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FDA committee votes yes on romosozumab for osteoporosis
In an 18-1 vote, the FDA’s Bone, Reproductive, and Urologic Drugs Advisory Committee agreed that the risk-benefit profile of romosozumab, to be marketed by Amgen as Evenity, was favorable enough to support approval. Relative risk reductions of up to 75%, compared with placebo, and 36%, compared with alendronate, were seen in pivotal clinical trials.
A signal for increased major adverse cardiovascular events (MACE) among those receiving romosozumab had been seen in just one of the clinical trials, with a hazard ratio for MACE of 1.87 for those taking romosozumab, compared with those taking alendronate (95% confidence interval, 1.11-3.14).
Committee members were enthusiastic about the efficacy of the monoclonal antibody, which binds to sclerostin and prevents its inhibiting effect, allowing robust new bone formation. “I want to emphasize the remarkable skeletal efficacy of this drug; truly, it’s better than anything we’ve seen before,” said committee member Sundeep Khosla, MD, professor of medicine and physiology at the Mayo Clinic, Rochester, Minn.
In its application, the sponsor relied on two clinical trials. In the first, 7,180 women with osteoporosis aged 55-90 years were randomized 1:1 to receive romosozumab or placebo for 12 months in a double-blind trial. After this time, participants in each arm received follow-on treatment with denosumab (Prolia) for another 12 months. This study, dubbed Trial 337, followed morphometric vertebral fractures at 12 and 24 months. Morphometric fractures included both symptomatic and asymptomatic fractures.
Those treated with romosozumab had relative risk reductions of new vertebral fractures of 73% and 75%, compared with those given placebo at 12 and 24 months. Absolute risk reductions for vertebral fractures were 1.30% and 1.89% at 1 and 2 years (P less than .001 for both).
The second study, Trial 142, was a double-blind, active-controlled study that included 4,093 women aged 55-90 years with osteoporosis and a history of prior fragility fracture. Participants were randomized 1:1 to receive either romosozumab or alendronate for 12 months, with an additional variable period of alendronate follow-on of at least 12 months for both arms.
For Trial 142, one primary endpoint was morphometric vertebral fractures at month 24. An additional endpoint, clinical fracture, was a composite of symptomatic vertebral fractures and nonvertebral fractures. This second endpoint was assessed at the time of primary analysis, an event-driven cut point that occurred when at least 330 participants experienced a clinical fracture and all participants had completed the 24-month visit.
Hip fractures were less common among those given romosozumab, and bone mineral density increased significantly as well.
Vertebral fractures were reduced by 36% in the romosozumab group relative to the alendronate group, and clinical fractures by 27% (P less than .001 for both).
Overall, the number of adverse events for the more than 7,500 patients in the safety population was similar between those receiving romosozumab and either placebo or alendronate, said Scott Wasserman, MD, vice president of global development for Amgen.
However, in Trial 142, which included patients who were slightly older and on more cardiovascular medications at baseline than in Trial 337, MACE – defined as cardiovascular death, MI, and stroke – occurred more frequently among those taking romosozumab, driven primarily by increased cardiac and cerebral ischemic events occurring within the first 12 months of beginning the study drug. At 12 months, the romosozumab arm saw 41 instances of MACE, compared with 22 in the alendronate arm to produce the HR of 1.87 (2.0% vs. 1.1%).
With regard to the imbalance in MACE seen in Trial 142, both the FDA and presenters for the sponsor entertained the notion that alendronate may have been somewhat protective for cardiovascular events. Although there is some biologic plausibility for a cardioprotective event for bisphosphonates, alendronate is highly specific for bone activity and the preponderance of previous studies have not shown such cardioprotection, the FDA, sponsors, and committee members all agreed.
Marc Sabatine, MD, the Lewis Dexter, MD Distinguished Chair in Cardiovascular Medicine at Harvard Medical School, Boston, was available to answer questions on behalf of the study’s sponsor. He noted at several points during the meeting just how few total cardiovascular events were seen overall in the romosozumab trial. The overall small numbers, he said, made it very difficult to distinguish whether the smaller number of MACE seen in the alendronate arm of Trial 142 were a true safety signal or just “a play of chance.”
Almost all the committee’s questioning and discussion centered on this potential increased cardiovascular risk. Amgen, in discussion with the FDA, had agreed to a black box warning designed to wave off prescribing romosozumab to those at increased risk for cardiovascular disease, focusing on those with a history of MI or stroke.
Additionally, the sponsor proposed a postmarketing real-world observational study to track incidence of MACE in those receiving romosozumab, comparing them with those receiving standard of care for osteoporosis.
Several committee members pointed out a problem with the proposed safety mitigation scheme: By conducting a postmarketing observational study for a drug that has a black-box warning to exclude those at high risk for MACE, the chance of detecting an actual cardiovascular safety problem plummets. “This is the textbook example of when observational studies struggle or are virtually guaranteed to fail,” noted Tobias Gerhard, PhD, a pharmacoepidemiologist at Rutgers University, New Brunswick, N.J.
