User login
Think twice: Choosing Wisely recommendations on testing to avoid in pediatric hematology
ORLANDO – There’s 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.
ORLANDO – There’s 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.
ORLANDO – There’s 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.
REPORTING FROM ASH 2019
Novel approaches to treating NASH in diabetes
BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.
Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.
Currently, no medications for NAFLD or NASH have been approved in the United States.
CENTAUR with cenicriviroc
Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.
CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m2, and just more than half the patients (52%) had type 2 diabetes.
The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.
Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.
Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).
In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.
Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.
The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.
Tirzepatide for NASH
Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.
Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.
The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.
The study population was typical of type 2 diabetes: baseline HbA1c was 8.1%; the average body mass index was 32 kg/m2, with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.
The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.
Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).
Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.
At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”
By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).
“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.
That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”
DURATION-8: Exenatide plus dapagliflozin
In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.
“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.
The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.
A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.
At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.
At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).
Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”
The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.
SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.
BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.
Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.
Currently, no medications for NAFLD or NASH have been approved in the United States.
CENTAUR with cenicriviroc
Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.
CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m2, and just more than half the patients (52%) had type 2 diabetes.
The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.
Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.
Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).
In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.
Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.
The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.
Tirzepatide for NASH
Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.
Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.
The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.
The study population was typical of type 2 diabetes: baseline HbA1c was 8.1%; the average body mass index was 32 kg/m2, with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.
The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.
Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).
Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.
At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”
By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).
“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.
That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”
DURATION-8: Exenatide plus dapagliflozin
In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.
“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.
The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.
A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.
At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.
At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).
Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”
The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.
SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.
BARCELONA – The investigational oral agent cenicriviroc showed positive effects on liver fibrosis in adults with nonalcoholic steatohepatitis (NASH), many of whom had type 2 diabetes, in a phase 2b trial reported at the annual meeting of the European Association for the Study of Diabetes.
Other data released at the meeting, which showed potential positive effects of novel or existing diabetes treatments on nonalcoholic fatty liver disease (NAFLD), included post hoc analyses of a phase 2b study with tirzepatide and a phase 3 study that combined exenatide and dapagliflozin.
Currently, no medications for NAFLD or NASH have been approved in the United States.
CENTAUR with cenicriviroc
Results of the previously reported CENTAUR trial showed that the antifibrotic effects of cenicriviroc, a dual chemokine receptor antagonist, were greatest in patients with more-severe liver disease (Hepatology. 2018;67[5]:1754-67). At the meeting, Henrik Landgren, PhD, of Allergan, presented data from the 2-year trial overall, and specifically in patients with advanced, stage 3 fibrosis.
CENTAUR was a randomized, double-blind, placebo-controlled, multinational study with 289 adults who had biopsy-confirmed NASH, an NAFLD Activity Score (NAS; range, 0-8; score of 5 or more diagnostic of NASH) of 4 or more, and stages 1-3 liver fibrosis as determined by the NASH clinical research network system (Contemp Clin Trials. 2016;47:356-65). The mean age of the patients enrolled at baseline was 54 years, the mean body mass index was 33.9 kg/m2, and just more than half the patients (52%) had type 2 diabetes.
The patients were randomized to three treatment arms: cenicriviroc 150 mg for 2 years; placebo for 1 year, then cenicriviroc 150 mg for 1 year; or placebo for 2 years. The primary endpoint was histologic improvement (reduction of 2 or more points in overall NAS, with reduction of 1 or more points in more than one category of the NAS without worsening of fibrosis at the end of year 1. The key secondary endpoint was complete NASH resolution without worsening of fibrosis at year 2.
Dr. Landgren reported that, at year 1, of the total number of patients, 28.6% of those receiving cenicriviroc achieved an improvement in fibrosis of one or more stages, compared with 19.0% of those receiving placebo. Of the 97 patients who had advanced fibrosis at baseline, 38.3% of those on cenicriviroc and 28.0% of those on placebo achieved the same endpoint.
Those effects were sustained at year 2, Dr. Landgren emphasized, with twice as many cenicriviroc- than placebo-treated patients achieving one or more stage improvement in fibrosis and no worsening of NASH at year 2 (60% and 30%, respectively), with more pronounced improvements in those who had advanced fibrosis at baseline (86% and 60%).
In addition, analyses of biomarkers suggested that cenicriviroc had systematic anti-inflammatory activity, with reductions observed in high-sensitivity C-reactive protein; fibrinogen; and levels of interleukin-6, IL-8, and IL-1-beta.
Dr. Landgren and colleagues noted that cenicriviroc provided antifibrotic benefit in patients with NASH and fibrosis. Those benefits were sustained through year 2 and were more pronounced in patients who had advanced fibrosis at baseline.
The safety of cenicriviroc was “comparable with placebo,” he said, suggesting that the data supported the phase 3 AURORA study that is currently recruiting.
Tirzepatide for NASH
Another approach worth exploring for the treatment of NASH, is the use of tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and the glucagonlike peptide–1 (GLP-1) receptor, according to Axel Haupt, MD, PhD, of Eli Lilly.
Tirzepatide (LY3298176) is currently under investigation for the treatment of type 2 diabetes, and Dr. Haupt reported data from a post hoc analysis of a double-blind, placebo-controlled, phase 2b study showing that “exploratory” serum markers of apoptosis and fibrosis – keratin-18 (K-18) and Pro-C3, respectively – were decreased from baseline to a greater extent in patients treated with tirzepatide than with placebo, while total adiponectin was increased. The latter is “thought to protect the liver from inflammation and fibrosis,” Dr. Haupt observed.
The main results of the trial were published last year (Lancet. 2018;392:2180-93) and showed that, after 26 weeks, there was a dose-dependent decrease in both glycated hemoglobin (HbA1c) and body weight with tirzepatide 10 mg and 15 mg, compared with placebo and an active comparator, dulaglutide 1.5 mg.
The study population was typical of type 2 diabetes: baseline HbA1c was 8.1%; the average body mass index was 32 kg/m2, with a diabetes duration of 5 years; and the main treatment (90%) had been metformin.
The rationale for the NASH-related biomarker analysis was that type 2 diabetes and NAFLD were known to be overlapping conditions, and weight loss had been shown to be an effective means of resolving NASH, Dr. Haupt said. In addition, a small “proof-of-concept” study with the GLP-1 receptor agonist liraglutide had suggested that these drugs may be effective in NASH.
Tirzepatide, at doses of 5, 10, and 15 mg, was associated with significant decreases in K-18 from baseline to week 26 and compared with placebo and the 1-mg tirzepatide dose. Mean baseline concentrations of K-18 were 394.4 U/L in the placebo group and reduced by 22.6 U/L by week 26. Corresponding baseline values for tirzepatide 5 mg were 375.8 U/L (change, –87.6 U/L); for 10 mg, 409.9 U/L (–157.8 U/L); and for 15 mg, 376.2 U/L (–110.6 U/L).
Dr. Haupt noted that a K-18 value of 250 U/L was considered a cutoff for a diagnosis of NASH. “So we really think that we have some NASH patients in this population,” he observed.
At week 26, Pro-C3 levels significantly decreased by 1.2 ng/mL from a baseline of 8.6 ng/mL with tirzepatide 15 mg, compared with an increase of 0.9 ng/mL from a baseline of 9.3 ng/mL for placebo (P less than .05). However, values of between 15-20 ng/mL would be expected for advanced fibrosis, Dr. Haupt said, “so we think we [don’t] have a lot of patients with advanced fibrosis, we have a lower grade of fibrosis or no fibrosis in our patient population.”
By week 26, adiponectin levels significantly increased by 0.9 mg/L from baseline, both with tirzepatide 10 mg (P less than .05) and 15 mg (P less than .05), compared with placebo (–0.1 mg/L; both P less than .05).
“This study was really designed as a type 2 diabetes efficacy study, so the NASH biomarker work is exploratory and only hypothesis generating,” Dr. Haupt noted. “We think there is overlap in type 2 diabetes and NASH, but it is not an ideal population to look into those biomarkers.” There are also other limitations, such as the baseline values across treatment groups not being matched, so there is likely to be some inconsistency in these data, he added.
That said, Dr. Haupt concluded that, “along with the weight-loss findings,” these exploratory biomarker findings supported the further evaluation of tirzepatide in patients with NASH.”
DURATION-8: Exenatide plus dapagliflozin
In another hypothesis-generating post hoc analysis, this time of the phase 3 DURATION-8 clinical trial, a combination of exenatide and dapagliflozin was found to have a beneficial effect on markers of hepatic steatosis and fibrosis in patients with type 2 diabetes.
“We have some good evidence that both GLP-1 receptor agonists and SGLT2 [sodium-glucose cotransporter 2] inhibitors may have benefits in reducing steatosis and even steatohepatitis in [patients with] type 2 diabetes. So the association of two diabetes drugs might provide an advantage. However, this had not previously been tested in a randomized, controlled trial,” observed Cristian Guja, MD, PhD, of Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.
The main aims of the DURATION-8 clinical trial, which ran for 104 weeks, was to compare the efficacy and safety of combining exenatide (2 mg, once a week) and dapagliflozin (10 mg, daily) with either exenatide 2 mg with placebo or dapagliflozin 10 mg with placebo. Results showed greater improved glycemic control and reductions in body weight and systolic BP with the exenatide-dapagliflozin combination.
A total of 685 patients were included in the post hoc analysis, of whom 228 had been treated with the combination, 228 with exenatide plus placebo, and 230 with dapagliflozin plus placebo. At baseline, levels of the markers of NAFLD and fibrosis that were assessed were similar between the groups. Between 81% and 93% of study participants had fatty liver or steatosis as defined by a Fatty Liver Index (FLI) of 60 or more or an overall NAFLD Liver Fat Score (NLFS) of –0.64 or higher. Between 9% and 13% of patients had liver fibrosis, as defined as an NAFLD Fibrosis Score (NFS) above 0.676, a Fibrosis-4 score (FIB-4) of 1.46 or more, or both.
At 28 weeks, the proportion of patients with biomarker scores suggestive of fatty liver disease or steatosis was significantly reduced from baseline with the exenatide-dapagliflozin combination (–10.5% for FLI of 60 or more; –6.5% for NLFS of –0.640 or more), Dr. Guja said, and biomarker scores suggestive of advanced fibrosis (NFS greater than 0.676; FIB-4 of 1.46 or more) were reduced by 4.1% and 3.6%, respectively.
At 28 and 52 weeks, the combination therapy showed stronger effects than exenatide and dapagliflozin alone in improving markers of hepatic steatosis (FLI: 28 weeks, –6.81, –3.90, –4.04; and 52 weeks, –6.23, –3.00, –4.58). The combination therapy also showed improvement for advanced fibrosis biomarkers at both time points (FIB-4: 28 weeks, –0.06, –0.03, –0.04; and 52 weeks, –0.05, –0.02, –0,04).
Dr. Guja noted that, although the study was not powered to assess the effect of on fatty liver, making all these data exploratory, this was the first analysis to describe improvements in biomarkers of fatty liver or steatosis and fibrosis from a large trial. “Some specific, dedicated, prospective trials are needed in the future to validate these findings.”
The CENTAUR study was funded by Allergan, of which Dr. Landgren is an employee. The phase 2b study with tirzepatide was supported by Eli Lilly. Dr. Haupt disclosed being an employee and also holding stocks in the company. The DURATION-8 study was sponsored by AstraZeneca. Dr. Guja disclosed that he had participated in scientific advisory boards and received consulting fees from AstraZeneca and other companies.
SOURCES: Landgren H et al. EASD 2019, Oral Presentation 179; Haupt A et al. EASD 2019, Oral Presentation 177; Guja C et al. EASD 2019, Oral Presentation 178.
REPORTING FROM EASD 2019
Unit-based rounding in the real world
Balance and flexibility are essential
Many hospitalists agree that their most productive and also sometimes least productive work can happen in the setting of interdisciplinary rounds. How can this paradox be true?
Most hospitals strive to assemble the health care team every day for a brief discussion of each patient’s needs as well as barriers to a safe/successful discharge. On most floors this requires a well-choreographed “dance” of nurses, case managers, social workers, physicians, and advanced practice providers coming together at agreed-upon times. All team members commit to efficient synchronized swimming through the most high-yield details for each patient in order to benefit the patients and families being served.
Of course, there are always challenges to this process in the unpredictable world of patients with acute needs. One variable that is at least partially controllable and tends to promote a more cohesive interdisciplinary experience is that of hospitalist unit-based rounding.
The 2018 State of Hospital Medicine (SoHM) survey reveals that 68% of hospital medicine groups serving adults with greater than 30 physicians employ some degree of unit-based rounding; this trend decreases with smaller group size. About 54% of academic hospital medicine groups use some amount of unit-based rounding. Not surprisingly, smaller hospitals are less likely to have this routine, likely because of fewer total nursing units.
One of the most obvious benefits to unit-based rounding is that the physician or advanced practice provider is more reliably able to participate in the interdisciplinary discussions that day. When more of the team members are at the table each day, patients and families have the best chance of hearing a consistent message around the treatment and discharge plans.
There are challenges to unit-based rounding as well. If patients transfer to different floors for any variety of reasons, strict unit-based rounding may increase handoffs in care. If a hospital has times when it isn’t completely full and nursing units have a varying percentage of being occupied, strict unit-based rounding can cause significant workload inequities among physicians on different units, depending on numbers of patients on each unit.
If there is no attempt at unit-based rounding in larger hospitals, some physicians may be running among five or more units. They work to find different care managers, nurses, and pharmacists – not to mention the challenges of catching patients in their rooms between their departures for diagnostic studies and procedures.
