is significantly associated with improvement in executive function among patients with Dravet syndrome, according to data presented at the annual meeting of the American Epilepsy Society. Large reductions in convulsive seizure frequency for prolonged periods may improve everyday deficits in executive function in these patients, according to the investigators.

Dravet syndrome often entails cognitive impairment, including deficits in executive function. The frequency and severity of convulsive seizures are believed to worsen cognitive impairment over time, but few researchers have conducted long-term studies to test this hypothesis. Adjunctive fenfluramine significantly reduced the frequency of convulsive seizures and improved executive function after 14 weeks in a phase 3 study of patients with Dravet syndrome.
 

An open-label extension of a phase 3 study

In an open-label extension of this study, Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco, Benioff Children’s Hospital, and colleagues analyzed the relationship between changes in convulsive seizure frequency and executive function. The investigators also examined the effect of reducing convulsive seizure frequency by comparing patients with profound reductions (greater than 75%) versus patients with minimal reductions (less than 25%).

Patients aged 2-18 years entered the open-label study and received adjunctive fenfluramine for 1 year. At the beginning of the open-label phase, the dose was titrated to effect. The dose ranged from 0.2 mg/kg per day to 0.7 mg/kg per day and was administered as 2.5 mg/mL of fenfluramine. The maximum dose was 17 mg with stiripentol or 26 mg without.

The investigators calculated the percent difference in convulsive seizure frequency per 28 days from baseline to the end of the open-label study. They evaluated executive function using the Behavior Rating Inventory of Executive Function (BRIEF), which caregivers completed at baseline and year 1 for patients aged 5-18 years. Scores on the BRIEF were updated to the newer version: BRIEF2. Dr. Sullivan and colleagues calculated Spearman’s rho correlation coefficients to evaluate the association between BRIEF2 Behavior Regulation Index, Emotion Regulation Index, Cognitive Regulation Index, and Global Executive Composite scores. Lower scores on the BRIEF2 indexes and composite indicate better executive functioning. In addition, the researchers compared clinically meaningful change in BRIEF2 indexes and composite scores from baseline to year 1 between patients with minimal and profound reductions in convulsive seizure frequency using Fisher’s exact test. They defined a clinically meaningful change as an improvement in the Reliable Change Index of greater than 95%.
 

Profound reduction in seizure frequency was common

At the time of analysis, 53 patients had completed at least 1 year of open-label fenfluramine and had baseline and year 1 BRIEF2 data. Patients’ median age was 10 years, and 57% of patients were male. The median reduction from prerandomization baseline in convulsive seizure frequency was 71%. The reduction ranged from 99.7% to 55.0%.

Twenty-four (45%) patients had a reduction in convulsive seizure frequency of greater than 75%, and 11 (21%) had a reduction of less than 25%. Change in convulsive seizure frequency correlated significantly with Emotion Regulation Index and Global Executive Composite. Change in seizure frequency tended to correlate with Cognitive Regulation Index, but the result was not statistically significant. Change in convulsive seizure frequency was not significantly associated with Behavior Regulation Index. A significantly higher percentage of patients in the profound responder group had significant, clinically meaningful improvements on Emotion Regulation Index and Global Executive Composite, compared with minimal responders.

Zogenix, the company that is developing fenfluramine as a treatment for Dravet syndrome, funded the study. Several investigators are employees of Zogenix.

[email protected]

SOURCE: Bishop KI et al. AES 2019, Abstract 2.438.

BALTIMORE – Decrease in the frequency of convulsive seizures is significantly associated with improvement in executive function among patients with Dravet syndrome, according to data presented at the annual meeting of the American Epilepsy Society. Large reductions in convulsive seizure frequency for prolonged periods may improve everyday deficits in executive function in these patients, according to the investigators.

Dravet syndrome often entails cognitive impairment, including deficits in executive function. The frequency and severity of convulsive seizures are believed to worsen cognitive impairment over time, but few researchers have conducted long-term studies to test this hypothesis. Adjunctive fenfluramine significantly reduced the frequency of convulsive seizures and improved executive function after 14 weeks in a phase 3 study of patients with Dravet syndrome.
 

An open-label extension of a phase 3 study

In an open-label extension of this study, Joseph Sullivan, MD, director of the pediatric epilepsy center at the University of California, San Francisco, Benioff Children’s Hospital, and colleagues analyzed the relationship between changes in convulsive seizure frequency and executive function. The investigators also examined the effect of reducing convulsive seizure frequency by comparing patients with profound reductions (greater than 75%) versus patients with minimal reductions (less than 25%).

Patients aged 2-18 years entered the open-label study and received adjunctive fenfluramine for 1 year. At the beginning of the open-label phase, the dose was titrated to effect. The dose ranged from 0.2 mg/kg per day to 0.7 mg/kg per day and was administered as 2.5 mg/mL of fenfluramine. The maximum dose was 17 mg with stiripentol or 26 mg without.

The investigators calculated the percent difference in convulsive seizure frequency per 28 days from baseline to the end of the open-label study. They evaluated executive function using the Behavior Rating Inventory of Executive Function (BRIEF), which caregivers completed at baseline and year 1 for patients aged 5-18 years. Scores on the BRIEF were updated to the newer version: BRIEF2. Dr. Sullivan and colleagues calculated Spearman’s rho correlation coefficients to evaluate the association between BRIEF2 Behavior Regulation Index, Emotion Regulation Index, Cognitive Regulation Index, and Global Executive Composite scores. Lower scores on the BRIEF2 indexes and composite indicate better executive functioning. In addition, the researchers compared clinically meaningful change in BRIEF2 indexes and composite scores from baseline to year 1 between patients with minimal and profound reductions in convulsive seizure frequency using Fisher’s exact test. They defined a clinically meaningful change as an improvement in the Reliable Change Index of greater than 95%.
 

Profound reduction in seizure frequency was common

At the time of analysis, 53 patients had completed at least 1 year of open-label fenfluramine and had baseline and year 1 BRIEF2 data. Patients’ median age was 10 years, and 57% of patients were male. The median reduction from prerandomization baseline in convulsive seizure frequency was 71%. The reduction ranged from 99.7% to 55.0%.