On the other hand, noted several committee members, pausing to conduct a premarketing randomized, controlled trial would keep a beneficial drug away from a population in need. A postmarketing randomized, controlled trial, even a simple trial, still presents challenges, some of the committee acknowledged. Dr. Khosla voiced the opinion that “A randomized, controlled trial is virtually impossible.”
The committee, which was charged with discussing, but not voting on, what additional data should be obtained – and when – to sort out the cardiovascular safety question, was approximately evenly divided in the matter of whether an observational or registry-based trial, or a controlled trial, would be the best path forward.
Committee member Robert A. Adler, MD, put a realistic frame around the debate. “As an endocrinologist, I deal with nuances every day. I really think the kind of clinician who is going to be using this drug is used to dealing with benefits and risks and trying to tailor treatment to a given patient,” said Dr. Adler, professor of internal medicine and epidemiology at Virginia Commonwealth University, Richmond.
In its proposed indication, Amgen defined the population of menopausal women at high risk of fracture as those with a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Romosozumab would be given as a once-monthly subcutaneous injection of 210 mg for a period of 12 months, to be followed by antiresorptive therapy.
Most of the participants in the clinical trials resided outside the United States, primarily because of the difficulty of recruiting clinical trial participants in the United States, Amgen officials said during their presentation. However, neither the time to the first positively adjudicated MACE nor bone mineral density responses at month 12 differed significantly across the various geographic regions where clinical trial sites were located, said Rachel Wagman, MD, the executive medical director of global clinical development for Amgen. Still, several committee members called for postmarketing data to focus on U.S. patients.
Romosozumab was approved for marketing in Japan on Jan. 8, 2019; approval is also being sought in Europe .
The FDA usually follows the recommendations of its advisory panels.
In an 18-1 vote, the FDA’s Bone, Reproductive, and Urologic Drugs Advisory Committee agreed that the risk-benefit profile of romosozumab, to be marketed by Amgen as Evenity, was favorable enough to support approval. Relative risk reductions of up to 75%, compared with placebo, and 36%, compared with alendronate, were seen in pivotal clinical trials.
A signal for increased major adverse cardiovascular events (MACE) among those receiving romosozumab had been seen in just one of the clinical trials, with a hazard ratio for MACE of 1.87 for those taking romosozumab, compared with those taking alendronate (95% confidence interval, 1.11-3.14).
Committee members were enthusiastic about the efficacy of the monoclonal antibody, which binds to sclerostin and prevents its inhibiting effect, allowing robust new bone formation. “I want to emphasize the remarkable skeletal efficacy of this drug; truly, it’s better than anything we’ve seen before,” said committee member Sundeep Khosla, MD, professor of medicine and physiology at the Mayo Clinic, Rochester, Minn.
In its application, the sponsor relied on two clinical trials. In the first, 7,180 women with osteoporosis aged 55-90 years were randomized 1:1 to receive romosozumab or placebo for 12 months in a double-blind trial. After this time, participants in each arm received follow-on treatment with denosumab (Prolia) for another 12 months. This study, dubbed Trial 337, followed morphometric vertebral fractures at 12 and 24 months. Morphometric fractures included both symptomatic and asymptomatic fractures.
Those treated with romosozumab had relative risk reductions of new vertebral fractures of 73% and 75%, compared with those given placebo at 12 and 24 months. Absolute risk reductions for vertebral fractures were 1.30% and 1.89% at 1 and 2 years (P less than .001 for both).
The second study, Trial 142, was a double-blind, active-controlled study that included 4,093 women aged 55-90 years with osteoporosis and a history of prior fragility fracture. Participants were randomized 1:1 to receive either romosozumab or alendronate for 12 months, with an additional variable period of alendronate follow-on of at least 12 months for both arms.
For Trial 142, one primary endpoint was morphometric vertebral fractures at month 24. An additional endpoint, clinical fracture, was a composite of symptomatic vertebral fractures and nonvertebral fractures. This second endpoint was assessed at the time of primary analysis, an event-driven cut point that occurred when at least 330 participants experienced a clinical fracture and all participants had completed the 24-month visit.
Hip fractures were less common among those given romosozumab, and bone mineral density increased significantly as well.
Vertebral fractures were reduced by 36% in the romosozumab group relative to the alendronate group, and clinical fractures by 27% (P less than .001 for both).
Overall, the number of adverse events for the more than 7,500 patients in the safety population was similar between those receiving romosozumab and either placebo or alendronate, said Scott Wasserman, MD, vice president of global development for Amgen.
However, in Trial 142, which included patients who were slightly older and on more cardiovascular medications at baseline than in Trial 337, MACE – defined as cardiovascular death, MI, and stroke – occurred more frequently among those taking romosozumab, driven primarily by increased cardiac and cerebral ischemic events occurring within the first 12 months of beginning the study drug. At 12 months, the romosozumab arm saw 41 instances of MACE, compared with 22 in the alendronate arm to produce the HR of 1.87 (2.0% vs. 1.1%).