It is often good to balance the benefit of promoting unit-based rounds with the reality of everyday patient care. Some groups maintain that the physician/patient relationship trumps the idea of perfect unit-based rounding. In other words, if a physician establishes a relationship with a patient while they are in the ED being admitted or boarding from overnight, that physician will continue seeing the patient regardless of the patient being assigned to a different unit. It can help for groups to agree that the pursuit of unit-based rounding may create some inequity in the numbers of patients seen each day because of these issues.
In a larger hospital, certain units are often dedicated to specialty care such as cardiac or stroke care. While most hospitalists want to maintain general medical knowledge, there are some who may enjoy having portions of their practice devoted to perioperative medicine or cardiac care, for instance. This promotes familiarity among hospitalists and groups of consultant physicians and nurse practitioners/physician assistants. Over time this allows for enhanced teamwork among those physicians, the nursing team, and the specialty physicians.
Depending on the group’s schedule, patients can be reassigned coinciding with the primary change of service day. This resets the physicians’ patients in the most ideal unit-based way on the evening prior to the first day of rounding for that week or group of shifts.
No matter how you do it, the goal of unit-based rounding is time efficiency for the care team and care coordination benefits for patients and families. If you have other suggestions or questions, go online to SHM HMX to join the discussion.
Take-home message: Unit-based rounding likely has its benefits. Don’t let the inability to achieve perfection in patient distribution to the physicians each day lead to abandonment of attempting these processes.
Dr. McNeal is the division director of inpatient medicine at Baylor Scott & White Medical Center in Temple, Tex.
Balance and flexibility are essential
Balance and flexibility are essential
Many hospitalists agree that their most productive and also sometimes least productive work can happen in the setting of interdisciplinary rounds. How can this paradox be true?
Most hospitals strive to assemble the health care team every day for a brief discussion of each patient’s needs as well as barriers to a safe/successful discharge. On most floors this requires a well-choreographed “dance” of nurses, case managers, social workers, physicians, and advanced practice providers coming together at agreed-upon times. All team members commit to efficient synchronized swimming through the most high-yield details for each patient in order to benefit the patients and families being served.
Of course, there are always challenges to this process in the unpredictable world of patients with acute needs. One variable that is at least partially controllable and tends to promote a more cohesive interdisciplinary experience is that of hospitalist unit-based rounding.
The 2018 State of Hospital Medicine (SoHM) survey reveals that 68% of hospital medicine groups serving adults with greater than 30 physicians employ some degree of unit-based rounding; this trend decreases with smaller group size. About 54% of academic hospital medicine groups use some amount of unit-based rounding. Not surprisingly, smaller hospitals are less likely to have this routine, likely because of fewer total nursing units.
One of the most obvious benefits to unit-based rounding is that the physician or advanced practice provider is more reliably able to participate in the interdisciplinary discussions that day. When more of the team members are at the table each day, patients and families have the best chance of hearing a consistent message around the treatment and discharge plans.
There are challenges to unit-based rounding as well. If patients transfer to different floors for any variety of reasons, strict unit-based rounding may increase handoffs in care. If a hospital has times when it isn’t completely full and nursing units have a varying percentage of being occupied, strict unit-based rounding can cause significant workload inequities among physicians on different units, depending on numbers of patients on each unit.
If there is no attempt at unit-based rounding in larger hospitals, some physicians may be running among five or more units. They work to find different care managers, nurses, and pharmacists – not to mention the challenges of catching patients in their rooms between their departures for diagnostic studies and procedures.
It is often good to balance the benefit of promoting unit-based rounds with the reality of everyday patient care. Some groups maintain that the physician/patient relationship trumps the idea of perfect unit-based rounding. In other words, if a physician establishes a relationship with a patient while they are in the ED being admitted or boarding from overnight, that physician will continue seeing the patient regardless of the patient being assigned to a different unit. It can help for groups to agree that the pursuit of unit-based rounding may create some inequity in the numbers of patients seen each day because of these issues.
In a larger hospital, certain units are often dedicated to specialty care such as cardiac or stroke care. While most hospitalists want to maintain general medical knowledge, there are some who may enjoy having portions of their practice devoted to perioperative medicine or cardiac care, for instance. This promotes familiarity among hospitalists and groups of consultant physicians and nurse practitioners/physician assistants. Over time this allows for enhanced teamwork among those physicians, the nursing team, and the specialty physicians.
Depending on the group’s schedule, patients can be reassigned coinciding with the primary change of service day. This resets the physicians’ patients in the most ideal unit-based way on the evening prior to the first day of rounding for that week or group of shifts.
No matter how you do it, the goal of unit-based rounding is time efficiency for the care team and care coordination benefits for patients and families. If you have other suggestions or questions, go online to SHM HMX to join the discussion.
Take-home message: Unit-based rounding likely has its benefits. Don’t let the inability to achieve perfection in patient distribution to the physicians each day lead to abandonment of attempting these processes.
Dr. McNeal is the division director of inpatient medicine at Baylor Scott & White Medical Center in Temple, Tex.
Many hospitalists agree that their most productive and also sometimes least productive work can happen in the setting of interdisciplinary rounds. How can this paradox be true?
Most hospitals strive to assemble the health care team every day for a brief discussion of each patient’s needs as well as barriers to a safe/successful discharge. On most floors this requires a well-choreographed “dance” of nurses, case managers, social workers, physicians, and advanced practice providers coming together at agreed-upon times. All team members commit to efficient synchronized swimming through the most high-yield details for each patient in order to benefit the patients and families being served.
Of course, there are always challenges to this process in the unpredictable world of patients with acute needs. One variable that is at least partially controllable and tends to promote a more cohesive interdisciplinary experience is that of hospitalist unit-based rounding.
The 2018 State of Hospital Medicine (SoHM) survey reveals that 68% of hospital medicine groups serving adults with greater than 30 physicians employ some degree of unit-based rounding; this trend decreases with smaller group size. About 54% of academic hospital medicine groups use some amount of unit-based rounding. Not surprisingly, smaller hospitals are less likely to have this routine, likely because of fewer total nursing units.
One of the most obvious benefits to unit-based rounding is that the physician or advanced practice provider is more reliably able to participate in the interdisciplinary discussions that day. When more of the team members are at the table each day, patients and families have the best chance of hearing a consistent message around the treatment and discharge plans.
There are challenges to unit-based rounding as well. If patients transfer to different floors for any variety of reasons, strict unit-based rounding may increase handoffs in care. If a hospital has times when it isn’t completely full and nursing units have a varying percentage of being occupied, strict unit-based rounding can cause significant workload inequities among physicians on different units, depending on numbers of patients on each unit.
If there is no attempt at unit-based rounding in larger hospitals, some physicians may be running among five or more units. They work to find different care managers, nurses, and pharmacists – not to mention the challenges of catching patients in their rooms between their departures for diagnostic studies and procedures.
It is often good to balance the benefit of promoting unit-based rounds with the reality of everyday patient care. Some groups maintain that the physician/patient relationship trumps the idea of perfect unit-based rounding. In other words, if a physician establishes a relationship with a patient while they are in the ED being admitted or boarding from overnight, that physician will continue seeing the patient regardless of the patient being assigned to a different unit. It can help for groups to agree that the pursuit of unit-based rounding may create some inequity in the numbers of patients seen each day because of these issues.
In a larger hospital, certain units are often dedicated to specialty care such as cardiac or stroke care. While most hospitalists want to maintain general medical knowledge, there are some who may enjoy having portions of their practice devoted to perioperative medicine or cardiac care, for instance. This promotes familiarity among hospitalists and groups of consultant physicians and nurse practitioners/physician assistants. Over time this allows for enhanced teamwork among those physicians, the nursing team, and the specialty physicians.
Depending on the group’s schedule, patients can be reassigned coinciding with the primary change of service day. This resets the physicians’ patients in the most ideal unit-based way on the evening prior to the first day of rounding for that week or group of shifts.
No matter how you do it, the goal of unit-based rounding is time efficiency for the care team and care coordination benefits for patients and families. If you have other suggestions or questions, go online to SHM HMX to join the discussion.
Take-home message: Unit-based rounding likely has its benefits. Don’t let the inability to achieve perfection in patient distribution to the physicians each day lead to abandonment of attempting these processes.
Dr. McNeal is the division director of inpatient medicine at Baylor Scott & White Medical Center in Temple, Tex.
Repeat LTBI testing best in patients taking biologics with new risk factors
ATLANTA – Patients taking biologics who received latent tuberculosis testing on an annual basis were unlikely to convert from a negative QuantiFERON test to a positive result, which suggests that the test may be unnecessary for patients without new tuberculosis risk factors, according to research presented at the annual meeting of the American College of Rheumatology.
In addition, nearly all of the cost of repeat testing for latent tuberculosis infection (LTBI) went to patients who were not diagnosed with or treated for LTBI, noted Urmi Khanna, MD, a dermatologist with the Cleveland Clinic.
“All in all, about $1.4 million U.S. dollars was spent just on additional QuantiFERON testing, and only 1% of this additional cost was actually spent on testing patients who were diagnosed with and treated for latent tuberculosis,” Dr. Khanna said in her presentation at the meeting.
“Based on this study, we would like to propose that, in low incidence TB regions such as the United States, repeat LTBI testing in patients on biologic therapies should be focused on patients who have new risk factors for TB infection since their last screening,” she said.
The National Psoriasis Foundation has recommended patients be screened annually for LTBI, and the Centers for Disease Control and Prevention and the ACR have recommended patients taking biologics be screened annually for LTBI if they have new risk factors for TB, such as coming into contact with immigrants, a person infected with TB, immunosuppressed individuals, or persons working in areas where TB might be present. Annual screening was also recently added to the Medicare Merit-Based Incentive Payment System (MIPS), which will affect physician reimbursement. “Based on [the addition of this quality outcome measure], we expect that more and more physicians will adopt this practice of annual LTBI screening in all patients on biologics,” Dr. Khanna said.
She and her colleagues examined QuantiFERON tuberculosis test (QFT) results of 10,914 patients from the Cleveland Clinic Foundation between August 2007 and March 2019 where patients were receiving systemic biologic therapy for inflammatory or autoimmune conditions, including nearly 32% with inflammatory bowel disease, 29% with rheumatoid arthritis, and 25% with psoriatic disease. Overall, 5,212 patients were included in the final analysis, and patients had a median of three QFT results. Patients had a median age of 41 years, had taken an average of 1.80 biologics during follow-up, and had a median biologic therapy duration of about 49 months. The most common biologics used were adalimumab (33%), etanercept (17%), and infliximab (17%).
Of these patients, 4,561 patients had negative QFTs (88%), 172 patients had one or more positive QFTs (3%), and 479 patients had one or more indeterminate QFTs (9%). For patients who converted from a negative QFT to a positive QFT, the most common risk factors were exposure to someone with TB (26%), immigrating or traveling to an endemic area (26%), and occupational exposure (16%).
Within the group with one or more positive QFTs, there were 108 patients with baseline positive QFTs prior to starting biologic therapy (2.1%), 61 patients who converted from a baseline negative QFT to a positive QFT (1.2%), and 3 patients where a positive result overlapped with a negative result (0.1%). The majority of patients who converted to a positive QFT result had borderline positive results (70.5%), defined as 0.35 to 1 IU/mL, compared with 29.5% of converters who had a positive QFT result of more than 1.0 IU/mL.
Among the 61 patients who converted to a positive QFT result, 28 patients with LTBI (46%) and 1 patient with an active case of TB (2%) were diagnosed and treated. The active TB case was a 29-year-old patient with inflammatory bowel disease and ankylosing spondylitis receiving adalimumab who had recently traveled to India.
The researchers also examined the cost of additional QFTs in each group. Among negative QFTs, the cost of an additional 9,611 tests was $1,201,375. The cost of additional tests for indeterminate QFTs was $136,200, but Dr. Khanna noted that 99.99% of additional tests in this group were for patients never diagnosed with or treated for LTBI. Additional tests for positive QFTs cost another $47,700, and 26.1% of patients in this group were diagnosed and received treatment for LTBI, compared with 73.9% who did not receive an LTBI diagnosis or treatment.
In the discussion session following the presentation, Dr. Khanna emphasized that discontinuing annual screening in low-risk patients was not standard of care at the Cleveland Clinic, and this study was conducted to raise awareness of focusing testing on patients with new TB risk factors.
Dr. Khanna reported no relevant financial disclosures. A few of her coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Khanna U et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1802.
ATLANTA – Patients taking biologics who received latent tuberculosis testing on an annual basis were unlikely to convert from a negative QuantiFERON test to a positive result, which suggests that the test may be unnecessary for patients without new tuberculosis risk factors, according to research presented at the annual meeting of the American College of Rheumatology.
In addition, nearly all of the cost of repeat testing for latent tuberculosis infection (LTBI) went to patients who were not diagnosed with or treated for LTBI, noted Urmi Khanna, MD, a dermatologist with the Cleveland Clinic.
“All in all, about $1.4 million U.S. dollars was spent just on additional QuantiFERON testing, and only 1% of this additional cost was actually spent on testing patients who were diagnosed with and treated for latent tuberculosis,” Dr. Khanna said in her presentation at the meeting.
“Based on this study, we would like to propose that, in low incidence TB regions such as the United States, repeat LTBI testing in patients on biologic therapies should be focused on patients who have new risk factors for TB infection since their last screening,” she said.