Twenty-four (45%) patients had a reduction in convulsive seizure frequency of greater than 75%, and 11 (21%) had a reduction of less than 25%. Change in convulsive seizure frequency correlated significantly with Emotion Regulation Index and Global Executive Composite. Change in seizure frequency tended to correlate with Cognitive Regulation Index, but the result was not statistically significant. Change in convulsive seizure frequency was not significantly associated with Behavior Regulation Index. A significantly higher percentage of patients in the profound responder group had significant, clinically meaningful improvements on Emotion Regulation Index and Global Executive Composite, compared with minimal responders.

Zogenix, the company that is developing fenfluramine as a treatment for Dravet syndrome, funded the study. Several investigators are employees of Zogenix.

[email protected]

SOURCE: Bishop KI et al. AES 2019, Abstract 2.438.

A variety of socio-demographic variables – including residing in a lower-income zip code and lacking private insurance – can influence treatment decisions for orthopedic trauma patients, according to a new study on the management of calcaneus fractures.

“While our study demonstrated socio-demographic disparities regarding utilization of open reduction and internal fixation of calcaneus fractures, the exact reasons for these disparities remain unclear,” wrote Boris A. Zelle, MD, of UT Health San Antonio and his coauthors. The study was published in the Journal of Orthopaedic Surgery and Research.

To assess how certain variables might impact how patients manage decisions regarding orthopedic trauma surgery, the researchers identified 17,156 patients with closed calcaneus fractures via the National Inpatient Sample (NIS) and analyzed their treatment and demographic data. The statistical analysis included variables such as age, sex, insurance status, race/ethnicity, income, hospital location, and hospital size. A total of 59% of the patients (n = 10,117) underwent nonoperative management of their calcaneus fracture while 41% (n = 7,039) underwent open reduction and internal fixation. A multivariate logistic regression determined that variables like older age, female gender, being on Medicare, being African American or Hispanic, and having a lower estimated income by zip code were all associated with significantly lower use of surgical treatment (P less than .05). Not surprisingly, clinical comorbidities that were also associated with lower surgical rates included diabetes, peripheral vascular disease, a history of drug and alcohol abuse, and psychosis (P less than .05).

The authors acknowledged their study’s potential limitations, including a lack of research data on why these patients and providers chose surgery or otherwise. In addition, all available patient data came from a multicenter database, which can come with data entry issues. Finally, relying on data from only inpatient admissions “introduces a potential selection bias” by overrepresenting patients with “potentially more comorbidities and social issues.”

One author reported receiving consultant fees, speaker fees, and grant support from several organizations and medical corporations. The other authors reported no potential conflicts of interest.

SOURCE: Zelle BA et al. J Orthop Surg Res. 2019 Nov 12. doi: 10.1186/s13018-019-1402-8.

A variety of socio-demographic variables – including residing in a lower-income zip code and lacking private insurance – can influence treatment decisions for orthopedic trauma patients, according to a new study on the management of calcaneus fractures.

“While our study demonstrated socio-demographic disparities regarding utilization of open reduction and internal fixation of calcaneus fractures, the exact reasons for these disparities remain unclear,” wrote Boris A. Zelle, MD, of UT Health San Antonio and his coauthors. The study was published in the Journal of Orthopaedic Surgery and Research.

To assess how certain variables might impact how patients manage decisions regarding orthopedic trauma surgery, the researchers identified 17,156 patients with closed calcaneus fractures via the National Inpatient Sample (NIS) and analyzed their treatment and demographic data. The statistical analysis included variables such as age, sex, insurance status, race/ethnicity, income, hospital location, and hospital size. A total of 59% of the patients (n = 10,117) underwent nonoperative management of their calcaneus fracture while 41% (n = 7,039) underwent open reduction and internal fixation. A multivariate logistic regression determined that variables like older age, female gender, being on Medicare, being African American or Hispanic, and having a lower estimated income by zip code were all associated with significantly lower use of surgical treatment (P less than .05). Not surprisingly, clinical comorbidities that were also associated with lower surgical rates included diabetes, peripheral vascular disease, a history of drug and alcohol abuse, and psychosis (P less than .05).

The authors acknowledged their study’s potential limitations, including a lack of research data on why these patients and providers chose surgery or otherwise. In addition, all available patient data came from a multicenter database, which can come with data entry issues. Finally, relying on data from only inpatient admissions “introduces a potential selection bias” by overrepresenting patients with “potentially more comorbidities and social issues.”

One author reported receiving consultant fees, speaker fees, and grant support from several organizations and medical corporations. The other authors reported no potential conflicts of interest.

SOURCE: Zelle BA et al. J Orthop Surg Res. 2019 Nov 12. doi: 10.1186/s13018-019-1402-8.

A variety of socio-demographic variables – including residing in a lower-income zip code and lacking private insurance – can influence treatment decisions for orthopedic trauma patients, according to a new study on the management of calcaneus fractures.

“While our study demonstrated socio-demographic disparities regarding utilization of open reduction and internal fixation of calcaneus fractures, the exact reasons for these disparities remain unclear,” wrote Boris A. Zelle, MD, of UT Health San Antonio and his coauthors. The study was published in the Journal of Orthopaedic Surgery and Research.

To assess how certain variables might impact how patients manage decisions regarding orthopedic trauma surgery, the researchers identified 17,156 patients with closed calcaneus fractures via the National Inpatient Sample (NIS) and analyzed their treatment and demographic data. The statistical analysis included variables such as age, sex, insurance status, race/ethnicity, income, hospital location, and hospital size. A total of 59% of the patients (n = 10,117) underwent nonoperative management of their calcaneus fracture while 41% (n = 7,039) underwent open reduction and internal fixation. A multivariate logistic regression determined that variables like older age, female gender, being on Medicare, being African American or Hispanic, and having a lower estimated income by zip code were all associated with significantly lower use of surgical treatment (P less than .05). Not surprisingly, clinical comorbidities that were also associated with lower surgical rates included diabetes, peripheral vascular disease, a history of drug and alcohol abuse, and psychosis (P less than .05).

The authors acknowledged their study’s potential limitations, including a lack of research data on why these patients and providers chose surgery or otherwise. In addition, all available patient data came from a multicenter database, which can come with data entry issues. Finally, relying on data from only inpatient admissions “introduces a potential selection bias” by overrepresenting patients with “potentially more comorbidities and social issues.”

One author reported receiving consultant fees, speaker fees, and grant support from several organizations and medical corporations. The other authors reported no potential conflicts of interest.

SOURCE: Zelle BA et al. J Orthop Surg Res. 2019 Nov 12. doi: 10.1186/s13018-019-1402-8.