With regard to the imbalance in MACE seen in Trial 142, both the FDA and presenters for the sponsor entertained the notion that alendronate may have been somewhat protective for cardiovascular events. Although there is some biologic plausibility for a cardioprotective event for bisphosphonates, alendronate is highly specific for bone activity and the preponderance of previous studies have not shown such cardioprotection, the FDA, sponsors, and committee members all agreed.
Marc Sabatine, MD, the Lewis Dexter, MD Distinguished Chair in Cardiovascular Medicine at Harvard Medical School, Boston, was available to answer questions on behalf of the study’s sponsor. He noted at several points during the meeting just how few total cardiovascular events were seen overall in the romosozumab trial. The overall small numbers, he said, made it very difficult to distinguish whether the smaller number of MACE seen in the alendronate arm of Trial 142 were a true safety signal or just “a play of chance.”
Almost all the committee’s questioning and discussion centered on this potential increased cardiovascular risk. Amgen, in discussion with the FDA, had agreed to a black box warning designed to wave off prescribing romosozumab to those at increased risk for cardiovascular disease, focusing on those with a history of MI or stroke.
Additionally, the sponsor proposed a postmarketing real-world observational study to track incidence of MACE in those receiving romosozumab, comparing them with those receiving standard of care for osteoporosis.
Several committee members pointed out a problem with the proposed safety mitigation scheme: By conducting a postmarketing observational study for a drug that has a black-box warning to exclude those at high risk for MACE, the chance of detecting an actual cardiovascular safety problem plummets. “This is the textbook example of when observational studies struggle or are virtually guaranteed to fail,” noted Tobias Gerhard, PhD, a pharmacoepidemiologist at Rutgers University, New Brunswick, N.J.
On the other hand, noted several committee members, pausing to conduct a premarketing randomized, controlled trial would keep a beneficial drug away from a population in need. A postmarketing randomized, controlled trial, even a simple trial, still presents challenges, some of the committee acknowledged. Dr. Khosla voiced the opinion that “A randomized, controlled trial is virtually impossible.”
The committee, which was charged with discussing, but not voting on, what additional data should be obtained – and when – to sort out the cardiovascular safety question, was approximately evenly divided in the matter of whether an observational or registry-based trial, or a controlled trial, would be the best path forward.
Committee member Robert A. Adler, MD, put a realistic frame around the debate. “As an endocrinologist, I deal with nuances every day. I really think the kind of clinician who is going to be using this drug is used to dealing with benefits and risks and trying to tailor treatment to a given patient,” said Dr. Adler, professor of internal medicine and epidemiology at Virginia Commonwealth University, Richmond.
In its proposed indication, Amgen defined the population of menopausal women at high risk of fracture as those with a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Romosozumab would be given as a once-monthly subcutaneous injection of 210 mg for a period of 12 months, to be followed by antiresorptive therapy.
Most of the participants in the clinical trials resided outside the United States, primarily because of the difficulty of recruiting clinical trial participants in the United States, Amgen officials said during their presentation. However, neither the time to the first positively adjudicated MACE nor bone mineral density responses at month 12 differed significantly across the various geographic regions where clinical trial sites were located, said Rachel Wagman, MD, the executive medical director of global clinical development for Amgen. Still, several committee members called for postmarketing data to focus on U.S. patients.
Romosozumab was approved for marketing in Japan on Jan. 8, 2019; approval is also being sought in Europe .
The FDA usually follows the recommendations of its advisory panels.
In an 18-1 vote, the FDA’s Bone, Reproductive, and Urologic Drugs Advisory Committee agreed that the risk-benefit profile of romosozumab, to be marketed by Amgen as Evenity, was favorable enough to support approval. Relative risk reductions of up to 75%, compared with placebo, and 36%, compared with alendronate, were seen in pivotal clinical trials.
A signal for increased major adverse cardiovascular events (MACE) among those receiving romosozumab had been seen in just one of the clinical trials, with a hazard ratio for MACE of 1.87 for those taking romosozumab, compared with those taking alendronate (95% confidence interval, 1.11-3.14).
Committee members were enthusiastic about the efficacy of the monoclonal antibody, which binds to sclerostin and prevents its inhibiting effect, allowing robust new bone formation. “I want to emphasize the remarkable skeletal efficacy of this drug; truly, it’s better than anything we’ve seen before,” said committee member Sundeep Khosla, MD, professor of medicine and physiology at the Mayo Clinic, Rochester, Minn.
In its application, the sponsor relied on two clinical trials. In the first, 7,180 women with osteoporosis aged 55-90 years were randomized 1:1 to receive romosozumab or placebo for 12 months in a double-blind trial. After this time, participants in each arm received follow-on treatment with denosumab (Prolia) for another 12 months. This study, dubbed Trial 337, followed morphometric vertebral fractures at 12 and 24 months. Morphometric fractures included both symptomatic and asymptomatic fractures.