The National Psoriasis Foundation has recommended patients be screened annually for LTBI, and the Centers for Disease Control and Prevention and the ACR have recommended patients taking biologics be screened annually for LTBI if they have new risk factors for TB, such as coming into contact with immigrants, a person infected with TB, immunosuppressed individuals, or persons working in areas where TB might be present. Annual screening was also recently added to the Medicare Merit-Based Incentive Payment System (MIPS), which will affect physician reimbursement. “Based on [the addition of this quality outcome measure], we expect that more and more physicians will adopt this practice of annual LTBI screening in all patients on biologics,” Dr. Khanna said.
She and her colleagues examined QuantiFERON tuberculosis test (QFT) results of 10,914 patients from the Cleveland Clinic Foundation between August 2007 and March 2019 where patients were receiving systemic biologic therapy for inflammatory or autoimmune conditions, including nearly 32% with inflammatory bowel disease, 29% with rheumatoid arthritis, and 25% with psoriatic disease. Overall, 5,212 patients were included in the final analysis, and patients had a median of three QFT results. Patients had a median age of 41 years, had taken an average of 1.80 biologics during follow-up, and had a median biologic therapy duration of about 49 months. The most common biologics used were adalimumab (33%), etanercept (17%), and infliximab (17%).
Of these patients, 4,561 patients had negative QFTs (88%), 172 patients had one or more positive QFTs (3%), and 479 patients had one or more indeterminate QFTs (9%). For patients who converted from a negative QFT to a positive QFT, the most common risk factors were exposure to someone with TB (26%), immigrating or traveling to an endemic area (26%), and occupational exposure (16%).
Within the group with one or more positive QFTs, there were 108 patients with baseline positive QFTs prior to starting biologic therapy (2.1%), 61 patients who converted from a baseline negative QFT to a positive QFT (1.2%), and 3 patients where a positive result overlapped with a negative result (0.1%). The majority of patients who converted to a positive QFT result had borderline positive results (70.5%), defined as 0.35 to 1 IU/mL, compared with 29.5% of converters who had a positive QFT result of more than 1.0 IU/mL.
Among the 61 patients who converted to a positive QFT result, 28 patients with LTBI (46%) and 1 patient with an active case of TB (2%) were diagnosed and treated. The active TB case was a 29-year-old patient with inflammatory bowel disease and ankylosing spondylitis receiving adalimumab who had recently traveled to India.
The researchers also examined the cost of additional QFTs in each group. Among negative QFTs, the cost of an additional 9,611 tests was $1,201,375. The cost of additional tests for indeterminate QFTs was $136,200, but Dr. Khanna noted that 99.99% of additional tests in this group were for patients never diagnosed with or treated for LTBI. Additional tests for positive QFTs cost another $47,700, and 26.1% of patients in this group were diagnosed and received treatment for LTBI, compared with 73.9% who did not receive an LTBI diagnosis or treatment.
In the discussion session following the presentation, Dr. Khanna emphasized that discontinuing annual screening in low-risk patients was not standard of care at the Cleveland Clinic, and this study was conducted to raise awareness of focusing testing on patients with new TB risk factors.
Dr. Khanna reported no relevant financial disclosures. A few of her coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Khanna U et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1802.
ATLANTA – Patients taking biologics who received latent tuberculosis testing on an annual basis were unlikely to convert from a negative QuantiFERON test to a positive result, which suggests that the test may be unnecessary for patients without new tuberculosis risk factors, according to research presented at the annual meeting of the American College of Rheumatology.
In addition, nearly all of the cost of repeat testing for latent tuberculosis infection (LTBI) went to patients who were not diagnosed with or treated for LTBI, noted Urmi Khanna, MD, a dermatologist with the Cleveland Clinic.
“All in all, about $1.4 million U.S. dollars was spent just on additional QuantiFERON testing, and only 1% of this additional cost was actually spent on testing patients who were diagnosed with and treated for latent tuberculosis,” Dr. Khanna said in her presentation at the meeting.
“Based on this study, we would like to propose that, in low incidence TB regions such as the United States, repeat LTBI testing in patients on biologic therapies should be focused on patients who have new risk factors for TB infection since their last screening,” she said.
The National Psoriasis Foundation has recommended patients be screened annually for LTBI, and the Centers for Disease Control and Prevention and the ACR have recommended patients taking biologics be screened annually for LTBI if they have new risk factors for TB, such as coming into contact with immigrants, a person infected with TB, immunosuppressed individuals, or persons working in areas where TB might be present. Annual screening was also recently added to the Medicare Merit-Based Incentive Payment System (MIPS), which will affect physician reimbursement. “Based on [the addition of this quality outcome measure], we expect that more and more physicians will adopt this practice of annual LTBI screening in all patients on biologics,” Dr. Khanna said.
She and her colleagues examined QuantiFERON tuberculosis test (QFT) results of 10,914 patients from the Cleveland Clinic Foundation between August 2007 and March 2019 where patients were receiving systemic biologic therapy for inflammatory or autoimmune conditions, including nearly 32% with inflammatory bowel disease, 29% with rheumatoid arthritis, and 25% with psoriatic disease. Overall, 5,212 patients were included in the final analysis, and patients had a median of three QFT results. Patients had a median age of 41 years, had taken an average of 1.80 biologics during follow-up, and had a median biologic therapy duration of about 49 months. The most common biologics used were adalimumab (33%), etanercept (17%), and infliximab (17%).
Of these patients, 4,561 patients had negative QFTs (88%), 172 patients had one or more positive QFTs (3%), and 479 patients had one or more indeterminate QFTs (9%). For patients who converted from a negative QFT to a positive QFT, the most common risk factors were exposure to someone with TB (26%), immigrating or traveling to an endemic area (26%), and occupational exposure (16%).
Within the group with one or more positive QFTs, there were 108 patients with baseline positive QFTs prior to starting biologic therapy (2.1%), 61 patients who converted from a baseline negative QFT to a positive QFT (1.2%), and 3 patients where a positive result overlapped with a negative result (0.1%). The majority of patients who converted to a positive QFT result had borderline positive results (70.5%), defined as 0.35 to 1 IU/mL, compared with 29.5% of converters who had a positive QFT result of more than 1.0 IU/mL.
Among the 61 patients who converted to a positive QFT result, 28 patients with LTBI (46%) and 1 patient with an active case of TB (2%) were diagnosed and treated. The active TB case was a 29-year-old patient with inflammatory bowel disease and ankylosing spondylitis receiving adalimumab who had recently traveled to India.
The researchers also examined the cost of additional QFTs in each group. Among negative QFTs, the cost of an additional 9,611 tests was $1,201,375. The cost of additional tests for indeterminate QFTs was $136,200, but Dr. Khanna noted that 99.99% of additional tests in this group were for patients never diagnosed with or treated for LTBI. Additional tests for positive QFTs cost another $47,700, and 26.1% of patients in this group were diagnosed and received treatment for LTBI, compared with 73.9% who did not receive an LTBI diagnosis or treatment.
In the discussion session following the presentation, Dr. Khanna emphasized that discontinuing annual screening in low-risk patients was not standard of care at the Cleveland Clinic, and this study was conducted to raise awareness of focusing testing on patients with new TB risk factors.
Dr. Khanna reported no relevant financial disclosures. A few of her coauthors reported financial relationships with pharmaceutical companies.
SOURCE: Khanna U et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 1802.
REPORTING FROM ACR 2019
Moderate coffee intake associated with few seizures in drug-refractory patients with epilepsy
BALTIMORE – The effect of caffeine on seizures may be dose dependent, according to research presented at the annual meeting of the American Epilepsy Society. Moderate doses of caffeine may benefit patients with epilepsy, whereas high doses – four cups of coffee per day or more – may increase seizure susceptibility, said Julie Bourgeois-Vionnet, MD, of the department of functional neurology and epileptology at Hospices Civils de Lyon in France.
In rodent model studies, caffeine has been found in general to increase seizure susceptibility but with variable results according to dose and route of administration, but other studies of chronic low-dose exposure to caffeine have reported protective effects against seizures and sudden unexpected death in epilepsy (SUDEP; Epilepsy Behav. 2018 Mar;80:37-47). In patients, however, the relationship between caffeine consumption and seizure frequency has been less clear.
To examine the relationship between caffeine consumption and seizure frequency in patients with drug-resistant epilepsy, Dr. Bourgeois-Vionnet and colleagues analyzed data patients in the Safety of Antiepileptic Withdrawal in Long Term Video-EEG Monitoring (SAVE) study. This ongoing, multicenter, open-label trial is evaluating the management of antiepileptic drugs withdrawal during long-term monitoring in patients with drug-resistant focal epilepsy.
For the present analysis, the researchers examined data from 620 adults who were included in the SAVE study between 2016 and 2018 and had information available about coffee consumption and seizure frequency, including seizure frequency during the previous 3 months and number of focal seizure evolving to generalized tonic-clonic seizures (secondary generalized tonic-clonic seizures [sGTCS]) during the past year. Patients provided information about coffee consumption via a standardized questionnaire.
The investigators classified caffeine consumption as none, rare (less than 1 cup/week to up to 3 cups/week), moderate (between 4 cups/week and 3 cups/day) and high (more than 4 cups/day). The researchers evaluated risk of SUDEP using the revised SUDEP-7 inventory.
The patients had an average age of 36.2 years and an average duration of epilepsy of 18.1 years. In the 3 months preceding study inclusion, the median seizure frequency of any type was 4.33 per month. In all, 217 patients reported sGTCS in the past year.
Overall, 194 patients reported no coffee consumption, 149 reported rare coffee consumption, 177 moderate consumption, and 100 high consumption. The revised SUDEP-7 inventory was available for 607 patients, and the median score was 3.0.
Patients with moderate coffee consumption were more likely to not have any sGTCS (73.4%), compared with patients with no coffee consumption (64.4%), rare consumption (61.7%), and high consumption (56%). Likewise, patients with moderate coffee consumption were less likely to have more than three sGTCS per year (19.2%), compared with patients no coffee consumption (28.9%), rare consumption (24.8%), and high consumption (30%).
“There was no relation between caffeine consumption and seizure frequency of any type,” Dr. Bourgeois-Vionnet and colleagues reported. “However, we observed a bimodal association between frequency of sGTCS and coffee consumption. In contrast, no significant association was observed between score of the SUDEP-7 inventory and level of caffeine consumption.”
While these findings still need to be confirmed in prospective studies, they suggest possible guidance for patients, Dr. Bourgeois-Vionnet said. “They are allowed to drink coffee, but maybe avoid high doses,” she said.
The study was funded by the French Ministry of Health. The researchers had no disclosures.
SOURCE: Bourgeois-Vionnet J. AES 2019, Abstract 2.141.
BALTIMORE – The effect of caffeine on seizures may be dose dependent, according to research presented at the annual meeting of the American Epilepsy Society. Moderate doses of caffeine may benefit patients with epilepsy, whereas high doses – four cups of coffee per day or more – may increase seizure susceptibility, said Julie Bourgeois-Vionnet, MD, of the department of functional neurology and epileptology at Hospices Civils de Lyon in France.
In rodent model studies, caffeine has been found in general to increase seizure susceptibility but with variable results according to dose and route of administration, but other studies of chronic low-dose exposure to caffeine have reported protective effects against seizures and sudden unexpected death in epilepsy (SUDEP; Epilepsy Behav. 2018 Mar;80:37-47). In patients, however, the relationship between caffeine consumption and seizure frequency has been less clear.
To examine the relationship between caffeine consumption and seizure frequency in patients with drug-resistant epilepsy, Dr. Bourgeois-Vionnet and colleagues analyzed data patients in the Safety of Antiepileptic Withdrawal in Long Term Video-EEG Monitoring (SAVE) study. This ongoing, multicenter, open-label trial is evaluating the management of antiepileptic drugs withdrawal during long-term monitoring in patients with drug-resistant focal epilepsy.
For the present analysis, the researchers examined data from 620 adults who were included in the SAVE study between 2016 and 2018 and had information available about coffee consumption and seizure frequency, including seizure frequency during the previous 3 months and number of focal seizure evolving to generalized tonic-clonic seizures (secondary generalized tonic-clonic seizures [sGTCS]) during the past year. Patients provided information about coffee consumption via a standardized questionnaire.
The investigators classified caffeine consumption as none, rare (less than 1 cup/week to up to 3 cups/week), moderate (between 4 cups/week and 3 cups/day) and high (more than 4 cups/day). The researchers evaluated risk of SUDEP using the revised SUDEP-7 inventory.
The patients had an average age of 36.2 years and an average duration of epilepsy of 18.1 years. In the 3 months preceding study inclusion, the median seizure frequency of any type was 4.33 per month. In all, 217 patients reported sGTCS in the past year.
Overall, 194 patients reported no coffee consumption, 149 reported rare coffee consumption, 177 moderate consumption, and 100 high consumption. The revised SUDEP-7 inventory was available for 607 patients, and the median score was 3.0.
Patients with moderate coffee consumption were more likely to not have any sGTCS (73.4%), compared with patients with no coffee consumption (64.4%), rare consumption (61.7%), and high consumption (56%). Likewise, patients with moderate coffee consumption were less likely to have more than three sGTCS per year (19.2%), compared with patients no coffee consumption (28.9%), rare consumption (24.8%), and high consumption (30%).
“There was no relation between caffeine consumption and seizure frequency of any type,” Dr. Bourgeois-Vionnet and colleagues reported. “However, we observed a bimodal association between frequency of sGTCS and coffee consumption. In contrast, no significant association was observed between score of the SUDEP-7 inventory and level of caffeine consumption.”
While these findings still need to be confirmed in prospective studies, they suggest possible guidance for patients, Dr. Bourgeois-Vionnet said. “They are allowed to drink coffee, but maybe avoid high doses,” she said.
The study was funded by the French Ministry of Health. The researchers had no disclosures.
SOURCE: Bourgeois-Vionnet J. AES 2019, Abstract 2.141.