Question: Mr. M, a car mechanic, was treated with long-term ACTH and Kenalog after he developed severe contact dermatitis from daily exposure to petroleum-based solvents. His subsequent course was complicated by cataracts and osteoporosis. Which of the following is true in case he files a malpractice action?



A. Treatment with steroids was medically indicated for Mr. Mechanic’s dermatologic condition, so the doctor could not have breached the standard of care.

B. Under the “Learned Intermediary” doctrine, both the manufacturer and the prescribing doctor are jointly liable.

C. Corticosteroids are a known cause of osteoporosis and other complications, but not of cataracts, so that part of the malpractice action should be thrown out.

D. The plaintiff would prevail even if he could not find an expert witnesses to testify as to standard of care, since it is “common knowledge” that steroids cause osteoporosis.

E. Lack of informed consent may be his best legal theory of liability, as many jurisdictions now use the patient-centered standard, which does not require expert testimony.



Answer: E. The above hypothetical was modified from an old Montana case¹ in which the patient failed in his negligence lawsuit because he did not have expert witnesses to testify as to standard of care and to adequacy of warning label. However, in some jurisdictions under today’s case law, informed consent relies on a subjective, i.e., patient-oriented standard, and expert testimony is unnecessary to prove breach of duty, although still needed to prove causation.
 

Steroid-related litigation

Steroid-related malpractice litigation is quite prevalent. In a retrospective study of a tertiary medical center from 1996 to 2008, Nash and coworkers identified 83 such cases.² Steroids were prescribed for pain (23%), asthma or another pulmonary condition (20%), a dermatologic condition (18%), an autoimmune condition (17%), or allergies (6%).

Learned intermediary

“Drug reps” have a responsibility to inform doctors of both benefits and risks of their medications, a process termed “fair balance.” Generally speaking, if a doctor fails to warn the patient of a medication risk, and injury results, the patient may have a claim against the doctor but not the drug manufacturer. This is termed the “learned intermediary” doctrine, which is also applicable to medical devices such as dialysis equipment, breast implants, and blood products.

The justification is that manufacturers can reasonably rely on the treating doctor to warn of adverse effects, which are disclosed to the profession through their sales reps and in the package insert and PDR. The treating doctor, in turn, is expected to use his or her professional judgment to adequately warn the patient. It is simply not feasible for the manufacturer to directly warn every patient without usurping the doctor-patient relationship. However, where known complications were undisclosed to the FDA and the profession, then plaintiff attorneys can file class action lawsuits directed at the manufacturer.
 

Complications

Complications arising out of the use of steroids are typical examples of medical products liability. This may be on the basis of the doctor having prescribed the medication without a proper indication or where contraindicated, or may have prescribed “the wrong dose for the wrong patient by the wrong route.” In addition, there may have been a lack of informed consent, i.e., failure to explain the underlying condition and the material risks associated with using the drug. Other acts of negligence, e.g., vicarious liability, may also apply.

Corticosteroids such as Prednisone, Decadron, Kenalog, etc., are widely prescribed, and can cause serious complications, especially when used in high doses for extended periods. Examples include suppression of the immune system with supervening infections, steroid osteoporosis and fractures,³ aseptic necrosis, steroid diabetes, hypertension, emotional changes, weight gain, cataracts, neurological complications, and many others. As in all malpractice actions, the plaintiff bears the burden of proof covering the four requisite tort elements, i.e., duty, breach of duty, causation, and damages. Expert testimony is almost always needed in a professional negligence lawsuit.

Aseptic necrosis is a feared complication of steroid therapy.

A recent report⁴ featured a nurse in her 40s who developed aseptic necrosis of the right shoulder and both hips after taking high dose prednisone for 6 months. She was being treated for idiopathic thrombocytopenic purpura by a hematologist as well as sarcoidosis by a pulmonologist. The plaintiff claimed that both defendants negligently prescribed the medication for an extended period of time without proper monitoring, which caused her severe bone complications requiring a hip and shoulder replacement. The defendants maintained that the steroid medication was necessary to treat the life-threatening conditions from which the plaintiff suffered and that the dosage was carefully monitored and was not excessive. However, in a jury trial, the defendant hematologist and pulmonologist were each found 50% negligent, and the patient was awarded $4.1 million in damages.

In a case⁵ of steroid-related neurological sequelae, a Colorado jury awarded $14.9 million to a couple against an outpatient surgery center for negligently administering an epidural dose of Kenalog that rendered the patient paraplegic, and for failure to obtain informed consent. The jury awarded the woman, age 57, approximately $1.7 million in past and future medical expenses; $3.2 million in unspecified economic damages; and $6.5 million in past and future noneconomic damages such as pain and suffering. Her husband will receive $3.5 million in past and future noneconomic damages for loss of consortium, according to the verdict. Two years before the injection date of 2013, the drug maker had announced that Kenalog should not be used for epidural procedures because of cord complications including infarction and paraplegia.
 

Contributory role

The putative offending drug does not have to be the sole cause of injury; if it played a contributory role, the court may find the presence of liability. For example, a Kansas appeals court⁶ upheld a jury award of $2.88 million in the case of a 40-year-old man who took his life after neurologic complications followed an epidural injection. During one of patient’s visits for chronic low back pain, the defendant-anesthesiologist administered an epidural steroid injection into an area left swollen from a previous injection.

The patient developed neurologic symptoms, and lumbar puncture yielded green pus caused by methicillin-resistant Staphylococcus aureus. He went on to develop arachnoiditis, which left him with impotence, incontinence, and excruciating pain. His lawsuit contended the injection needle had passed through an infected edematous area, causing meningitis and arachnoiditis. Before the case went to trial, the patient took his life because of unremitting pain.

In March 2014, a Johnson County jury found the doctor 75% at fault and the clinic 25% at fault and awarded damages, which were reduced to $1.67 million because Kansas caps noneconomic damages at $250,000. The court rejected the defendants’ argument that the trial judge improperly instructed the jury it could find liability only if negligence “caused” rather than merely “contributed to” the patient’s death, holding that “... one who contributes to a wrongful death is a cause of that death as contemplated by the wrongful death statute.”
 

Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected] .
 