Those treated with romosozumab had relative risk reductions of new vertebral fractures of 73% and 75%, compared with those given placebo at 12 and 24 months. Absolute risk reductions for vertebral fractures were 1.30% and 1.89% at 1 and 2 years (P less than .001 for both).
The second study, Trial 142, was a double-blind, active-controlled study that included 4,093 women aged 55-90 years with osteoporosis and a history of prior fragility fracture. Participants were randomized 1:1 to receive either romosozumab or alendronate for 12 months, with an additional variable period of alendronate follow-on of at least 12 months for both arms.
For Trial 142, one primary endpoint was morphometric vertebral fractures at month 24. An additional endpoint, clinical fracture, was a composite of symptomatic vertebral fractures and nonvertebral fractures. This second endpoint was assessed at the time of primary analysis, an event-driven cut point that occurred when at least 330 participants experienced a clinical fracture and all participants had completed the 24-month visit.
Hip fractures were less common among those given romosozumab, and bone mineral density increased significantly as well.
Vertebral fractures were reduced by 36% in the romosozumab group relative to the alendronate group, and clinical fractures by 27% (P less than .001 for both).
Overall, the number of adverse events for the more than 7,500 patients in the safety population was similar between those receiving romosozumab and either placebo or alendronate, said Scott Wasserman, MD, vice president of global development for Amgen.
However, in Trial 142, which included patients who were slightly older and on more cardiovascular medications at baseline than in Trial 337, MACE – defined as cardiovascular death, MI, and stroke – occurred more frequently among those taking romosozumab, driven primarily by increased cardiac and cerebral ischemic events occurring within the first 12 months of beginning the study drug. At 12 months, the romosozumab arm saw 41 instances of MACE, compared with 22 in the alendronate arm to produce the HR of 1.87 (2.0% vs. 1.1%).
With regard to the imbalance in MACE seen in Trial 142, both the FDA and presenters for the sponsor entertained the notion that alendronate may have been somewhat protective for cardiovascular events. Although there is some biologic plausibility for a cardioprotective event for bisphosphonates, alendronate is highly specific for bone activity and the preponderance of previous studies have not shown such cardioprotection, the FDA, sponsors, and committee members all agreed.
Marc Sabatine, MD, the Lewis Dexter, MD Distinguished Chair in Cardiovascular Medicine at Harvard Medical School, Boston, was available to answer questions on behalf of the study’s sponsor. He noted at several points during the meeting just how few total cardiovascular events were seen overall in the romosozumab trial. The overall small numbers, he said, made it very difficult to distinguish whether the smaller number of MACE seen in the alendronate arm of Trial 142 were a true safety signal or just “a play of chance.”
Almost all the committee’s questioning and discussion centered on this potential increased cardiovascular risk. Amgen, in discussion with the FDA, had agreed to a black box warning designed to wave off prescribing romosozumab to those at increased risk for cardiovascular disease, focusing on those with a history of MI or stroke.
Additionally, the sponsor proposed a postmarketing real-world observational study to track incidence of MACE in those receiving romosozumab, comparing them with those receiving standard of care for osteoporosis.
Several committee members pointed out a problem with the proposed safety mitigation scheme: By conducting a postmarketing observational study for a drug that has a black-box warning to exclude those at high risk for MACE, the chance of detecting an actual cardiovascular safety problem plummets. “This is the textbook example of when observational studies struggle or are virtually guaranteed to fail,” noted Tobias Gerhard, PhD, a pharmacoepidemiologist at Rutgers University, New Brunswick, N.J.
On the other hand, noted several committee members, pausing to conduct a premarketing randomized, controlled trial would keep a beneficial drug away from a population in need. A postmarketing randomized, controlled trial, even a simple trial, still presents challenges, some of the committee acknowledged. Dr. Khosla voiced the opinion that “A randomized, controlled trial is virtually impossible.”
The committee, which was charged with discussing, but not voting on, what additional data should be obtained – and when – to sort out the cardiovascular safety question, was approximately evenly divided in the matter of whether an observational or registry-based trial, or a controlled trial, would be the best path forward.
Committee member Robert A. Adler, MD, put a realistic frame around the debate. “As an endocrinologist, I deal with nuances every day. I really think the kind of clinician who is going to be using this drug is used to dealing with benefits and risks and trying to tailor treatment to a given patient,” said Dr. Adler, professor of internal medicine and epidemiology at Virginia Commonwealth University, Richmond.
In its proposed indication, Amgen defined the population of menopausal women at high risk of fracture as those with a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Romosozumab would be given as a once-monthly subcutaneous injection of 210 mg for a period of 12 months, to be followed by antiresorptive therapy.
Most of the participants in the clinical trials resided outside the United States, primarily because of the difficulty of recruiting clinical trial participants in the United States, Amgen officials said during their presentation. However, neither the time to the first positively adjudicated MACE nor bone mineral density responses at month 12 differed significantly across the various geographic regions where clinical trial sites were located, said Rachel Wagman, MD, the executive medical director of global clinical development for Amgen. Still, several committee members called for postmarketing data to focus on U.S. patients.