BALTIMORE – The effect of caffeine on seizures may be dose dependent, according to research presented at the annual meeting of the American Epilepsy Society. Moderate doses of caffeine may benefit patients with epilepsy, whereas high doses – four cups of coffee per day or more – may increase seizure susceptibility, said Julie Bourgeois-Vionnet, MD, of the department of functional neurology and epileptology at Hospices Civils de Lyon in France.
In rodent model studies, caffeine has been found in general to increase seizure susceptibility but with variable results according to dose and route of administration, but other studies of chronic low-dose exposure to caffeine have reported protective effects against seizures and sudden unexpected death in epilepsy (SUDEP; Epilepsy Behav. 2018 Mar;80:37-47). In patients, however, the relationship between caffeine consumption and seizure frequency has been less clear.
To examine the relationship between caffeine consumption and seizure frequency in patients with drug-resistant epilepsy, Dr. Bourgeois-Vionnet and colleagues analyzed data patients in the Safety of Antiepileptic Withdrawal in Long Term Video-EEG Monitoring (SAVE) study. This ongoing, multicenter, open-label trial is evaluating the management of antiepileptic drugs withdrawal during long-term monitoring in patients with drug-resistant focal epilepsy.
For the present analysis, the researchers examined data from 620 adults who were included in the SAVE study between 2016 and 2018 and had information available about coffee consumption and seizure frequency, including seizure frequency during the previous 3 months and number of focal seizure evolving to generalized tonic-clonic seizures (secondary generalized tonic-clonic seizures [sGTCS]) during the past year. Patients provided information about coffee consumption via a standardized questionnaire.
The investigators classified caffeine consumption as none, rare (less than 1 cup/week to up to 3 cups/week), moderate (between 4 cups/week and 3 cups/day) and high (more than 4 cups/day). The researchers evaluated risk of SUDEP using the revised SUDEP-7 inventory.
The patients had an average age of 36.2 years and an average duration of epilepsy of 18.1 years. In the 3 months preceding study inclusion, the median seizure frequency of any type was 4.33 per month. In all, 217 patients reported sGTCS in the past year.
Overall, 194 patients reported no coffee consumption, 149 reported rare coffee consumption, 177 moderate consumption, and 100 high consumption. The revised SUDEP-7 inventory was available for 607 patients, and the median score was 3.0.
Patients with moderate coffee consumption were more likely to not have any sGTCS (73.4%), compared with patients with no coffee consumption (64.4%), rare consumption (61.7%), and high consumption (56%). Likewise, patients with moderate coffee consumption were less likely to have more than three sGTCS per year (19.2%), compared with patients no coffee consumption (28.9%), rare consumption (24.8%), and high consumption (30%).
“There was no relation between caffeine consumption and seizure frequency of any type,” Dr. Bourgeois-Vionnet and colleagues reported. “However, we observed a bimodal association between frequency of sGTCS and coffee consumption. In contrast, no significant association was observed between score of the SUDEP-7 inventory and level of caffeine consumption.”
While these findings still need to be confirmed in prospective studies, they suggest possible guidance for patients, Dr. Bourgeois-Vionnet said. “They are allowed to drink coffee, but maybe avoid high doses,” she said.
The study was funded by the French Ministry of Health. The researchers had no disclosures.
SOURCE: Bourgeois-Vionnet J. AES 2019, Abstract 2.141.
REPORTING FROM AES 2019
Drug recall in U.S. causes extreme hardship for hypoparathyroid patients
The recall of injectable recombinant parathyroid hormone (PTH; Natpara) in the United States over safety concerns about the product is gravely affecting the lives of American patients with severe hypoparathyroidism who need replacement PTH therapy to adequately control symptoms.
Approximately 2,700 patients in the United States have been affected by the recall of Natpara, according to one of the manufacturers, Takeda. Those who were taking it have had to transition back to controlling their symptoms with just oral medications, including active vitamin D or calcitriol (Rocaltrol) plus calcium supplements, which has had a negative impact on the management of their disease in most cases, with some patients hospitalized because of severe hypocalcemia.
One patient related in an interview that even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, individuals can still feel pretty awful because the benefits of the Natpara are subtle – patients just feel better on it. And one report indicates at least 100 patients who had to stop Natpara because of the Food and Drug Administration recall have been hospitalized.
“It’s been a rough time for all patients previously on Natpara adjusting to oral medications after they have been on a replacement therapy,” endocrinologist Dolores Shoback, MD, University of California, San Francisco, said in an email.
Aliya Khan, MD, agrees: “This molecule ... is life changing ... [It] makes a huge difference in patients’ quality of life and in their ability to function normally.”
“The FDA in the United States made the recall decision, and we have to respect that,” added Dr. Khan, a professor of clinical medicine at McMaster University in Hamilton, Ontario.
“We need to address patients’ needs and [try to] reinstate it,” Dr. Khan added, who is the lead author of recent guidelines on the treatment of hypoparathyroidism and who has received research funding from Takeda and Ascendis Pharma, both of which make injectable PTH.
Dr. Kahn also has advice for U.S. endocrinologists who are having to deal with patients who were previously on Natpara and no longer have access to the drug.
She explains how they can transition patients back to other available therapies.
Oral treatments a 'Band-Aid'
Hypoparathyroidism is a rare endocrine disorder that affects approximately 60,000 people in the United States. The FDA approved Natpara as an orphan drug and as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism in January 2015.
The FDA issued the recall for Natpara in September, out of concern that rubber particulate matter originating from the rubber septum of the drug’s cartridge might be contaminating the product.
But the European Medicines Agency, which approved the product under the brand name Natpar in 2017, has not reached the same decision as the FDA; patients in Europe who qualify for injectable PTH still have access to the drug.
As Dr. Khan explained in an interview, PTH is critical for the control of calcium and phosphate homeostasis.
When functioning normally, the parathyroid glands are able to regulate blood calcium levels very finely, sensing how much calcium is being resorbed through the kidney, how much is going in and out of bone, how active vitamin D levels are, and the amount the body is absorbing from the bowel and bone. “It’s all being very carefully fine-tuned continuously,” she said.
Patients with hypoparathyroidism suffer from very low levels of serum calcium, which can, in turn, lead to seizures and cardiac irregularities as well as bronchospasm and even respiratory failure. Magnesium levels can also be dysregulated by hypocalcemia.
“All these are serious results of very low calcium levels,” Dr. Khan emphasized.
These patients “are also not able to eliminate phosphate through the kidneys so their phosphate levels rise,” she added.
Standard treatment for hypoparathyroidism is active vitamin D or calcitriol plus oral calcium supplements.
However, for patients with severe hypoparathyroidism, for whom injectable PTH is indicated, standard treatment is like a “Band-Aid” because what they really need is replacement PTH to help them regulate calcium levels as finely as possible, Dr. Khan said.
High risk for severe hypocalcemia
If PTH is stopped abruptly, calcium levels will likely plummet, a phenomenon sometimes referred to as hungry bone syndrome, placing patients at risk for the consequences of severe hypocalcemia, Dr. Khan added.
(Hungry bone syndrome refers to the rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia, which is exacerbated by suppressed PTH).
One report suggests at least 100 patients who had to stop Natpara because of the FDA recall had to seek hospitalization to have calcium levels restored intravenously.
And even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, patients can still feel pretty awful.
“When you look at my blood levels on and off Natpara, they look very similar,” Danette Astolfi, a former Natpara user in the United States who recently transitioned from the injectable to standard of care, said in an interview.
“But I felt much, much better on Natpara, so this is an interesting ‘wild card’ that patients have with this drug – they just feel better on it. They don’t have the fatigue, they don’t have the brain fog, they don’t have the aches and pains even if their calcium levels are normal,” Ms. Astolfi said.
So patients who are candidates for injectable PTH therapy are by definition those who do not do very well on standard-of-care calcium and calcitriol.
“With the recall, patients are going back to this regimen they already did not have great success with,” Ms. Astolfi explained. “And that’s the tricky part because if you fall into this category, as I do, there is not much you can do about it.”
Ms. Astolfi, who is also on the board of directors of the Hypoparathyroidism Association in Pennsylvania, was lucky because she did not have to stop treatment with injectable PTH abruptly.
“I was fortunate. My physician did not want me to stop the drug right away, so we had time to develop a discontinuation plan,” she noted.
Transitioning safely to other therapies
Dr. Khan has advice for endocrinologists dealing with patients who were previously on Natpara and no longer have access to the drug.
First, “endocrinologists need to be aware that when you stop PTH treatment suddenly, patients’ need for calcium supplements and calcitriol may be as high as two times what they were on before they started PTH therapy,” she noted.
Physicians also need to follow patients closely by monitoring not only calcium and vitamin D levels but also phosphate and magnesium almost daily.
Dr. Khan said she does this because it’s difficult to predict how much calcium and calcitriol a patient will require and doses will likely have to be titrated up or down based on lab results.
It is noteworthy that a joint statement on the Natpara recall by the Endocrine Society and the American Society of Bone and Mineral Research (ASBMR) also emphasizes these points.
And Dr. Khan – as well as the Endocrine Society and ASBMR – also point out that patients may be transitioned from Natpara to teriparatide (Forteo), another recombinant form of PTH that is licensed for use in osteoporosis but has not been approved for hypoparathyroidism.
In Dr. Khan’s experience, patients often do quite well on teriparatide.
The big downside of prescribing teriparatide in the United States, however, is that the drug has to be used off label, and as such, insurance companies are unlikely to pick up the tab for what is an expensive treatment, she explained.
Furthermore, teriparatide has a very short shelf-life once injected so patients may need to use up to four needles a day to stabilize calcium levels.
If teriparatide is prescribed, subcutaneous injections given in the thigh are recommended for the treatment of hypoparathyroidism, according to the joint Endocrine Society/ASBMR statement.
Takeda vs. FDA
In the meantime, Takeda says it has been in regular contact with the FDA to try and work out how to bring Natpara back to U.S. patients who require it for symptom control.
Current outstanding issues between the company and FDA involve considerations related to dose accuracy, safety, and supply continuity, which the company hopes will be resolved in a timely manner.
Furthermore, shortly after the recall order, the company created a special use program that continues to support patients previously prescribed Natpara who would otherwise be at extreme risk of serious complications if forced to stop taking the drug.
“Originally intended for an extremely limited number of patients, the special use program has now enrolled approximately 300 patients,” Cheryl Schwartz, head, U.S. Hematology & Rare Business Unit, Takeda, said in a letter to members of the U.S. Hypoparathyroidism Association on Nov. 21.
The number is higher than expected and reflects the significant treatment needs of patients with serious disease, Ms. Schwartz noted.
“I want to reiterate that we do understand and sincerely regret the impact the Natpara recall is having on patients. We will provide another update as soon as we have more information to share. We continue to work around the clock to find ways to bring Natpara back to the broader hypoparathyroidism community,” she added.
“Patient safety always has been, and continues to be, the highest priority for Takeda,” she said.
Final efforts
Dr. Khan is currently involved in clinical trials evaluating Natpara in Canada (where it is not yet approved).
She was also involved in some of the pivotal studies that helped gain support of the product in the United States and European Union, including REPLACE, which showed that the injectable PTH molecule maintained serum calcium while reducing or eliminating requirements for calcium and active vitamin D supplementation.
“We now have 8 years of experience with this molecule, so we know that it’s safe and effective,” Dr. Khan emphasized.
Health Canada has not deemed Natpara problematic enough to stop the ongoing research program into injectable PTH therapies there, which is being headed up by Dr. Khan at McMaster University.
“The company has not yet applied for approval here, but when they do apply, I am sure they will have fixed this problem by then,” Dr. Khan said. “And I expect it will be fixed momentarily in the United States, where patients have been most affected.”
Asked if she was looking forward to getting Natpara back on track, Ms. Astolfi said “absolutely” several times.
“This recall has really had a large impact on our community,” she stressed. “And while it’s good that critically ill patients have access to the drug through the special-use program, we want to get everyone back to their best life and feeling great.”
A version of this story originally appeared on Medscape.com.
The recall of injectable recombinant parathyroid hormone (PTH; Natpara) in the United States over safety concerns about the product is gravely affecting the lives of American patients with severe hypoparathyroidism who need replacement PTH therapy to adequately control symptoms.
Approximately 2,700 patients in the United States have been affected by the recall of Natpara, according to one of the manufacturers, Takeda. Those who were taking it have had to transition back to controlling their symptoms with just oral medications, including active vitamin D or calcitriol (Rocaltrol) plus calcium supplements, which has had a negative impact on the management of their disease in most cases, with some patients hospitalized because of severe hypocalcemia.
One patient related in an interview that even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, individuals can still feel pretty awful because the benefits of the Natpara are subtle – patients just feel better on it. And one report indicates at least 100 patients who had to stop Natpara because of the Food and Drug Administration recall have been hospitalized.
“It’s been a rough time for all patients previously on Natpara adjusting to oral medications after they have been on a replacement therapy,” endocrinologist Dolores Shoback, MD, University of California, San Francisco, said in an email.
Aliya Khan, MD, agrees: “This molecule ... is life changing ... [It] makes a huge difference in patients’ quality of life and in their ability to function normally.”
“The FDA in the United States made the recall decision, and we have to respect that,” added Dr. Khan, a professor of clinical medicine at McMaster University in Hamilton, Ontario.
“We need to address patients’ needs and [try to] reinstate it,” Dr. Khan added, who is the lead author of recent guidelines on the treatment of hypoparathyroidism and who has received research funding from Takeda and Ascendis Pharma, both of which make injectable PTH.