References

1. Hill v. Squibb Sons, E.R, 592 P.2d 1383 (Mont. 1979).

2. Nash JJ et al, Medical malpractice and corticosteroid use. Otolaryngol Head Neck Surg. 2011; 144:10-5.

3. Buckley L. et al, Glucocorticoid-Induced Osteoporosis. N Engl J Med 2018; 379:2547-56.

4. Zarin’s Jury Verdict: Review and Analysis. Article ID 40229, Philadelphia County.

5. Robbin Smith et al. v. The Surgery Center at Lone Tree, 2015-CV-30922, Douglas County District Court, Colo. Verdict for plaintiff, March 23, 2017.

6. Burnette v. Kimber L. Eubanks, M.D., & Paincare, P.A., 379 P.3d 372 (Kan. Ct. App. 2016).

Question: Mr. M, a car mechanic, was treated with long-term ACTH and Kenalog after he developed severe contact dermatitis from daily exposure to petroleum-based solvents. His subsequent course was complicated by cataracts and osteoporosis. Which of the following is true in case he files a malpractice action?



A. Treatment with steroids was medically indicated for Mr. Mechanic’s dermatologic condition, so the doctor could not have breached the standard of care.

B. Under the “Learned Intermediary” doctrine, both the manufacturer and the prescribing doctor are jointly liable.

C. Corticosteroids are a known cause of osteoporosis and other complications, but not of cataracts, so that part of the malpractice action should be thrown out.

D. The plaintiff would prevail even if he could not find an expert witnesses to testify as to standard of care, since it is “common knowledge” that steroids cause osteoporosis.

E. Lack of informed consent may be his best legal theory of liability, as many jurisdictions now use the patient-centered standard, which does not require expert testimony.



Answer: E. The above hypothetical was modified from an old Montana case¹ in which the patient failed in his negligence lawsuit because he did not have expert witnesses to testify as to standard of care and to adequacy of warning label. However, in some jurisdictions under today’s case law, informed consent relies on a subjective, i.e., patient-oriented standard, and expert testimony is unnecessary to prove breach of duty, although still needed to prove causation.
 

Steroid-related litigation

Steroid-related malpractice litigation is quite prevalent. In a retrospective study of a tertiary medical center from 1996 to 2008, Nash and coworkers identified 83 such cases.² Steroids were prescribed for pain (23%), asthma or another pulmonary condition (20%), a dermatologic condition (18%), an autoimmune condition (17%), or allergies (6%).

Learned intermediary

“Drug reps” have a responsibility to inform doctors of both benefits and risks of their medications, a process termed “fair balance.” Generally speaking, if a doctor fails to warn the patient of a medication risk, and injury results, the patient may have a claim against the doctor but not the drug manufacturer. This is termed the “learned intermediary” doctrine, which is also applicable to medical devices such as dialysis equipment, breast implants, and blood products.

The justification is that manufacturers can reasonably rely on the treating doctor to warn of adverse effects, which are disclosed to the profession through their sales reps and in the package insert and PDR. The treating doctor, in turn, is expected to use his or her professional judgment to adequately warn the patient. It is simply not feasible for the manufacturer to directly warn every patient without usurping the doctor-patient relationship. However, where known complications were undisclosed to the FDA and the profession, then plaintiff attorneys can file class action lawsuits directed at the manufacturer.
 

Complications

Complications arising out of the use of steroids are typical examples of medical products liability. This may be on the basis of the doctor having prescribed the medication without a proper indication or where contraindicated, or may have prescribed “the wrong dose for the wrong patient by the wrong route.” In addition, there may have been a lack of informed consent, i.e., failure to explain the underlying condition and the material risks associated with using the drug. Other acts of negligence, e.g., vicarious liability, may also apply.

Corticosteroids such as Prednisone, Decadron, Kenalog, etc., are widely prescribed, and can cause serious complications, especially when used in high doses for extended periods. Examples include suppression of the immune system with supervening infections, steroid osteoporosis and fractures,³ aseptic necrosis, steroid diabetes, hypertension, emotional changes, weight gain, cataracts, neurological complications, and many others. As in all malpractice actions, the plaintiff bears the burden of proof covering the four requisite tort elements, i.e., duty, breach of duty, causation, and damages. Expert testimony is almost always needed in a professional negligence lawsuit.

Aseptic necrosis is a feared complication of steroid therapy.

A recent report⁴ featured a nurse in her 40s who developed aseptic necrosis of the right shoulder and both hips after taking high dose prednisone for 6 months. She was being treated for idiopathic thrombocytopenic purpura by a hematologist as well as sarcoidosis by a pulmonologist. The plaintiff claimed that both defendants negligently prescribed the medication for an extended period of time without proper monitoring, which caused her severe bone complications requiring a hip and shoulder replacement. The defendants maintained that the steroid medication was necessary to treat the life-threatening conditions from which the plaintiff suffered and that the dosage was carefully monitored and was not excessive. However, in a jury trial, the defendant hematologist and pulmonologist were each found 50% negligent, and the patient was awarded $4.1 million in damages.

In a case⁵ of steroid-related neurological sequelae, a Colorado jury awarded $14.9 million to a couple against an outpatient surgery center for negligently administering an epidural dose of Kenalog that rendered the patient paraplegic, and for failure to obtain informed consent. The jury awarded the woman, age 57, approximately $1.7 million in past and future medical expenses; $3.2 million in unspecified economic damages; and $6.5 million in past and future noneconomic damages such as pain and suffering. Her husband will receive $3.5 million in past and future noneconomic damages for loss of consortium, according to the verdict. Two years before the injection date of 2013, the drug maker had announced that Kenalog should not be used for epidural procedures because of cord complications including infarction and paraplegia.
 

Contributory role

The putative offending drug does not have to be the sole cause of injury; if it played a contributory role, the court may find the presence of liability. For example, a Kansas appeals court⁶ upheld a jury award of $2.88 million in the case of a 40-year-old man who took his life after neurologic complications followed an epidural injection. During one of patient’s visits for chronic low back pain, the defendant-anesthesiologist administered an epidural steroid injection into an area left swollen from a previous injection.

The patient developed neurologic symptoms, and lumbar puncture yielded green pus caused by methicillin-resistant Staphylococcus aureus. He went on to develop arachnoiditis, which left him with impotence, incontinence, and excruciating pain. His lawsuit contended the injection needle had passed through an infected edematous area, causing meningitis and arachnoiditis. Before the case went to trial, the patient took his life because of unremitting pain.