Romosozumab was approved for marketing in Japan on Jan. 8, 2019; approval is also being sought in Europe .
The FDA usually follows the recommendations of its advisory panels.
More than 23% of antibiotic fills deemed unnecessary
More than 23% of all antibiotic prescriptions filled in 2016 were medically unnecessary, and another 36% were questionable, according to an analysis of prescribing data for 19.2 million children and nonelderly adults.
Based on the diagnosis codes for 15.5 million prescriptions filled that year, at least 3.6 million (23.2%) were “inappropriate” – prescribed for conditions for which an antibiotic is almost never recommended, such as acute upper respiratory conditions – and 5.5 million (35.5%) were “potentially inappropriate” – conditions such as acute sinusitis or otitis media, for which an antibiotic is only sometimes recommended, Kao-Ping Chua, MD, PhD, of the University of Michigan, Ann Arbor, and his associates reported in the BMJ.
Only 12.8% of filled prescriptions for the 39 oral antibiotics assessed were classified as “appropriate” under the investigators’ scheme, which assigned an antibiotic appropriateness level to all 91,738 diagnostic codes in the 2016 ICD-10-CM. Finally, 28.5% of antibiotic fills were not associated with a recent diagnosis code, suggesting that they involved phone consultations that did not result in claims or visits that were paid out of pocket and did not make it into the Truven MarketScan Commercial Claims and Encounters database used in the study, the investigators said.
The three highest levels of inappropriate fills were 70.7% in office-based settings, 6.2% in urgent care centers, and 4.7% in emergency departments.
“The unacceptable scale of inappropriate antibiotic prescribing in the United States ... underscores the need to learn more about prescriptions that aren’t justified by a diagnosis – or are written after no diagnosis at all,” coinvestigator Jeffrey Linder, MD, of Northwestern University, Chicago, said in a written statement.
Prescriptions for children, who represented almost a quarter of all antibiotic fills, were less likely to be inappropriate than those for adults aged 18-64 years. Proportions for children were 17.1% inappropriate, 48.7% potentially inappropriate, and 17.0% appropriate, compared with 25.2%, 31.4%, and 11.4%, respectively, for adults, Dr. Chua and his associates said.
“This study shows how data and analytics can help us identify and understand important challenges facing the American health care system,” said Gopal Khanna, director of the Agency for Healthcare Research and Quality, which funded the study. “We now need to use these data to spur change in the prescribing of these very common medications.”
SOURCE: Chua K-P et al. BMJ. 2019;364:k5092. doi: 10.1136/bmj.k5092.
More than 23% of all antibiotic prescriptions filled in 2016 were medically unnecessary, and another 36% were questionable, according to an analysis of prescribing data for 19.2 million children and nonelderly adults.
Based on the diagnosis codes for 15.5 million prescriptions filled that year, at least 3.6 million (23.2%) were “inappropriate” – prescribed for conditions for which an antibiotic is almost never recommended, such as acute upper respiratory conditions – and 5.5 million (35.5%) were “potentially inappropriate” – conditions such as acute sinusitis or otitis media, for which an antibiotic is only sometimes recommended, Kao-Ping Chua, MD, PhD, of the University of Michigan, Ann Arbor, and his associates reported in the BMJ.
Only 12.8% of filled prescriptions for the 39 oral antibiotics assessed were classified as “appropriate” under the investigators’ scheme, which assigned an antibiotic appropriateness level to all 91,738 diagnostic codes in the 2016 ICD-10-CM. Finally, 28.5% of antibiotic fills were not associated with a recent diagnosis code, suggesting that they involved phone consultations that did not result in claims or visits that were paid out of pocket and did not make it into the Truven MarketScan Commercial Claims and Encounters database used in the study, the investigators said.
The three highest levels of inappropriate fills were 70.7% in office-based settings, 6.2% in urgent care centers, and 4.7% in emergency departments.
“The unacceptable scale of inappropriate antibiotic prescribing in the United States ... underscores the need to learn more about prescriptions that aren’t justified by a diagnosis – or are written after no diagnosis at all,” coinvestigator Jeffrey Linder, MD, of Northwestern University, Chicago, said in a written statement.
Prescriptions for children, who represented almost a quarter of all antibiotic fills, were less likely to be inappropriate than those for adults aged 18-64 years. Proportions for children were 17.1% inappropriate, 48.7% potentially inappropriate, and 17.0% appropriate, compared with 25.2%, 31.4%, and 11.4%, respectively, for adults, Dr. Chua and his associates said.
“This study shows how data and analytics can help us identify and understand important challenges facing the American health care system,” said Gopal Khanna, director of the Agency for Healthcare Research and Quality, which funded the study. “We now need to use these data to spur change in the prescribing of these very common medications.”