Dr. Kahn also has advice for U.S. endocrinologists who are having to deal with patients who were previously on Natpara and no longer have access to the drug.
She explains how they can transition patients back to other available therapies.
Oral treatments a 'Band-Aid'
Hypoparathyroidism is a rare endocrine disorder that affects approximately 60,000 people in the United States. The FDA approved Natpara as an orphan drug and as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism in January 2015.
The FDA issued the recall for Natpara in September, out of concern that rubber particulate matter originating from the rubber septum of the drug’s cartridge might be contaminating the product.
But the European Medicines Agency, which approved the product under the brand name Natpar in 2017, has not reached the same decision as the FDA; patients in Europe who qualify for injectable PTH still have access to the drug.
As Dr. Khan explained in an interview, PTH is critical for the control of calcium and phosphate homeostasis.
When functioning normally, the parathyroid glands are able to regulate blood calcium levels very finely, sensing how much calcium is being resorbed through the kidney, how much is going in and out of bone, how active vitamin D levels are, and the amount the body is absorbing from the bowel and bone. “It’s all being very carefully fine-tuned continuously,” she said.
Patients with hypoparathyroidism suffer from very low levels of serum calcium, which can, in turn, lead to seizures and cardiac irregularities as well as bronchospasm and even respiratory failure. Magnesium levels can also be dysregulated by hypocalcemia.
“All these are serious results of very low calcium levels,” Dr. Khan emphasized.
These patients “are also not able to eliminate phosphate through the kidneys so their phosphate levels rise,” she added.
Standard treatment for hypoparathyroidism is active vitamin D or calcitriol plus oral calcium supplements.
However, for patients with severe hypoparathyroidism, for whom injectable PTH is indicated, standard treatment is like a “Band-Aid” because what they really need is replacement PTH to help them regulate calcium levels as finely as possible, Dr. Khan said.
High risk for severe hypocalcemia
If PTH is stopped abruptly, calcium levels will likely plummet, a phenomenon sometimes referred to as hungry bone syndrome, placing patients at risk for the consequences of severe hypocalcemia, Dr. Khan added.
(Hungry bone syndrome refers to the rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia, which is exacerbated by suppressed PTH).
One report suggests at least 100 patients who had to stop Natpara because of the FDA recall had to seek hospitalization to have calcium levels restored intravenously.
And even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, patients can still feel pretty awful.
“When you look at my blood levels on and off Natpara, they look very similar,” Danette Astolfi, a former Natpara user in the United States who recently transitioned from the injectable to standard of care, said in an interview.
“But I felt much, much better on Natpara, so this is an interesting ‘wild card’ that patients have with this drug – they just feel better on it. They don’t have the fatigue, they don’t have the brain fog, they don’t have the aches and pains even if their calcium levels are normal,” Ms. Astolfi said.
So patients who are candidates for injectable PTH therapy are by definition those who do not do very well on standard-of-care calcium and calcitriol.
“With the recall, patients are going back to this regimen they already did not have great success with,” Ms. Astolfi explained. “And that’s the tricky part because if you fall into this category, as I do, there is not much you can do about it.”
Ms. Astolfi, who is also on the board of directors of the Hypoparathyroidism Association in Pennsylvania, was lucky because she did not have to stop treatment with injectable PTH abruptly.
“I was fortunate. My physician did not want me to stop the drug right away, so we had time to develop a discontinuation plan,” she noted.
Transitioning safely to other therapies
Dr. Khan has advice for endocrinologists dealing with patients who were previously on Natpara and no longer have access to the drug.
First, “endocrinologists need to be aware that when you stop PTH treatment suddenly, patients’ need for calcium supplements and calcitriol may be as high as two times what they were on before they started PTH therapy,” she noted.
Physicians also need to follow patients closely by monitoring not only calcium and vitamin D levels but also phosphate and magnesium almost daily.
Dr. Khan said she does this because it’s difficult to predict how much calcium and calcitriol a patient will require and doses will likely have to be titrated up or down based on lab results.
It is noteworthy that a joint statement on the Natpara recall by the Endocrine Society and the American Society of Bone and Mineral Research (ASBMR) also emphasizes these points.
And Dr. Khan – as well as the Endocrine Society and ASBMR – also point out that patients may be transitioned from Natpara to teriparatide (Forteo), another recombinant form of PTH that is licensed for use in osteoporosis but has not been approved for hypoparathyroidism.
In Dr. Khan’s experience, patients often do quite well on teriparatide.
The big downside of prescribing teriparatide in the United States, however, is that the drug has to be used off label, and as such, insurance companies are unlikely to pick up the tab for what is an expensive treatment, she explained.
Furthermore, teriparatide has a very short shelf-life once injected so patients may need to use up to four needles a day to stabilize calcium levels.
If teriparatide is prescribed, subcutaneous injections given in the thigh are recommended for the treatment of hypoparathyroidism, according to the joint Endocrine Society/ASBMR statement.
Takeda vs. FDA
In the meantime, Takeda says it has been in regular contact with the FDA to try and work out how to bring Natpara back to U.S. patients who require it for symptom control.
Current outstanding issues between the company and FDA involve considerations related to dose accuracy, safety, and supply continuity, which the company hopes will be resolved in a timely manner.
Furthermore, shortly after the recall order, the company created a special use program that continues to support patients previously prescribed Natpara who would otherwise be at extreme risk of serious complications if forced to stop taking the drug.
“Originally intended for an extremely limited number of patients, the special use program has now enrolled approximately 300 patients,” Cheryl Schwartz, head, U.S. Hematology & Rare Business Unit, Takeda, said in a letter to members of the U.S. Hypoparathyroidism Association on Nov. 21.
The number is higher than expected and reflects the significant treatment needs of patients with serious disease, Ms. Schwartz noted.
“I want to reiterate that we do understand and sincerely regret the impact the Natpara recall is having on patients. We will provide another update as soon as we have more information to share. We continue to work around the clock to find ways to bring Natpara back to the broader hypoparathyroidism community,” she added.
“Patient safety always has been, and continues to be, the highest priority for Takeda,” she said.
Final efforts
Dr. Khan is currently involved in clinical trials evaluating Natpara in Canada (where it is not yet approved).
She was also involved in some of the pivotal studies that helped gain support of the product in the United States and European Union, including REPLACE, which showed that the injectable PTH molecule maintained serum calcium while reducing or eliminating requirements for calcium and active vitamin D supplementation.
“We now have 8 years of experience with this molecule, so we know that it’s safe and effective,” Dr. Khan emphasized.
Health Canada has not deemed Natpara problematic enough to stop the ongoing research program into injectable PTH therapies there, which is being headed up by Dr. Khan at McMaster University.
“The company has not yet applied for approval here, but when they do apply, I am sure they will have fixed this problem by then,” Dr. Khan said. “And I expect it will be fixed momentarily in the United States, where patients have been most affected.”
Asked if she was looking forward to getting Natpara back on track, Ms. Astolfi said “absolutely” several times.
“This recall has really had a large impact on our community,” she stressed. “And while it’s good that critically ill patients have access to the drug through the special-use program, we want to get everyone back to their best life and feeling great.”
A version of this story originally appeared on Medscape.com.
The recall of injectable recombinant parathyroid hormone (PTH; Natpara) in the United States over safety concerns about the product is gravely affecting the lives of American patients with severe hypoparathyroidism who need replacement PTH therapy to adequately control symptoms.
Approximately 2,700 patients in the United States have been affected by the recall of Natpara, according to one of the manufacturers, Takeda. Those who were taking it have had to transition back to controlling their symptoms with just oral medications, including active vitamin D or calcitriol (Rocaltrol) plus calcium supplements, which has had a negative impact on the management of their disease in most cases, with some patients hospitalized because of severe hypocalcemia.
One patient related in an interview that even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, individuals can still feel pretty awful because the benefits of the Natpara are subtle – patients just feel better on it. And one report indicates at least 100 patients who had to stop Natpara because of the Food and Drug Administration recall have been hospitalized.
“It’s been a rough time for all patients previously on Natpara adjusting to oral medications after they have been on a replacement therapy,” endocrinologist Dolores Shoback, MD, University of California, San Francisco, said in an email.
Aliya Khan, MD, agrees: “This molecule ... is life changing ... [It] makes a huge difference in patients’ quality of life and in their ability to function normally.”
“The FDA in the United States made the recall decision, and we have to respect that,” added Dr. Khan, a professor of clinical medicine at McMaster University in Hamilton, Ontario.
“We need to address patients’ needs and [try to] reinstate it,” Dr. Khan added, who is the lead author of recent guidelines on the treatment of hypoparathyroidism and who has received research funding from Takeda and Ascendis Pharma, both of which make injectable PTH.
Dr. Kahn also has advice for U.S. endocrinologists who are having to deal with patients who were previously on Natpara and no longer have access to the drug.
She explains how they can transition patients back to other available therapies.
Oral treatments a 'Band-Aid'
Hypoparathyroidism is a rare endocrine disorder that affects approximately 60,000 people in the United States. The FDA approved Natpara as an orphan drug and as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism in January 2015.
The FDA issued the recall for Natpara in September, out of concern that rubber particulate matter originating from the rubber septum of the drug’s cartridge might be contaminating the product.
But the European Medicines Agency, which approved the product under the brand name Natpar in 2017, has not reached the same decision as the FDA; patients in Europe who qualify for injectable PTH still have access to the drug.
As Dr. Khan explained in an interview, PTH is critical for the control of calcium and phosphate homeostasis.
When functioning normally, the parathyroid glands are able to regulate blood calcium levels very finely, sensing how much calcium is being resorbed through the kidney, how much is going in and out of bone, how active vitamin D levels are, and the amount the body is absorbing from the bowel and bone. “It’s all being very carefully fine-tuned continuously,” she said.
Patients with hypoparathyroidism suffer from very low levels of serum calcium, which can, in turn, lead to seizures and cardiac irregularities as well as bronchospasm and even respiratory failure. Magnesium levels can also be dysregulated by hypocalcemia.
“All these are serious results of very low calcium levels,” Dr. Khan emphasized.
These patients “are also not able to eliminate phosphate through the kidneys so their phosphate levels rise,” she added.
Standard treatment for hypoparathyroidism is active vitamin D or calcitriol plus oral calcium supplements.
However, for patients with severe hypoparathyroidism, for whom injectable PTH is indicated, standard treatment is like a “Band-Aid” because what they really need is replacement PTH to help them regulate calcium levels as finely as possible, Dr. Khan said.
High risk for severe hypocalcemia
If PTH is stopped abruptly, calcium levels will likely plummet, a phenomenon sometimes referred to as hungry bone syndrome, placing patients at risk for the consequences of severe hypocalcemia, Dr. Khan added.
(Hungry bone syndrome refers to the rapid, profound, and prolonged hypocalcemia associated with hypophosphatemia and hypomagnesemia, which is exacerbated by suppressed PTH).
One report suggests at least 100 patients who had to stop Natpara because of the FDA recall had to seek hospitalization to have calcium levels restored intravenously.
And even if the transition from injectable PTH back to calcium supplements and calcitriol goes smoothly, patients can still feel pretty awful.
“When you look at my blood levels on and off Natpara, they look very similar,” Danette Astolfi, a former Natpara user in the United States who recently transitioned from the injectable to standard of care, said in an interview.
“But I felt much, much better on Natpara, so this is an interesting ‘wild card’ that patients have with this drug – they just feel better on it. They don’t have the fatigue, they don’t have the brain fog, they don’t have the aches and pains even if their calcium levels are normal,” Ms. Astolfi said.
So patients who are candidates for injectable PTH therapy are by definition those who do not do very well on standard-of-care calcium and calcitriol.
“With the recall, patients are going back to this regimen they already did not have great success with,” Ms. Astolfi explained. “And that’s the tricky part because if you fall into this category, as I do, there is not much you can do about it.”
Ms. Astolfi, who is also on the board of directors of the Hypoparathyroidism Association in Pennsylvania, was lucky because she did not have to stop treatment with injectable PTH abruptly.
“I was fortunate. My physician did not want me to stop the drug right away, so we had time to develop a discontinuation plan,” she noted.
Transitioning safely to other therapies
Dr. Khan has advice for endocrinologists dealing with patients who were previously on Natpara and no longer have access to the drug.
First, “endocrinologists need to be aware that when you stop PTH treatment suddenly, patients’ need for calcium supplements and calcitriol may be as high as two times what they were on before they started PTH therapy,” she noted.
Physicians also need to follow patients closely by monitoring not only calcium and vitamin D levels but also phosphate and magnesium almost daily.
Dr. Khan said she does this because it’s difficult to predict how much calcium and calcitriol a patient will require and doses will likely have to be titrated up or down based on lab results.
It is noteworthy that a joint statement on the Natpara recall by the Endocrine Society and the American Society of Bone and Mineral Research (ASBMR) also emphasizes these points.
And Dr. Khan – as well as the Endocrine Society and ASBMR – also point out that patients may be transitioned from Natpara to teriparatide (Forteo), another recombinant form of PTH that is licensed for use in osteoporosis but has not been approved for hypoparathyroidism.
In Dr. Khan’s experience, patients often do quite well on teriparatide.
The big downside of prescribing teriparatide in the United States, however, is that the drug has to be used off label, and as such, insurance companies are unlikely to pick up the tab for what is an expensive treatment, she explained.
Furthermore, teriparatide has a very short shelf-life once injected so patients may need to use up to four needles a day to stabilize calcium levels.
If teriparatide is prescribed, subcutaneous injections given in the thigh are recommended for the treatment of hypoparathyroidism, according to the joint Endocrine Society/ASBMR statement.