In March 2014, a Johnson County jury found the doctor 75% at fault and the clinic 25% at fault and awarded damages, which were reduced to $1.67 million because Kansas caps noneconomic damages at $250,000. The court rejected the defendants’ argument that the trial judge improperly instructed the jury it could find liability only if negligence “caused” rather than merely “contributed to” the patient’s death, holding that “... one who contributes to a wrongful death is a cause of that death as contemplated by the wrongful death statute.”
 

Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected] .
 

References

1. Hill v. Squibb Sons, E.R, 592 P.2d 1383 (Mont. 1979).

2. Nash JJ et al, Medical malpractice and corticosteroid use. Otolaryngol Head Neck Surg. 2011; 144:10-5.

3. Buckley L. et al, Glucocorticoid-Induced Osteoporosis. N Engl J Med 2018; 379:2547-56.

4. Zarin’s Jury Verdict: Review and Analysis. Article ID 40229, Philadelphia County.

5. Robbin Smith et al. v. The Surgery Center at Lone Tree, 2015-CV-30922, Douglas County District Court, Colo. Verdict for plaintiff, March 23, 2017.

6. Burnette v. Kimber L. Eubanks, M.D., & Paincare, P.A., 379 P.3d 372 (Kan. Ct. App. 2016).

Question: Mr. M, a car mechanic, was treated with long-term ACTH and Kenalog after he developed severe contact dermatitis from daily exposure to petroleum-based solvents. His subsequent course was complicated by cataracts and osteoporosis. Which of the following is true in case he files a malpractice action?



A. Treatment with steroids was medically indicated for Mr. Mechanic’s dermatologic condition, so the doctor could not have breached the standard of care.

B. Under the “Learned Intermediary” doctrine, both the manufacturer and the prescribing doctor are jointly liable.

C. Corticosteroids are a known cause of osteoporosis and other complications, but not of cataracts, so that part of the malpractice action should be thrown out.

D. The plaintiff would prevail even if he could not find an expert witnesses to testify as to standard of care, since it is “common knowledge” that steroids cause osteoporosis.

E. Lack of informed consent may be his best legal theory of liability, as many jurisdictions now use the patient-centered standard, which does not require expert testimony.



Answer: E. The above hypothetical was modified from an old Montana case¹ in which the patient failed in his negligence lawsuit because he did not have expert witnesses to testify as to standard of care and to adequacy of warning label. However, in some jurisdictions under today’s case law, informed consent relies on a subjective, i.e., patient-oriented standard, and expert testimony is unnecessary to prove breach of duty, although still needed to prove causation.
 

Steroid-related litigation

Steroid-related malpractice litigation is quite prevalent. In a retrospective study of a tertiary medical center from 1996 to 2008, Nash and coworkers identified 83 such cases.² Steroids were prescribed for pain (23%), asthma or another pulmonary condition (20%), a dermatologic condition (18%), an autoimmune condition (17%), or allergies (6%).

Learned intermediary

“Drug reps” have a responsibility to inform doctors of both benefits and risks of their medications, a process termed “fair balance.” Generally speaking, if a doctor fails to warn the patient of a medication risk, and injury results, the patient may have a claim against the doctor but not the drug manufacturer. This is termed the “learned intermediary” doctrine, which is also applicable to medical devices such as dialysis equipment, breast implants, and blood products.

The justification is that manufacturers can reasonably rely on the treating doctor to warn of adverse effects, which are disclosed to the profession through their sales reps and in the package insert and PDR. The treating doctor, in turn, is expected to use his or her professional judgment to adequately warn the patient. It is simply not feasible for the manufacturer to directly warn every patient without usurping the doctor-patient relationship. However, where known complications were undisclosed to the FDA and the profession, then plaintiff attorneys can file class action lawsuits directed at the manufacturer.
 

Complications

Complications arising out of the use of steroids are typical examples of medical products liability. This may be on the basis of the doctor having prescribed the medication without a proper indication or where contraindicated, or may have prescribed “the wrong dose for the wrong patient by the wrong route.” In addition, there may have been a lack of informed consent, i.e., failure to explain the underlying condition and the material risks associated with using the drug. Other acts of negligence, e.g., vicarious liability, may also apply.

Corticosteroids such as Prednisone, Decadron, Kenalog, etc., are widely prescribed, and can cause serious complications, especially when used in high doses for extended periods. Examples include suppression of the immune system with supervening infections, steroid osteoporosis and fractures,³ aseptic necrosis, steroid diabetes, hypertension, emotional changes, weight gain, cataracts, neurological complications, and many others. As in all malpractice actions, the plaintiff bears the burden of proof covering the four requisite tort elements, i.e., duty, breach of duty, causation, and damages. Expert testimony is almost always needed in a professional negligence lawsuit.

Aseptic necrosis is a feared complication of steroid therapy.

A recent report⁴ featured a nurse in her 40s who developed aseptic necrosis of the right shoulder and both hips after taking high dose prednisone for 6 months. She was being treated for idiopathic thrombocytopenic purpura by a hematologist as well as sarcoidosis by a pulmonologist. The plaintiff claimed that both defendants negligently prescribed the medication for an extended period of time without proper monitoring, which caused her severe bone complications requiring a hip and shoulder replacement. The defendants maintained that the steroid medication was necessary to treat the life-threatening conditions from which the plaintiff suffered and that the dosage was carefully monitored and was not excessive. However, in a jury trial, the defendant hematologist and pulmonologist were each found 50% negligent, and the patient was awarded $4.1 million in damages.

In a case⁵ of steroid-related neurological sequelae, a Colorado jury awarded $14.9 million to a couple against an outpatient surgery center for negligently administering an epidural dose of Kenalog that rendered the patient paraplegic, and for failure to obtain informed consent. The jury awarded the woman, age 57, approximately $1.7 million in past and future medical expenses; $3.2 million in unspecified economic damages; and $6.5 million in past and future noneconomic damages such as pain and suffering. Her husband will receive $3.5 million in past and future noneconomic damages for loss of consortium, according to the verdict. Two years before the injection date of 2013, the drug maker had announced that Kenalog should not be used for epidural procedures because of cord complications including infarction and paraplegia.
 

Contributory role

The putative offending drug does not have to be the sole cause of injury; if it played a contributory role, the court may find the presence of liability. For example, a Kansas appeals court⁶ upheld a jury award of $2.88 million in the case of a 40-year-old man who took his life after neurologic complications followed an epidural injection. During one of patient’s visits for chronic low back pain, the defendant-anesthesiologist administered an epidural steroid injection into an area left swollen from a previous injection.