SOURCE: Chua K-P et al. BMJ. 2019;364:k5092. doi: 10.1136/bmj.k5092.
More than 23% of all antibiotic prescriptions filled in 2016 were medically unnecessary, and another 36% were questionable, according to an analysis of prescribing data for 19.2 million children and nonelderly adults.
Based on the diagnosis codes for 15.5 million prescriptions filled that year, at least 3.6 million (23.2%) were “inappropriate” – prescribed for conditions for which an antibiotic is almost never recommended, such as acute upper respiratory conditions – and 5.5 million (35.5%) were “potentially inappropriate” – conditions such as acute sinusitis or otitis media, for which an antibiotic is only sometimes recommended, Kao-Ping Chua, MD, PhD, of the University of Michigan, Ann Arbor, and his associates reported in the BMJ.
Only 12.8% of filled prescriptions for the 39 oral antibiotics assessed were classified as “appropriate” under the investigators’ scheme, which assigned an antibiotic appropriateness level to all 91,738 diagnostic codes in the 2016 ICD-10-CM. Finally, 28.5% of antibiotic fills were not associated with a recent diagnosis code, suggesting that they involved phone consultations that did not result in claims or visits that were paid out of pocket and did not make it into the Truven MarketScan Commercial Claims and Encounters database used in the study, the investigators said.
The three highest levels of inappropriate fills were 70.7% in office-based settings, 6.2% in urgent care centers, and 4.7% in emergency departments.
“The unacceptable scale of inappropriate antibiotic prescribing in the United States ... underscores the need to learn more about prescriptions that aren’t justified by a diagnosis – or are written after no diagnosis at all,” coinvestigator Jeffrey Linder, MD, of Northwestern University, Chicago, said in a written statement.
Prescriptions for children, who represented almost a quarter of all antibiotic fills, were less likely to be inappropriate than those for adults aged 18-64 years. Proportions for children were 17.1% inappropriate, 48.7% potentially inappropriate, and 17.0% appropriate, compared with 25.2%, 31.4%, and 11.4%, respectively, for adults, Dr. Chua and his associates said.
“This study shows how data and analytics can help us identify and understand important challenges facing the American health care system,” said Gopal Khanna, director of the Agency for Healthcare Research and Quality, which funded the study. “We now need to use these data to spur change in the prescribing of these very common medications.”
SOURCE: Chua K-P et al. BMJ. 2019;364:k5092. doi: 10.1136/bmj.k5092.
FROM THE BMJ
FDA approves generic version of vigabatrin
The drug is approved for the adjunctive treatment of focal seizures in patients aged 10 years and older who have not had an adequate response to other therapies.
The approval was granted to Teva Pharmaceuticals.
An FDA announcement noted that the agency has prioritized the approval of generic versions of drugs to improve access to treatments and to lower drug costs. Vigabatrin had been included on an FDA list of off-patent, off-exclusivity branded drugs without approved generics. The approval of generic vigabatrin “demonstrates that there is an open pathway to approving products like this one,” said FDA Commissioner Scott Gottlieb, MD.
The label for vigabatrin tablets includes a boxed warning for permanent vision loss. The generic vigabatrin tablets are part of a single shared-system Risk Evaluation and Mitigation Strategy (REMS) program with other drug products containing vigabatrin.
The most common side effects associated with vigabatrin tablets include dizziness, fatigue, sleepiness, involuntary eye movement, tremor, blurred vision, memory impairment, weight gain, joint pain, upper respiratory tract infection, aggression, double vision, abnormal coordination, and a confused state. Serious side effects associated with vigabatrin tablets include permanent vision loss and risk of suicidal thoughts or actions.
The drug is approved for the adjunctive treatment of focal seizures in patients aged 10 years and older who have not had an adequate response to other therapies.
The approval was granted to Teva Pharmaceuticals.
An FDA announcement noted that the agency has prioritized the approval of generic versions of drugs to improve access to treatments and to lower drug costs. Vigabatrin had been included on an FDA list of off-patent, off-exclusivity branded drugs without approved generics. The approval of generic vigabatrin “demonstrates that there is an open pathway to approving products like this one,” said FDA Commissioner Scott Gottlieb, MD.
The label for vigabatrin tablets includes a boxed warning for permanent vision loss. The generic vigabatrin tablets are part of a single shared-system Risk Evaluation and Mitigation Strategy (REMS) program with other drug products containing vigabatrin.
The most common side effects associated with vigabatrin tablets include dizziness, fatigue, sleepiness, involuntary eye movement, tremor, blurred vision, memory impairment, weight gain, joint pain, upper respiratory tract infection, aggression, double vision, abnormal coordination, and a confused state. Serious side effects associated with vigabatrin tablets include permanent vision loss and risk of suicidal thoughts or actions.
The drug is approved for the adjunctive treatment of focal seizures in patients aged 10 years and older who have not had an adequate response to other therapies.
The approval was granted to Teva Pharmaceuticals.