Takeda vs. FDA
In the meantime, Takeda says it has been in regular contact with the FDA to try and work out how to bring Natpara back to U.S. patients who require it for symptom control.
Current outstanding issues between the company and FDA involve considerations related to dose accuracy, safety, and supply continuity, which the company hopes will be resolved in a timely manner.
Furthermore, shortly after the recall order, the company created a special use program that continues to support patients previously prescribed Natpara who would otherwise be at extreme risk of serious complications if forced to stop taking the drug.
“Originally intended for an extremely limited number of patients, the special use program has now enrolled approximately 300 patients,” Cheryl Schwartz, head, U.S. Hematology & Rare Business Unit, Takeda, said in a letter to members of the U.S. Hypoparathyroidism Association on Nov. 21.
The number is higher than expected and reflects the significant treatment needs of patients with serious disease, Ms. Schwartz noted.
“I want to reiterate that we do understand and sincerely regret the impact the Natpara recall is having on patients. We will provide another update as soon as we have more information to share. We continue to work around the clock to find ways to bring Natpara back to the broader hypoparathyroidism community,” she added.
“Patient safety always has been, and continues to be, the highest priority for Takeda,” she said.
Final efforts
Dr. Khan is currently involved in clinical trials evaluating Natpara in Canada (where it is not yet approved).
She was also involved in some of the pivotal studies that helped gain support of the product in the United States and European Union, including REPLACE, which showed that the injectable PTH molecule maintained serum calcium while reducing or eliminating requirements for calcium and active vitamin D supplementation.
“We now have 8 years of experience with this molecule, so we know that it’s safe and effective,” Dr. Khan emphasized.
Health Canada has not deemed Natpara problematic enough to stop the ongoing research program into injectable PTH therapies there, which is being headed up by Dr. Khan at McMaster University.
“The company has not yet applied for approval here, but when they do apply, I am sure they will have fixed this problem by then,” Dr. Khan said. “And I expect it will be fixed momentarily in the United States, where patients have been most affected.”
Asked if she was looking forward to getting Natpara back on track, Ms. Astolfi said “absolutely” several times.
“This recall has really had a large impact on our community,” she stressed. “And while it’s good that critically ill patients have access to the drug through the special-use program, we want to get everyone back to their best life and feeling great.”
A version of this story originally appeared on Medscape.com.
EVALI outbreak ongoing, but new cases decline
The vaping lung disease outbreak continues, but according to the Centers for Disease Control and Prevention, it may have peaked and the number of new hospitalized cases reported to the CDC may be decreasing.
In the Dec. 6, 2019, Morbidity and Mortality Weekly Report, the CDC has updated information about cases of e-cigarette, or vaping, product use–associated lung injury (EVALI): As of Dec. 3, there have been 2,291 cases reported from all 50 states, Washington, D.C., and two U.S. territories (Puerto Rico and U.S. Virgin Islands). A total of 48 deaths have been confirmed in 25 states and Washington, D.C., the CDC reported.
The largest number of weekly hospitalized cases occurred during the week of Sept. 15, 2019; since then, hospitalized cases have steadily declined. “Among all hospitalized EVALI patients reported to CDC weekly, the percentage of recent cases (patients hospitalized within the preceding 3 weeks) declined from 58% reported November 12 to 30% reported December 3,” the report stated.
About 80%of hospitalized EVALI patients reported using tetrahydrocannabinol (THC)–containing e-cigarette, or vaping, products. “Dank Vapes,” counterfeit THC-containing products of unknown origin, were the most commonly reported THC-containing branded products used. Dank Vapes were used by 56% of hospitalized EVALI patients nationwide, followed by TKO brand (15%), Smart Cart (13%), and Rove (12%).
Of EVALI patients for whom data were available, 67% were male, and the median age was 24 years (range, 13-77 years); 78% were aged under 35 years and 16% were under 18 years. About 75% of EVALI patients were non-Hispanic white and 16% were Hispanic. Among the 48 deaths, 54% of patients were male, and the median age was 52 years (range, 17-75 years).
CDC research on EVALI continues to be limited by the self-reported data, lack of data on substances used, missing data, loss to follow-up, and reporting lags, but the intensive investigation and data collection is ongoing.
The report concludes: “While the investigation continues, persons should consider refraining from the use of all e-cigarette, or vaping, products. Adults using e-cigarette, or vaping, products to quit smoking should not return to smoking cigarettes; they should weigh all risks and benefits and consider using [Food and Drug Administration]–approved cessation medications. Adults who continue to use e-cigarette, or vaping, products should carefully monitor themselves for symptoms and see a health care provider immediately if they develop symptoms similar to those reported in this outbreak. Irrespective of the ongoing investigation, e-cigarette, or vaping, products should never be used by youths, young adults or pregnant women.”
Information on the current investigation, reporting of cases, and other resources can be found on the CDC website.
SOURCE: Lozier MJ et al. MMWR Morb Mortal Wkly Rep. 2019 Dec 6. doi: 10.15585/mmwr.mm6849e1.
The vaping lung disease outbreak continues, but according to the Centers for Disease Control and Prevention, it may have peaked and the number of new hospitalized cases reported to the CDC may be decreasing.
In the Dec. 6, 2019, Morbidity and Mortality Weekly Report, the CDC has updated information about cases of e-cigarette, or vaping, product use–associated lung injury (EVALI): As of Dec. 3, there have been 2,291 cases reported from all 50 states, Washington, D.C., and two U.S. territories (Puerto Rico and U.S. Virgin Islands). A total of 48 deaths have been confirmed in 25 states and Washington, D.C., the CDC reported.
The largest number of weekly hospitalized cases occurred during the week of Sept. 15, 2019; since then, hospitalized cases have steadily declined. “Among all hospitalized EVALI patients reported to CDC weekly, the percentage of recent cases (patients hospitalized within the preceding 3 weeks) declined from 58% reported November 12 to 30% reported December 3,” the report stated.
About 80%of hospitalized EVALI patients reported using tetrahydrocannabinol (THC)–containing e-cigarette, or vaping, products. “Dank Vapes,” counterfeit THC-containing products of unknown origin, were the most commonly reported THC-containing branded products used. Dank Vapes were used by 56% of hospitalized EVALI patients nationwide, followed by TKO brand (15%), Smart Cart (13%), and Rove (12%).
Of EVALI patients for whom data were available, 67% were male, and the median age was 24 years (range, 13-77 years); 78% were aged under 35 years and 16% were under 18 years. About 75% of EVALI patients were non-Hispanic white and 16% were Hispanic. Among the 48 deaths, 54% of patients were male, and the median age was 52 years (range, 17-75 years).
CDC research on EVALI continues to be limited by the self-reported data, lack of data on substances used, missing data, loss to follow-up, and reporting lags, but the intensive investigation and data collection is ongoing.
The report concludes: “While the investigation continues, persons should consider refraining from the use of all e-cigarette, or vaping, products. Adults using e-cigarette, or vaping, products to quit smoking should not return to smoking cigarettes; they should weigh all risks and benefits and consider using [Food and Drug Administration]–approved cessation medications. Adults who continue to use e-cigarette, or vaping, products should carefully monitor themselves for symptoms and see a health care provider immediately if they develop symptoms similar to those reported in this outbreak. Irrespective of the ongoing investigation, e-cigarette, or vaping, products should never be used by youths, young adults or pregnant women.”
Information on the current investigation, reporting of cases, and other resources can be found on the CDC website.
SOURCE: Lozier MJ et al. MMWR Morb Mortal Wkly Rep. 2019 Dec 6. doi: 10.15585/mmwr.mm6849e1.
The vaping lung disease outbreak continues, but according to the Centers for Disease Control and Prevention, it may have peaked and the number of new hospitalized cases reported to the CDC may be decreasing.
In the Dec. 6, 2019, Morbidity and Mortality Weekly Report, the CDC has updated information about cases of e-cigarette, or vaping, product use–associated lung injury (EVALI): As of Dec. 3, there have been 2,291 cases reported from all 50 states, Washington, D.C., and two U.S. territories (Puerto Rico and U.S. Virgin Islands). A total of 48 deaths have been confirmed in 25 states and Washington, D.C., the CDC reported.
The largest number of weekly hospitalized cases occurred during the week of Sept. 15, 2019; since then, hospitalized cases have steadily declined. “Among all hospitalized EVALI patients reported to CDC weekly, the percentage of recent cases (patients hospitalized within the preceding 3 weeks) declined from 58% reported November 12 to 30% reported December 3,” the report stated.
About 80%of hospitalized EVALI patients reported using tetrahydrocannabinol (THC)–containing e-cigarette, or vaping, products. “Dank Vapes,” counterfeit THC-containing products of unknown origin, were the most commonly reported THC-containing branded products used. Dank Vapes were used by 56% of hospitalized EVALI patients nationwide, followed by TKO brand (15%), Smart Cart (13%), and Rove (12%).
Of EVALI patients for whom data were available, 67% were male, and the median age was 24 years (range, 13-77 years); 78% were aged under 35 years and 16% were under 18 years. About 75% of EVALI patients were non-Hispanic white and 16% were Hispanic. Among the 48 deaths, 54% of patients were male, and the median age was 52 years (range, 17-75 years).
CDC research on EVALI continues to be limited by the self-reported data, lack of data on substances used, missing data, loss to follow-up, and reporting lags, but the intensive investigation and data collection is ongoing.
The report concludes: “While the investigation continues, persons should consider refraining from the use of all e-cigarette, or vaping, products. Adults using e-cigarette, or vaping, products to quit smoking should not return to smoking cigarettes; they should weigh all risks and benefits and consider using [Food and Drug Administration]–approved cessation medications. Adults who continue to use e-cigarette, or vaping, products should carefully monitor themselves for symptoms and see a health care provider immediately if they develop symptoms similar to those reported in this outbreak. Irrespective of the ongoing investigation, e-cigarette, or vaping, products should never be used by youths, young adults or pregnant women.”
Information on the current investigation, reporting of cases, and other resources can be found on the CDC website.
SOURCE: Lozier MJ et al. MMWR Morb Mortal Wkly Rep. 2019 Dec 6. doi: 10.15585/mmwr.mm6849e1.
FROM THE MMWR
Oral BTK inhibitor shows continued promise for pemphigus
MADRID – A novel Dedee F. Murrell, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
“In pemphigus, we have a considerable unmet medical need. We could do with a treatment that has rapid onset, is steroid sparing or avoiding, safe for chronic administration, avoids chronic B cell depletion – which is an issue with rituxumab – is efficacious in both newly diagnosed as well as in our commonly relapsing patients, and is convenient to administer,” observed Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
In the phase 2 BELIEVE trial, the BTK inhibitor known for now only as PRN1008 appeared to check all the boxes. However, definitive evidence of the drug’s efficacy and safety must await the results of the ongoing, double-bind, placebo-controlled, pivotal phase 3 PEGASUS trial, which is enrolling a planned 120 patients with pemphigus vulgaris or foliaceus in 19 countries.
Pemphigus is driven by autoantibodies against desmogleins 1 and 3. Even in contemporary practice, this blistering disease has roughly a 5% mortality rate. Current management of the disease with high-dose corticosteroids at 1 mg/kg per day or more with or without rituximab (Rituxan) is challenging because of the associated pronounced toxicities. And even when rituximab is utilized, patients need to be on high-dose steroids for at least 3-6 months before a rituximab response is achieved, Dr. Murrell said.
PRN1008 has three mechanisms of action targeting the drivers of pemphigus and other immune-mediated diseases, she explained. The drug blocks inflammatory B cells, neutrophils, and macrophages; eliminates downstream signalling by antidesmoglein autoantibodies; and prevents production of new autoantibodies. The drug has a double lock-and-key mechanism which makes it highly specific for its target, so treated patients are much less likely to experience bruising, diarrhea, and other off-target effects than is the case with other tyrosine kinase inhibitors.
“Also, PRN1008 is reversible. It comes off its target receptor after about 12 hours, at which point serum levels become low. So if any side effects do develop, the patient can recover quickly, unlike with rituximab, which involves ongoing inhibition of B cells for a long period of time,” the dermatologist noted.
BELIEVE was a phase 2 dose-ranging study of 27 patients with pemphigus treated open-label with PRN1008 for 12 weeks. The primary endpoint was control of disease activity, meaning no new lesions while established lesions showed some evidence of healing on no more than 0.5 mg/kg per day of prednisone. This outcome was achieved in 27% of participants at 2 weeks, 54% at 4 weeks, and 73% at 12 weeks. Autoantibody levels dropped by a mean of 65% at 12 weeks, with a median 70% reduction in Pemphigus Disease Activity Index scores while patients were on an average of just 12 mg of prednisone per day.
Phase 2b of BELIEVE included a separate group of 15 patients on PRN1008 for 24 weeks. Nine achieved a Pemphigus Disease Activity Index score of 0 or 1. Six patients had a complete response, meaning an absence of both new and established lesions while on no or a very low dose of prednisone. Another five patients were unable to achieve a complete response, and the jury was still out on another four still on treatment.
The side effect profile was benign in comparison with that of current standard therapies, she said. It consisted of a handful of cases of mild, transient nausea, headache, or upper abdominal pain and a few Grade 1 infections. There have been no severe treatment-related adverse events in BELIEVE participants.
Patients enrolled in the ongoing phase 3 PEGASUS trial start with a short course of high-dose corticosteroids, followed by double-blind randomization to PRN1008 at 400 mg twice a day or placebo, with a corticosteroid taper. The primary endpoint is durable complete remission at week 37, defined as no lesions being present for at least the previous 8 weeks while on no more than 5 mg/day of prednisone.