The patient developed neurologic symptoms, and lumbar puncture yielded green pus caused by methicillin-resistant Staphylococcus aureus. He went on to develop arachnoiditis, which left him with impotence, incontinence, and excruciating pain. His lawsuit contended the injection needle had passed through an infected edematous area, causing meningitis and arachnoiditis. Before the case went to trial, the patient took his life because of unremitting pain.

In March 2014, a Johnson County jury found the doctor 75% at fault and the clinic 25% at fault and awarded damages, which were reduced to $1.67 million because Kansas caps noneconomic damages at $250,000. The court rejected the defendants’ argument that the trial judge improperly instructed the jury it could find liability only if negligence “caused” rather than merely “contributed to” the patient’s death, holding that “... one who contributes to a wrongful death is a cause of that death as contemplated by the wrongful death statute.”
 

Dr. Tan is professor emeritus of medicine and former adjunct professor of law at the University of Hawaii. This article is meant to be educational and does not constitute medical, ethical, or legal advice. For additional information, readers may contact the author at [email protected] .
 

References

1. Hill v. Squibb Sons, E.R, 592 P.2d 1383 (Mont. 1979).

2. Nash JJ et al, Medical malpractice and corticosteroid use. Otolaryngol Head Neck Surg. 2011; 144:10-5.

3. Buckley L. et al, Glucocorticoid-Induced Osteoporosis. N Engl J Med 2018; 379:2547-56.

4. Zarin’s Jury Verdict: Review and Analysis. Article ID 40229, Philadelphia County.

5. Robbin Smith et al. v. The Surgery Center at Lone Tree, 2015-CV-30922, Douglas County District Court, Colo. Verdict for plaintiff, March 23, 2017.

6. Burnette v. Kimber L. Eubanks, M.D., & Paincare, P.A., 379 P.3d 372 (Kan. Ct. App. 2016).

ORLANDO – There’s a new Choosing Wisely list in hematology focused specifically on children, with five tests or procedures that experts advise should be avoided, with some exceptions.

The list, which was produced by an expert panel with representatives from the American Society of Hematology and the American Society of Pediatric Hematology/Oncology (ASPHO), includes five tests or procedures that are considered unnecessary. The recommendations were released at the annual meeting of the American Society of Hematology.

The five recommendations are:

• Don’t perform routine preoperative hemostatic testing in an otherwise healthy child with no prior personal or family history of bleeding.
• Don’t transfuse platelets in a nonbleeding pediatric patient with a platelet count greater than 10,000/mcL, unless other signs of bleeding are present, or if the patient is set to undergo an invasive procedure.
• Don’t order thrombophilia testing on children with venous access-associated thrombosis in the absence of a positive family history.
• Don’t transfuse packed RBCs for iron-deficiency anemia in asymptomatic pediatric patients when there is no evidence of hemodynamic instability or active bleeding.
• Don’t routinely administer granulocyte colony–stimulating factor (G-CSF) for empiric treatment of pediatric patients with asymptomatic autoimmune neutropenia in the absence of recurrent or severe bacterial and/or fungal infections.

This is the third Choosing Wisely list produced by ASH. The group released the first list in 2013 and the second in 2014. But officials at both ASH and ASPHO have received feedback over the years that there should also be a pediatric-focused list in hematology, said Sarah O’Brien, MD, of Nationwide Children’s Hospital in Columbus, Ohio, and cochair of the expert panel that put together the recommendations.

Hemostatic testing

The panel recommended against preoperative hemostatic screening in healthy children with no personal or family history of excessive bleeding because the test does not effectively predict who will have unexpected surgical bleeding. The testing could instead identify artifacts or disorders unrelated to bleeding risk, such as factor XII deficiency or an infection-associated, transient lupus anticoagulant, according to Veronica H. Flood, MD, of the Medical College of Wisconsin, Milwaukee, and a member of the expert panel.

Performing this type of testing also adds cost and stress for families, and often delays surgery.

A look at the current literature reveals that there is little evidence to support coagulation testing in healthy children undergoing surgery. “Despite all this evidence, there remain practitioners who perform such screening on a regular basis,” Dr. Flood said.

For physicians concerned about bleeding risk, Dr. Flood said that existing guidelines support taking a bleeding history in preoperative patients. “This may take a little more time, but in the end will result in better results and less expense.”

Platelet transfusion

The panel recommended against platelet transfusion in nonbleeding pediatric patients with hypoproliferative thrombocytopenia and a platelet count greater than 10,000/mcL. The caveats for this recommendation are that it does not apply if there are other signs or symptoms of bleeding, if the patient is undergoing an invasive procedure, if the patient is aged 1 year or younger, or if the patient has immune-mediated thrombocytopenia, according to Rachel Bercovitz, MD, of the Ann & Robert H. Lurie Children’s Hospital of Chicago and a member of the expert panel.

Previous studies on the platelet transfusions in patients with hematologic malignancies have shown that 10,000/mcL is the appropriate threshold, with no difference in bleeding above that number and increased bleeding below it, Dr. Bercovitz said.

Additionally, while platelet transfusion is a safe procedure, Dr. Bercovitz said, it is not without acute and long-term risks.

Cost is also a factor. “Platelets are a limited and expensive resource,” she said.

Thrombophilia testing

Thrombophilia testing in children with a central venous catheter-associated thrombosis was once common practice but should be avoided, explained Leslie J. Raffini, MD, of the Children’s Hospital of Philadelphia and a member of the expert panel.

Thrombophilia does not influence the initial management of a first episode of provoked venous thrombosis, it does not inform the intensity of duration of anticoagulant therapy, and it does not predict recurrence of venous thrombosis in children, Dr. Raffini said.

In the 2013 Choosing Wisely list, ASH made the same recommendation against testing in adult patients with venous thromboembolism occurring in the setting of major transient risk factors. Thrombophilia testing is also expensive, often has to be repeated, and can be misinterpreted, Dr. Raffini said.

Packed RBC transfusion

The panel recommended against transfusion with packed RBCs for children with iron-deficiency anemia who have no symptoms and no evidence of hemodynamic instability or active bleeding. Transfusion is appropriate if children are symptomatic or are hemodynamically unstable, said Patrick T. McGann, MD, of Cincinnati Children’s Hospital and a member of the expert panel.