An FDA announcement noted that the agency has prioritized the approval of generic versions of drugs to improve access to treatments and to lower drug costs. Vigabatrin had been included on an FDA list of off-patent, off-exclusivity branded drugs without approved generics. The approval of generic vigabatrin “demonstrates that there is an open pathway to approving products like this one,” said FDA Commissioner Scott Gottlieb, MD.
The label for vigabatrin tablets includes a boxed warning for permanent vision loss. The generic vigabatrin tablets are part of a single shared-system Risk Evaluation and Mitigation Strategy (REMS) program with other drug products containing vigabatrin.
The most common side effects associated with vigabatrin tablets include dizziness, fatigue, sleepiness, involuntary eye movement, tremor, blurred vision, memory impairment, weight gain, joint pain, upper respiratory tract infection, aggression, double vision, abnormal coordination, and a confused state. Serious side effects associated with vigabatrin tablets include permanent vision loss and risk of suicidal thoughts or actions.
Study supports need for less toxic therapies in FL
Despite improvements in the treatment for follicular lymphoma, including the introduction of anti-CD20 therapies like rituximab, the leading cause of death remains lymphoma, according to a recent analysis.
Researchers led by Clementine Sarkozy, MD, of the University of Lyon (France), analyzed the cause of death for 1,654 follicular lymphoma patients across one French and one U.S. cohort. The French cohort enrolled patients between 2001 and 2013 and the U.S. cohort enrolled patients between 2002 and 2012.
Among the 734 patients in the French cohort, there were 113 deaths after a median 89 months follow-up. Similarly, following a median follow-up of 84 months, there were 170 deaths among the 920 U.S. patients. The 10-year overall survival was similar in the two cohorts at 79.8% among the French patients and 76.6% among the U.S. patients, the researchers reported in the Journal of Clinical Oncology.
Cause of death information was available for 283 patients across the two cohorts. In 140 patients (56.5%), the cause of death was lymphoma; more than half of those cases occurred in patients whose disease had transformed at some point. That puts the cumulative risk of mortality from lymphoma at 10.3% at 10 years, according to the researchers.
The researchers also noted that the Follicular Lymphoma International Prognostic Index score was strongly linked to lymphoma-related mortality but not to nonlymphoma causes of death.
Another 42 patients (17%) died from treatment-related causes, mainly infection. About 13% of the cohort died from other cancers and another 13% died from other causes.
“Deaths related to treatment seem to also be a significant burden and new, less-toxic treatment options need to be investigated,” the researchers wrote.
The study was supported by the National Institutes of Health. Dr. Sarkozy reported financial relationships with Genentech, Celgene, and Takeda.
SOURCE: Sarkozy C et al. J Clin Oncol. 2019 Jan 10;37(2):144-52.
Despite improvements in the treatment for follicular lymphoma, including the introduction of anti-CD20 therapies like rituximab, the leading cause of death remains lymphoma, according to a recent analysis.
Researchers led by Clementine Sarkozy, MD, of the University of Lyon (France), analyzed the cause of death for 1,654 follicular lymphoma patients across one French and one U.S. cohort. The French cohort enrolled patients between 2001 and 2013 and the U.S. cohort enrolled patients between 2002 and 2012.
Among the 734 patients in the French cohort, there were 113 deaths after a median 89 months follow-up. Similarly, following a median follow-up of 84 months, there were 170 deaths among the 920 U.S. patients. The 10-year overall survival was similar in the two cohorts at 79.8% among the French patients and 76.6% among the U.S. patients, the researchers reported in the Journal of Clinical Oncology.
Cause of death information was available for 283 patients across the two cohorts. In 140 patients (56.5%), the cause of death was lymphoma; more than half of those cases occurred in patients whose disease had transformed at some point. That puts the cumulative risk of mortality from lymphoma at 10.3% at 10 years, according to the researchers.
The researchers also noted that the Follicular Lymphoma International Prognostic Index score was strongly linked to lymphoma-related mortality but not to nonlymphoma causes of death.
Another 42 patients (17%) died from treatment-related causes, mainly infection. About 13% of the cohort died from other cancers and another 13% died from other causes.
“Deaths related to treatment seem to also be a significant burden and new, less-toxic treatment options need to be investigated,” the researchers wrote.
The study was supported by the National Institutes of Health. Dr. Sarkozy reported financial relationships with Genentech, Celgene, and Takeda.
SOURCE: Sarkozy C et al. J Clin Oncol. 2019 Jan 10;37(2):144-52.
Despite improvements in the treatment for follicular lymphoma, including the introduction of anti-CD20 therapies like rituximab, the leading cause of death remains lymphoma, according to a recent analysis.
Researchers led by Clementine Sarkozy, MD, of the University of Lyon (France), analyzed the cause of death for 1,654 follicular lymphoma patients across one French and one U.S. cohort. The French cohort enrolled patients between 2001 and 2013 and the U.S. cohort enrolled patients between 2002 and 2012.