Secondary endpoints include cumulative corticosteroid dose through 36 weeks and patient-reported quality of life measures assessed out to 61 weeks. The trial is scheduled for completion in the spring of 2022.
Dr. Murrell reported serving as a consultant to the study sponsor, Principia Biopharma, as well as numerous other pharmaceutical companies.
MADRID – A novel Dedee F. Murrell, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
“In pemphigus, we have a considerable unmet medical need. We could do with a treatment that has rapid onset, is steroid sparing or avoiding, safe for chronic administration, avoids chronic B cell depletion – which is an issue with rituxumab – is efficacious in both newly diagnosed as well as in our commonly relapsing patients, and is convenient to administer,” observed Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
In the phase 2 BELIEVE trial, the BTK inhibitor known for now only as PRN1008 appeared to check all the boxes. However, definitive evidence of the drug’s efficacy and safety must await the results of the ongoing, double-bind, placebo-controlled, pivotal phase 3 PEGASUS trial, which is enrolling a planned 120 patients with pemphigus vulgaris or foliaceus in 19 countries.
Pemphigus is driven by autoantibodies against desmogleins 1 and 3. Even in contemporary practice, this blistering disease has roughly a 5% mortality rate. Current management of the disease with high-dose corticosteroids at 1 mg/kg per day or more with or without rituximab (Rituxan) is challenging because of the associated pronounced toxicities. And even when rituximab is utilized, patients need to be on high-dose steroids for at least 3-6 months before a rituximab response is achieved, Dr. Murrell said.
PRN1008 has three mechanisms of action targeting the drivers of pemphigus and other immune-mediated diseases, she explained. The drug blocks inflammatory B cells, neutrophils, and macrophages; eliminates downstream signalling by antidesmoglein autoantibodies; and prevents production of new autoantibodies. The drug has a double lock-and-key mechanism which makes it highly specific for its target, so treated patients are much less likely to experience bruising, diarrhea, and other off-target effects than is the case with other tyrosine kinase inhibitors.
“Also, PRN1008 is reversible. It comes off its target receptor after about 12 hours, at which point serum levels become low. So if any side effects do develop, the patient can recover quickly, unlike with rituximab, which involves ongoing inhibition of B cells for a long period of time,” the dermatologist noted.
BELIEVE was a phase 2 dose-ranging study of 27 patients with pemphigus treated open-label with PRN1008 for 12 weeks. The primary endpoint was control of disease activity, meaning no new lesions while established lesions showed some evidence of healing on no more than 0.5 mg/kg per day of prednisone. This outcome was achieved in 27% of participants at 2 weeks, 54% at 4 weeks, and 73% at 12 weeks. Autoantibody levels dropped by a mean of 65% at 12 weeks, with a median 70% reduction in Pemphigus Disease Activity Index scores while patients were on an average of just 12 mg of prednisone per day.
Phase 2b of BELIEVE included a separate group of 15 patients on PRN1008 for 24 weeks. Nine achieved a Pemphigus Disease Activity Index score of 0 or 1. Six patients had a complete response, meaning an absence of both new and established lesions while on no or a very low dose of prednisone. Another five patients were unable to achieve a complete response, and the jury was still out on another four still on treatment.
The side effect profile was benign in comparison with that of current standard therapies, she said. It consisted of a handful of cases of mild, transient nausea, headache, or upper abdominal pain and a few Grade 1 infections. There have been no severe treatment-related adverse events in BELIEVE participants.
Patients enrolled in the ongoing phase 3 PEGASUS trial start with a short course of high-dose corticosteroids, followed by double-blind randomization to PRN1008 at 400 mg twice a day or placebo, with a corticosteroid taper. The primary endpoint is durable complete remission at week 37, defined as no lesions being present for at least the previous 8 weeks while on no more than 5 mg/day of prednisone.
Secondary endpoints include cumulative corticosteroid dose through 36 weeks and patient-reported quality of life measures assessed out to 61 weeks. The trial is scheduled for completion in the spring of 2022.
Dr. Murrell reported serving as a consultant to the study sponsor, Principia Biopharma, as well as numerous other pharmaceutical companies.
MADRID – A novel Dedee F. Murrell, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
“In pemphigus, we have a considerable unmet medical need. We could do with a treatment that has rapid onset, is steroid sparing or avoiding, safe for chronic administration, avoids chronic B cell depletion – which is an issue with rituxumab – is efficacious in both newly diagnosed as well as in our commonly relapsing patients, and is convenient to administer,” observed Dr. Murrell, professor of dermatology at the University of New South Wales in Sydney.
In the phase 2 BELIEVE trial, the BTK inhibitor known for now only as PRN1008 appeared to check all the boxes. However, definitive evidence of the drug’s efficacy and safety must await the results of the ongoing, double-bind, placebo-controlled, pivotal phase 3 PEGASUS trial, which is enrolling a planned 120 patients with pemphigus vulgaris or foliaceus in 19 countries.
Pemphigus is driven by autoantibodies against desmogleins 1 and 3. Even in contemporary practice, this blistering disease has roughly a 5% mortality rate. Current management of the disease with high-dose corticosteroids at 1 mg/kg per day or more with or without rituximab (Rituxan) is challenging because of the associated pronounced toxicities. And even when rituximab is utilized, patients need to be on high-dose steroids for at least 3-6 months before a rituximab response is achieved, Dr. Murrell said.
PRN1008 has three mechanisms of action targeting the drivers of pemphigus and other immune-mediated diseases, she explained. The drug blocks inflammatory B cells, neutrophils, and macrophages; eliminates downstream signalling by antidesmoglein autoantibodies; and prevents production of new autoantibodies. The drug has a double lock-and-key mechanism which makes it highly specific for its target, so treated patients are much less likely to experience bruising, diarrhea, and other off-target effects than is the case with other tyrosine kinase inhibitors.
“Also, PRN1008 is reversible. It comes off its target receptor after about 12 hours, at which point serum levels become low. So if any side effects do develop, the patient can recover quickly, unlike with rituximab, which involves ongoing inhibition of B cells for a long period of time,” the dermatologist noted.
BELIEVE was a phase 2 dose-ranging study of 27 patients with pemphigus treated open-label with PRN1008 for 12 weeks. The primary endpoint was control of disease activity, meaning no new lesions while established lesions showed some evidence of healing on no more than 0.5 mg/kg per day of prednisone. This outcome was achieved in 27% of participants at 2 weeks, 54% at 4 weeks, and 73% at 12 weeks. Autoantibody levels dropped by a mean of 65% at 12 weeks, with a median 70% reduction in Pemphigus Disease Activity Index scores while patients were on an average of just 12 mg of prednisone per day.
Phase 2b of BELIEVE included a separate group of 15 patients on PRN1008 for 24 weeks. Nine achieved a Pemphigus Disease Activity Index score of 0 or 1. Six patients had a complete response, meaning an absence of both new and established lesions while on no or a very low dose of prednisone. Another five patients were unable to achieve a complete response, and the jury was still out on another four still on treatment.
The side effect profile was benign in comparison with that of current standard therapies, she said. It consisted of a handful of cases of mild, transient nausea, headache, or upper abdominal pain and a few Grade 1 infections. There have been no severe treatment-related adverse events in BELIEVE participants.
Patients enrolled in the ongoing phase 3 PEGASUS trial start with a short course of high-dose corticosteroids, followed by double-blind randomization to PRN1008 at 400 mg twice a day or placebo, with a corticosteroid taper. The primary endpoint is durable complete remission at week 37, defined as no lesions being present for at least the previous 8 weeks while on no more than 5 mg/day of prednisone.
Secondary endpoints include cumulative corticosteroid dose through 36 weeks and patient-reported quality of life measures assessed out to 61 weeks. The trial is scheduled for completion in the spring of 2022.
Dr. Murrell reported serving as a consultant to the study sponsor, Principia Biopharma, as well as numerous other pharmaceutical companies.
REPORTING FROM THE EADV CONGRESS
Adjuvant denosumab falls short in early-stage breast cancer
Adjuvant denosumab did not improve bone metastasis–free survival and related outcomes in women with early-stage breast cancer, according to a phase 3 trial.
“We hypothesised that denosumab would modify the clinical course of early breast cancer, delaying the development of clinical bone metastases with or without disease recurrence at other sites,” reported Robert Coleman, MBBS, MD, of the University of Sheffield, England, and colleagues. Their report is in The Lancet Oncology.
The randomized, placebo-controlled, phase 3 D-CARE study included 4,509 women with early-stage, high-risk disease. The effects of adding denosumab to standard-of-care adjuvant or neoadjuvant chemotherapy was studied in 389 institutions around the globe. In the initial treatment phase, study patients received denosumab or placebo every 3-4 weeks in combination with adjuvant or neoadjuvant chemotherapy for approximately 6 months.
After completion of chemotherapy, the dosing interval was extended to every 12 weeks (range, 14 days) for a total of 5 years. The median age of women who received denosumab was 50 years (range, 44-59 years), 65% of whom were hormone receptor positive, HER2-negative. In the study, patients were stratified by various factors, including type of therapy, age, lymph node status, geographical region, and others. The primary outcome was a composite endpoint of bone metastasis–free survival.
At 5-year follow-up, the researchers found no significant difference in bone metastasis–free survival between the denosumab and placebo treatment arms (median survival not reached in either arm; P = .70). With respect to safety, the most frequently seen grade 3 or higher treatment-emergent adverse events were neutropenia (15% vs. 15%), febrile neutropenia (5% vs. 6%), and leukopenia (3% vs. 3%). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2,241 patients treated with denosumab versus 4 (less than 1%) of 2,218 patients treated with placebo, Dr. Coleman and colleagues wrote.
The researchers acknowledged that a key limitation of the study was the smaller than anticipated number of events for efficacy outcomes. As a result, the study protocol was modified, which could have limited the statistical power of the study. “The results of this study do not support a role for denosumab as an antitumour agent in this setting,” they concluded.
Amgen funded the study. The authors reported financial affiliations with AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Covance, Lilly, Medivation, Merck Serono, Merck Sharp and Dohme, Novartis, Pfizer, and several others.
SOURCE: Coleman R et al. Lancet Oncol. 2019 Dec 2. doi: 10.1016/S1470-2045(19)30687-4.
Adjuvant denosumab did not improve bone metastasis–free survival and related outcomes in women with early-stage breast cancer, according to a phase 3 trial.
“We hypothesised that denosumab would modify the clinical course of early breast cancer, delaying the development of clinical bone metastases with or without disease recurrence at other sites,” reported Robert Coleman, MBBS, MD, of the University of Sheffield, England, and colleagues. Their report is in The Lancet Oncology.
The randomized, placebo-controlled, phase 3 D-CARE study included 4,509 women with early-stage, high-risk disease. The effects of adding denosumab to standard-of-care adjuvant or neoadjuvant chemotherapy was studied in 389 institutions around the globe. In the initial treatment phase, study patients received denosumab or placebo every 3-4 weeks in combination with adjuvant or neoadjuvant chemotherapy for approximately 6 months.
After completion of chemotherapy, the dosing interval was extended to every 12 weeks (range, 14 days) for a total of 5 years. The median age of women who received denosumab was 50 years (range, 44-59 years), 65% of whom were hormone receptor positive, HER2-negative. In the study, patients were stratified by various factors, including type of therapy, age, lymph node status, geographical region, and others. The primary outcome was a composite endpoint of bone metastasis–free survival.
At 5-year follow-up, the researchers found no significant difference in bone metastasis–free survival between the denosumab and placebo treatment arms (median survival not reached in either arm; P = .70). With respect to safety, the most frequently seen grade 3 or higher treatment-emergent adverse events were neutropenia (15% vs. 15%), febrile neutropenia (5% vs. 6%), and leukopenia (3% vs. 3%). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2,241 patients treated with denosumab versus 4 (less than 1%) of 2,218 patients treated with placebo, Dr. Coleman and colleagues wrote.
The researchers acknowledged that a key limitation of the study was the smaller than anticipated number of events for efficacy outcomes. As a result, the study protocol was modified, which could have limited the statistical power of the study. “The results of this study do not support a role for denosumab as an antitumour agent in this setting,” they concluded.
Amgen funded the study. The authors reported financial affiliations with AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Covance, Lilly, Medivation, Merck Serono, Merck Sharp and Dohme, Novartis, Pfizer, and several others.
SOURCE: Coleman R et al. Lancet Oncol. 2019 Dec 2. doi: 10.1016/S1470-2045(19)30687-4.
Adjuvant denosumab did not improve bone metastasis–free survival and related outcomes in women with early-stage breast cancer, according to a phase 3 trial.
“We hypothesised that denosumab would modify the clinical course of early breast cancer, delaying the development of clinical bone metastases with or without disease recurrence at other sites,” reported Robert Coleman, MBBS, MD, of the University of Sheffield, England, and colleagues. Their report is in The Lancet Oncology.
The randomized, placebo-controlled, phase 3 D-CARE study included 4,509 women with early-stage, high-risk disease. The effects of adding denosumab to standard-of-care adjuvant or neoadjuvant chemotherapy was studied in 389 institutions around the globe. In the initial treatment phase, study patients received denosumab or placebo every 3-4 weeks in combination with adjuvant or neoadjuvant chemotherapy for approximately 6 months.
After completion of chemotherapy, the dosing interval was extended to every 12 weeks (range, 14 days) for a total of 5 years. The median age of women who received denosumab was 50 years (range, 44-59 years), 65% of whom were hormone receptor positive, HER2-negative. In the study, patients were stratified by various factors, including type of therapy, age, lymph node status, geographical region, and others. The primary outcome was a composite endpoint of bone metastasis–free survival.