Rather than jump to transfusion, Dr. McGann said this group of asymptomatic and hemodynamically stable children should be treated for their iron deficiency through oral or intravenous iron. “This is not about ignoring iron deficiency.”

Both are effective treatments with multiple options available, he said. But sending a child to the hospital for transfusion is a costly option that is stressful for families and only provides a temporary solution to the issue, since treatment of the underlying iron deficiency still needs to be addressed, Dr. McGann said.

G-CSF treatment

The panel also recommended against routine administration of G-CSF in children with asymptomatic autoimmune neutropenia. Peter E. Newburger, MD, of Boston Children’s Hospital and a member of the expert guideline panel, said that there is limited evidence available and no published guidelines in this area, so the panel was guided by expert opinion.

In most cases, G-CSF is not necessary because autoimmune neutropenia resolves spontaneously by age 4-5 years and the risk of serious infection is extremely low. Appropriate management includes antibiotics for acute bacterial infection, good dental hygiene, and continued immunizations, Dr. Newburger said.

G-CSF may be appropriate in limited cases to improve quality of life, but it should be started at a low dose of 1-2 mcg/kg.

In cases of serious infection, Dr. Newburger said physicians should consider alternative diagnoses, such as congenital neutropenia or myelodysplastic syndromes.

[email protected]

ORLANDO – There’s a new Choosing Wisely list in hematology focused specifically on children, with five tests or procedures that experts advise should be avoided, with some exceptions.

The list, which was produced by an expert panel with representatives from the American Society of Hematology and the American Society of Pediatric Hematology/Oncology (ASPHO), includes five tests or procedures that are considered unnecessary. The recommendations were released at the annual meeting of the American Society of Hematology.

The five recommendations are:

• Don’t perform routine preoperative hemostatic testing in an otherwise healthy child with no prior personal or family history of bleeding.
• Don’t transfuse platelets in a nonbleeding pediatric patient with a platelet count greater than 10,000/mcL, unless other signs of bleeding are present, or if the patient is set to undergo an invasive procedure.
• Don’t order thrombophilia testing on children with venous access-associated thrombosis in the absence of a positive family history.
• Don’t transfuse packed RBCs for iron-deficiency anemia in asymptomatic pediatric patients when there is no evidence of hemodynamic instability or active bleeding.
• Don’t routinely administer granulocyte colony–stimulating factor (G-CSF) for empiric treatment of pediatric patients with asymptomatic autoimmune neutropenia in the absence of recurrent or severe bacterial and/or fungal infections.

This is the third Choosing Wisely list produced by ASH. The group released the first list in 2013 and the second in 2014. But officials at both ASH and ASPHO have received feedback over the years that there should also be a pediatric-focused list in hematology, said Sarah O’Brien, MD, of Nationwide Children’s Hospital in Columbus, Ohio, and cochair of the expert panel that put together the recommendations.

Hemostatic testing

The panel recommended against preoperative hemostatic screening in healthy children with no personal or family history of excessive bleeding because the test does not effectively predict who will have unexpected surgical bleeding. The testing could instead identify artifacts or disorders unrelated to bleeding risk, such as factor XII deficiency or an infection-associated, transient lupus anticoagulant, according to Veronica H. Flood, MD, of the Medical College of Wisconsin, Milwaukee, and a member of the expert panel.

Performing this type of testing also adds cost and stress for families, and often delays surgery.

A look at the current literature reveals that there is little evidence to support coagulation testing in healthy children undergoing surgery. “Despite all this evidence, there remain practitioners who perform such screening on a regular basis,” Dr. Flood said.

For physicians concerned about bleeding risk, Dr. Flood said that existing guidelines support taking a bleeding history in preoperative patients. “This may take a little more time, but in the end will result in better results and less expense.”

Platelet transfusion

The panel recommended against platelet transfusion in nonbleeding pediatric patients with hypoproliferative thrombocytopenia and a platelet count greater than 10,000/mcL. The caveats for this recommendation are that it does not apply if there are other signs or symptoms of bleeding, if the patient is undergoing an invasive procedure, if the patient is aged 1 year or younger, or if the patient has immune-mediated thrombocytopenia, according to Rachel Bercovitz, MD, of the Ann & Robert H. Lurie Children’s Hospital of Chicago and a member of the expert panel.

Previous studies on the platelet transfusions in patients with hematologic malignancies have shown that 10,000/mcL is the appropriate threshold, with no difference in bleeding above that number and increased bleeding below it, Dr. Bercovitz said.

Additionally, while platelet transfusion is a safe procedure, Dr. Bercovitz said, it is not without acute and long-term risks.

Cost is also a factor. “Platelets are a limited and expensive resource,” she said.

Thrombophilia testing

Thrombophilia testing in children with a central venous catheter-associated thrombosis was once common practice but should be avoided, explained Leslie J. Raffini, MD, of the Children’s Hospital of Philadelphia and a member of the expert panel.

Thrombophilia does not influence the initial management of a first episode of provoked venous thrombosis, it does not inform the intensity of duration of anticoagulant therapy, and it does not predict recurrence of venous thrombosis in children, Dr. Raffini said.

In the 2013 Choosing Wisely list, ASH made the same recommendation against testing in adult patients with venous thromboembolism occurring in the setting of major transient risk factors. Thrombophilia testing is also expensive, often has to be repeated, and can be misinterpreted, Dr. Raffini said.

Packed RBC transfusion

The panel recommended against transfusion with packed RBCs for children with iron-deficiency anemia who have no symptoms and no evidence of hemodynamic instability or active bleeding. Transfusion is appropriate if children are symptomatic or are hemodynamically unstable, said Patrick T. McGann, MD, of Cincinnati Children’s Hospital and a member of the expert panel.

Rather than jump to transfusion, Dr. McGann said this group of asymptomatic and hemodynamically stable children should be treated for their iron deficiency through oral or intravenous iron. “This is not about ignoring iron deficiency.”

Both are effective treatments with multiple options available, he said. But sending a child to the hospital for transfusion is a costly option that is stressful for families and only provides a temporary solution to the issue, since treatment of the underlying iron deficiency still needs to be addressed, Dr. McGann said.

G-CSF treatment

The panel also recommended against routine administration of G-CSF in children with asymptomatic autoimmune neutropenia. Peter E. Newburger, MD, of Boston Children’s Hospital and a member of the expert guideline panel, said that there is limited evidence available and no published guidelines in this area, so the panel was guided by expert opinion.

In most cases, G-CSF is not necessary because autoimmune neutropenia resolves spontaneously by age 4-5 years and the risk of serious infection is extremely low. Appropriate management includes antibiotics for acute bacterial infection, good dental hygiene, and continued immunizations, Dr. Newburger said.

G-CSF may be appropriate in limited cases to improve quality of life, but it should be started at a low dose of 1-2 mcg/kg.

In cases of serious infection, Dr. Newburger said physicians should consider alternative diagnoses, such as congenital neutropenia or myelodysplastic syndromes.

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ORLANDO – There’s a new Choosing Wisely list in hematology focused specifically on children, with five tests or procedures that experts advise should be avoided, with some exceptions.

The list, which was produced by an expert panel with representatives from the American Society of Hematology and the American Society of Pediatric Hematology/Oncology (ASPHO), includes five tests or procedures that are considered unnecessary. The recommendations were released at the annual meeting of the American Society of Hematology.

The five recommendations are:

• Don’t perform routine preoperative hemostatic testing in an otherwise healthy child with no prior personal or family history of bleeding.
• Don’t transfuse platelets in a nonbleeding pediatric patient with a platelet count greater than 10,000/mcL, unless other signs of bleeding are present, or if the patient is set to undergo an invasive procedure.
• Don’t order thrombophilia testing on children with venous access-associated thrombosis in the absence of a positive family history.
• Don’t transfuse packed RBCs for iron-deficiency anemia in asymptomatic pediatric patients when there is no evidence of hemodynamic instability or active bleeding.
• Don’t routinely administer granulocyte colony–stimulating factor (G-CSF) for empiric treatment of pediatric patients with asymptomatic autoimmune neutropenia in the absence of recurrent or severe bacterial and/or fungal infections.

This is the third Choosing Wisely list produced by ASH. The group released the first list in 2013 and the second in 2014. But officials at both ASH and ASPHO have received feedback over the years that there should also be a pediatric-focused list in hematology, said Sarah O’Brien, MD, of Nationwide Children’s Hospital in Columbus, Ohio, and cochair of the expert panel that put together the recommendations.

Hemostatic testing

The panel recommended against preoperative hemostatic screening in healthy children with no personal or family history of excessive bleeding because the test does not effectively predict who will have unexpected surgical bleeding. The testing could instead identify artifacts or disorders unrelated to bleeding risk, such as factor XII deficiency or an infection-associated, transient lupus anticoagulant, according to Veronica H. Flood, MD, of the Medical College of Wisconsin, Milwaukee, and a member of the expert panel.

Performing this type of testing also adds cost and stress for families, and often delays surgery.

A look at the current literature reveals that there is little evidence to support coagulation testing in healthy children undergoing surgery. “Despite all this evidence, there remain practitioners who perform such screening on a regular basis,” Dr. Flood said.

For physicians concerned about bleeding risk, Dr. Flood said that existing guidelines support taking a bleeding history in preoperative patients. “This may take a little more time, but in the end will result in better results and less expense.”

Platelet transfusion

The panel recommended against platelet transfusion in nonbleeding pediatric patients with hypoproliferative thrombocytopenia and a platelet count greater than 10,000/mcL. The caveats for this recommendation are that it does not apply if there are other signs or symptoms of bleeding, if the patient is undergoing an invasive procedure, if the patient is aged 1 year or younger, or if the patient has immune-mediated thrombocytopenia, according to Rachel Bercovitz, MD, of the Ann & Robert H. Lurie Children’s Hospital of Chicago and a member of the expert panel.

Previous studies on the platelet transfusions in patients with hematologic malignancies have shown that 10,000/mcL is the appropriate threshold, with no difference in bleeding above that number and increased bleeding below it, Dr. Bercovitz said.

Additionally, while platelet transfusion is a safe procedure, Dr. Bercovitz said, it is not without acute and long-term risks.

Cost is also a factor. “Platelets are a limited and expensive resource,” she said.

Thrombophilia testing

Thrombophilia testing in children with a central venous catheter-associated thrombosis was once common practice but should be avoided, explained Leslie J. Raffini, MD, of the Children’s Hospital of Philadelphia and a member of the expert panel.

Thrombophilia does not influence the initial management of a first episode of provoked venous thrombosis, it does not inform the intensity of duration of anticoagulant therapy, and it does not predict recurrence of venous thrombosis in children, Dr. Raffini said.

In the 2013 Choosing Wisely list, ASH made the same recommendation against testing in adult patients with venous thromboembolism occurring in the setting of major transient risk factors. Thrombophilia testing is also expensive, often has to be repeated, and can be misinterpreted, Dr. Raffini said.

Packed RBC transfusion

The panel recommended against transfusion with packed RBCs for children with iron-deficiency anemia who have no symptoms and no evidence of hemodynamic instability or active bleeding. Transfusion is appropriate if children are symptomatic or are hemodynamically unstable, said Patrick T. McGann, MD, of Cincinnati Children’s Hospital and a member of the expert panel.

Rather than jump to transfusion, Dr. McGann said this group of asymptomatic and hemodynamically stable children should be treated for their iron deficiency through oral or intravenous iron. “This is not about ignoring iron deficiency.”

Both are effective treatments with multiple options available, he said. But sending a child to the hospital for transfusion is a costly option that is stressful for families and only provides a temporary solution to the issue, since treatment of the underlying iron deficiency still needs to be addressed, Dr. McGann said.

G-CSF treatment

The panel also recommended against routine administration of G-CSF in children with asymptomatic autoimmune neutropenia. Peter E. Newburger, MD, of Boston Children’s Hospital and a member of the expert guideline panel, said that there is limited evidence available and no published guidelines in this area, so the panel was guided by expert opinion.

In most cases, G-CSF is not necessary because autoimmune neutropenia resolves spontaneously by age 4-5 years and the risk of serious infection is extremely low. Appropriate management includes antibiotics for acute bacterial infection, good dental hygiene, and continued immunizations, Dr. Newburger said.

G-CSF may be appropriate in limited cases to improve quality of life, but it should be started at a low dose of 1-2 mcg/kg.

In cases of serious infection, Dr. Newburger said physicians should consider alternative diagnoses, such as congenital neutropenia or myelodysplastic syndromes.

[email protected]