At 5-year follow-up, the researchers found no significant difference in bone metastasis–free survival between the denosumab and placebo treatment arms (median survival not reached in either arm; P = .70). With respect to safety, the most frequently seen grade 3 or higher treatment-emergent adverse events were neutropenia (15% vs. 15%), febrile neutropenia (5% vs. 6%), and leukopenia (3% vs. 3%). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2,241 patients treated with denosumab versus 4 (less than 1%) of 2,218 patients treated with placebo, Dr. Coleman and colleagues wrote.
The researchers acknowledged that a key limitation of the study was the smaller than anticipated number of events for efficacy outcomes. As a result, the study protocol was modified, which could have limited the statistical power of the study. “The results of this study do not support a role for denosumab as an antitumour agent in this setting,” they concluded.
Amgen funded the study. The authors reported financial affiliations with AbbVie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Covance, Lilly, Medivation, Merck Serono, Merck Sharp and Dohme, Novartis, Pfizer, and several others.
SOURCE: Coleman R et al. Lancet Oncol. 2019 Dec 2. doi: 10.1016/S1470-2045(19)30687-4.
FROM LANCET ONCOLOGY
Lp(a) molar concentration flags CVD, diabetes risk
Lipoprotein(a) molar concentration, rather than apolipoprotein(a) size, appears to be the factor that drives lipoprotein(a)-based cardiovascular disease, according to research published in the Journal of the American College of Cardiology.
The causal association between lipoprotein(a), or Lp(a), and cardiovascular disease has been previously established, but exactly what attribute of Lp(a) is related to cardiovascular risk is not known, Daniel F. Gudbjartsson, PhD, of deCODE genetics and the University of Iceland in Reykjavik, and colleagues wrote in their study. The researchers set out to determine whether Lp(a) molar concentration or apolipoprotein(a), or apo(a), size affects cardiovascular risk. In addition, Dr. Gudbjartsson and colleagues examined the relationship between Lp(a) and type 2 diabetes. While low levels of Lp(a) have been linked to type 2 diabetes, the researchers sought to examine whether low Lp(a) molar concentration levels were also associated with type 2 diabetes risk.
“With Lp(a)-lowering drugs being developed, it is important to understand which attributes of Lp(a) best capture the cardiovascular risk and the consequences of Lp(a) lowering,” noted Dr. Gudbjartsson and colleagues.
Using Mendelian randomization, the researchers assessed Lp(a) molar concentration and kringle IV type 2 (KIV-2) repeat sequence variants to determine a causal relationship between both variants and disease risk. Lp(a) molar concentration serum samples were measured using particle-enhanced turbidimetric immunoassay, while KIV-2 repeats were genotyped with real-time polymerase chain reaction.
Overall, 143,087 participants from Iceland had their genetic information analyzed; of these, 17,715 participants had coronary artery disease, and 8,734 had type 2 diabetes. Lp(a) molecular concentration was analyzed in 12,137 participants and genetically imputed into 130,950 Icelanders, and KIV-2 repeats were estimated in 22,771 Icelanders and genetically imputed into 120,316 Icelanders.
Dr. Gudbjartsson and colleagues found there was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. In participants in whom Lp(a) molar concentration was at the 79th percentile (50 units of molarity [nM]), the odds ratio was 1.11, and for those in the 99th percentile (250 nM), there was an odds ratio of 2.01 when compared with participants with a median Lp(a) molar concentration of 14 nM. “Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size,” the researchers said.
Participants who were not at increased risk for CAD included those with few KIV-2 repeats and participants with the splice variant G4925A. “This suggested that risk prediction based on Lp(a) should only depend on molar concentration and that treatment of Lp(a) should focus on lowering the molar concentration in subjects with high Lp(a) levels, regardless of the apo(a) size distribution,” Dr. Gudbjartsson and colleagues wrote.
Among participants with type 2 diabetes examined, the 10% of participants with Lp(a) molar concentrations of less than 3.5 nM were at the highest risk of developing type 2 diabetes.
In an accompanying editorial, Benoit J. Arsenault, PhD, of the Quebec Heart and Lung Institute, said that the findings of an association between Lp(a) concentration and atherosclerotic cardiovascular diseases (ASCVD) from Gudbjartsson et al. are important, particularly if they can be replicated in more diverse populations (doi: 10.1016/j.jacc.2019.06.083). “Investigating the association between Lp(a) levels, apo(a) isoform size, and ASCVD risk in different populations is important because the distribution of Lp(a) levels appears to be different across ethnic groups,” he said.
Despite the link between absolute Lp(a) concentrations and cardiovascular disease, cardiovascular outcome trials will need be conducted, Dr. Arsenault noted.
“In the post-statin and post-genomic era, finding much needed therapeutic targets for residual cardiovascular risk can be compared to a gold-digging expedition. Like a map to the location of the gold, GWAS [genome-wide association studies] and Mendelian randomization studies are consistently pointing us in the direction of Lp(a),” he said. “It is time to coordinate our efforts to dig where the map told us, to see once and for all if we will find the golden target of residual cardiovascular risk that we are hoping for and to give hope to high-risk patients with elevated Lp(a) levels.”
Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.
SOURCE: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.
Lipoprotein(a) molar concentration, rather than apolipoprotein(a) size, appears to be the factor that drives lipoprotein(a)-based cardiovascular disease, according to research published in the Journal of the American College of Cardiology.
The causal association between lipoprotein(a), or Lp(a), and cardiovascular disease has been previously established, but exactly what attribute of Lp(a) is related to cardiovascular risk is not known, Daniel F. Gudbjartsson, PhD, of deCODE genetics and the University of Iceland in Reykjavik, and colleagues wrote in their study. The researchers set out to determine whether Lp(a) molar concentration or apolipoprotein(a), or apo(a), size affects cardiovascular risk. In addition, Dr. Gudbjartsson and colleagues examined the relationship between Lp(a) and type 2 diabetes. While low levels of Lp(a) have been linked to type 2 diabetes, the researchers sought to examine whether low Lp(a) molar concentration levels were also associated with type 2 diabetes risk.
“With Lp(a)-lowering drugs being developed, it is important to understand which attributes of Lp(a) best capture the cardiovascular risk and the consequences of Lp(a) lowering,” noted Dr. Gudbjartsson and colleagues.
Using Mendelian randomization, the researchers assessed Lp(a) molar concentration and kringle IV type 2 (KIV-2) repeat sequence variants to determine a causal relationship between both variants and disease risk. Lp(a) molar concentration serum samples were measured using particle-enhanced turbidimetric immunoassay, while KIV-2 repeats were genotyped with real-time polymerase chain reaction.
Overall, 143,087 participants from Iceland had their genetic information analyzed; of these, 17,715 participants had coronary artery disease, and 8,734 had type 2 diabetes. Lp(a) molecular concentration was analyzed in 12,137 participants and genetically imputed into 130,950 Icelanders, and KIV-2 repeats were estimated in 22,771 Icelanders and genetically imputed into 120,316 Icelanders.
Dr. Gudbjartsson and colleagues found there was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. In participants in whom Lp(a) molar concentration was at the 79th percentile (50 units of molarity [nM]), the odds ratio was 1.11, and for those in the 99th percentile (250 nM), there was an odds ratio of 2.01 when compared with participants with a median Lp(a) molar concentration of 14 nM. “Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size,” the researchers said.
Participants who were not at increased risk for CAD included those with few KIV-2 repeats and participants with the splice variant G4925A. “This suggested that risk prediction based on Lp(a) should only depend on molar concentration and that treatment of Lp(a) should focus on lowering the molar concentration in subjects with high Lp(a) levels, regardless of the apo(a) size distribution,” Dr. Gudbjartsson and colleagues wrote.
Among participants with type 2 diabetes examined, the 10% of participants with Lp(a) molar concentrations of less than 3.5 nM were at the highest risk of developing type 2 diabetes.
In an accompanying editorial, Benoit J. Arsenault, PhD, of the Quebec Heart and Lung Institute, said that the findings of an association between Lp(a) concentration and atherosclerotic cardiovascular diseases (ASCVD) from Gudbjartsson et al. are important, particularly if they can be replicated in more diverse populations (doi: 10.1016/j.jacc.2019.06.083). “Investigating the association between Lp(a) levels, apo(a) isoform size, and ASCVD risk in different populations is important because the distribution of Lp(a) levels appears to be different across ethnic groups,” he said.
Despite the link between absolute Lp(a) concentrations and cardiovascular disease, cardiovascular outcome trials will need be conducted, Dr. Arsenault noted.
“In the post-statin and post-genomic era, finding much needed therapeutic targets for residual cardiovascular risk can be compared to a gold-digging expedition. Like a map to the location of the gold, GWAS [genome-wide association studies] and Mendelian randomization studies are consistently pointing us in the direction of Lp(a),” he said. “It is time to coordinate our efforts to dig where the map told us, to see once and for all if we will find the golden target of residual cardiovascular risk that we are hoping for and to give hope to high-risk patients with elevated Lp(a) levels.”
Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.
SOURCE: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.
Lipoprotein(a) molar concentration, rather than apolipoprotein(a) size, appears to be the factor that drives lipoprotein(a)-based cardiovascular disease, according to research published in the Journal of the American College of Cardiology.
The causal association between lipoprotein(a), or Lp(a), and cardiovascular disease has been previously established, but exactly what attribute of Lp(a) is related to cardiovascular risk is not known, Daniel F. Gudbjartsson, PhD, of deCODE genetics and the University of Iceland in Reykjavik, and colleagues wrote in their study. The researchers set out to determine whether Lp(a) molar concentration or apolipoprotein(a), or apo(a), size affects cardiovascular risk. In addition, Dr. Gudbjartsson and colleagues examined the relationship between Lp(a) and type 2 diabetes. While low levels of Lp(a) have been linked to type 2 diabetes, the researchers sought to examine whether low Lp(a) molar concentration levels were also associated with type 2 diabetes risk.
“With Lp(a)-lowering drugs being developed, it is important to understand which attributes of Lp(a) best capture the cardiovascular risk and the consequences of Lp(a) lowering,” noted Dr. Gudbjartsson and colleagues.
Using Mendelian randomization, the researchers assessed Lp(a) molar concentration and kringle IV type 2 (KIV-2) repeat sequence variants to determine a causal relationship between both variants and disease risk. Lp(a) molar concentration serum samples were measured using particle-enhanced turbidimetric immunoassay, while KIV-2 repeats were genotyped with real-time polymerase chain reaction.
Overall, 143,087 participants from Iceland had their genetic information analyzed; of these, 17,715 participants had coronary artery disease, and 8,734 had type 2 diabetes. Lp(a) molecular concentration was analyzed in 12,137 participants and genetically imputed into 130,950 Icelanders, and KIV-2 repeats were estimated in 22,771 Icelanders and genetically imputed into 120,316 Icelanders.
Dr. Gudbjartsson and colleagues found there was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. In participants in whom Lp(a) molar concentration was at the 79th percentile (50 units of molarity [nM]), the odds ratio was 1.11, and for those in the 99th percentile (250 nM), there was an odds ratio of 2.01 when compared with participants with a median Lp(a) molar concentration of 14 nM. “Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size,” the researchers said.
Participants who were not at increased risk for CAD included those with few KIV-2 repeats and participants with the splice variant G4925A. “This suggested that risk prediction based on Lp(a) should only depend on molar concentration and that treatment of Lp(a) should focus on lowering the molar concentration in subjects with high Lp(a) levels, regardless of the apo(a) size distribution,” Dr. Gudbjartsson and colleagues wrote.
Among participants with type 2 diabetes examined, the 10% of participants with Lp(a) molar concentrations of less than 3.5 nM were at the highest risk of developing type 2 diabetes.
In an accompanying editorial, Benoit J. Arsenault, PhD, of the Quebec Heart and Lung Institute, said that the findings of an association between Lp(a) concentration and atherosclerotic cardiovascular diseases (ASCVD) from Gudbjartsson et al. are important, particularly if they can be replicated in more diverse populations (doi: 10.1016/j.jacc.2019.06.083). “Investigating the association between Lp(a) levels, apo(a) isoform size, and ASCVD risk in different populations is important because the distribution of Lp(a) levels appears to be different across ethnic groups,” he said.
Despite the link between absolute Lp(a) concentrations and cardiovascular disease, cardiovascular outcome trials will need be conducted, Dr. Arsenault noted.
“In the post-statin and post-genomic era, finding much needed therapeutic targets for residual cardiovascular risk can be compared to a gold-digging expedition. Like a map to the location of the gold, GWAS [genome-wide association studies] and Mendelian randomization studies are consistently pointing us in the direction of Lp(a),” he said. “It is time to coordinate our efforts to dig where the map told us, to see once and for all if we will find the golden target of residual cardiovascular risk that we are hoping for and to give hope to high-risk patients with elevated Lp(a) levels.”
Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.
SOURCE: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Key clinical point:
Major finding: There was a dose-dependent association between Lp(a) molar concentration and risk of coronary artery disease (CAD), peripheral artery disease, aortic valve stenosis, heart failure, and lifespan.
Study details: A case-control study of genetic information from 143,087 Icelandic participants.
Disclosures: Dr. Gudbjartsson and 19 other authors reported being employees of deCODE genetics, owned by Amgen, which is developing Lp(a)-lowering drugs related to the study findings. The other authors reported no relevant conflict of interest. Dr. Arsenault reported being supported by the Fonds de recherche du Québec: Santé and the Canadian Institutes of Health Research; has received research funding from Pfizer, Merck, and Ionis; and was a former consultant for Pfizer and Novartis.
Source: Gudbjartsson DF et al. J Am Coll Cardiol. 2019. doi: 10.1016/j.jacc.2019.10.019.