Among the 734 patients in the French cohort, there were 113 deaths after a median 89 months follow-up. Similarly, following a median follow-up of 84 months, there were 170 deaths among the 920 U.S. patients. The 10-year overall survival was similar in the two cohorts at 79.8% among the French patients and 76.6% among the U.S. patients, the researchers reported in the Journal of Clinical Oncology.
Cause of death information was available for 283 patients across the two cohorts. In 140 patients (56.5%), the cause of death was lymphoma; more than half of those cases occurred in patients whose disease had transformed at some point. That puts the cumulative risk of mortality from lymphoma at 10.3% at 10 years, according to the researchers.
The researchers also noted that the Follicular Lymphoma International Prognostic Index score was strongly linked to lymphoma-related mortality but not to nonlymphoma causes of death.
Another 42 patients (17%) died from treatment-related causes, mainly infection. About 13% of the cohort died from other cancers and another 13% died from other causes.
“Deaths related to treatment seem to also be a significant burden and new, less-toxic treatment options need to be investigated,” the researchers wrote.
The study was supported by the National Institutes of Health. Dr. Sarkozy reported financial relationships with Genentech, Celgene, and Takeda.
SOURCE: Sarkozy C et al. J Clin Oncol. 2019 Jan 10;37(2):144-52.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point:
Major finding: The cumulative risk of mortality from lymphoma was 10.3% at 10 years for patients with follicular lymphoma.
Study details: A pooled cohort study of 1,654 patients with follicular lymphoma in the United States and France.
Disclosures: The study was supported by the National Institutes of Health. Dr. Sarkozy reported financial relationships with Genentech, Celgene, and Takeda.
Source: Sarkozy C et al. J Clin Oncol. 2019 Jan 10;37(2):144-52.
Obinutuzumab-based regimens yield durable remissions in CLL
Two different obinutuzumab-based chemoimmunotherapy regimens resulted in excellent long-term disease control as front-line therapy for chronic lymphocytic leukemia (CLL), investigators said in a follow-up report on a phase 1b study.
Both obinutuzumab plus fludarabine/cyclophosphamide (G-FC) and obinutuzumab plus bendamustine (G-B) were well tolerated, with adverse events similar to what has been reported in rituximab-containing immunotherapy regimens, they said in the report of final results from the GALTON trial.
Most evaluable patients had B-cell recovery by 36 months in the study, which included a population of CLL patients largely without 17p deletions, said Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, Boston, and her coinvestigators.
“These data support moving forward with these regimens in subsequent trials, which are currently ongoing,” they said in their report on the study, which appears in Blood.
The open-label, parallel-arm, multicenter phase 1b GALTON study included 41 patients with CLL, of whom 21 received G-FC and 20 received G-B for up to six cycles of 28 days each. The median age was 60 years, and about one-third of patients had Rai stage III or IV disease. Only one patient had del(17p), and nearly half of patients tested (17 of 38 patients) had unmutated immunoglobulin heavy-chain variable region gene (IGHV). Six patients had del(11q), including four in the G-FC arm and two in the G-B arm.
Both G-FC and G-B had manageable toxicities, with infusion-related reactions being the most common adverse event, occurring in 88% (20% grade 3 or 4), Dr. Brown and her colleagues reported, adding that grade 3 or 4 neutropenia was seen in 48% of the G-FC arm and 55% of the G-B arm.
The objective response rate (ORR) was 62% for G-FC and 90% for GB.
“The ORR in the G-FC arm likely does not reflect the true activity of the regimen, as it is based on an intent-to-treat analysis,” the investigators said.
With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Nine patients in the G-FC arm underwent minimal residual disease (MRD) testing in peripheral blood; 100% had undetectable MRD, according to the report.
“With the caveat of small patient numbers and inevitable differences in patient populations across studies, these results suggest that G-FC may clear residual disease more effectively than rituximab plus FC,” the investigators wrote.
Previous studies of R-FC showed an undetectable MRD rate of 45% or less, they said.
The study was sponsored by Genentech. The investigators reported disclosures related to Genentech/Roche and other companies.
SOURCE: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
Two different obinutuzumab-based chemoimmunotherapy regimens resulted in excellent long-term disease control as front-line therapy for chronic lymphocytic leukemia (CLL), investigators said in a follow-up report on a phase 1b study.
Both obinutuzumab plus fludarabine/cyclophosphamide (G-FC) and obinutuzumab plus bendamustine (G-B) were well tolerated, with adverse events similar to what has been reported in rituximab-containing immunotherapy regimens, they said in the report of final results from the GALTON trial.
Most evaluable patients had B-cell recovery by 36 months in the study, which included a population of CLL patients largely without 17p deletions, said Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, Boston, and her coinvestigators.
“These data support moving forward with these regimens in subsequent trials, which are currently ongoing,” they said in their report on the study, which appears in Blood.
The open-label, parallel-arm, multicenter phase 1b GALTON study included 41 patients with CLL, of whom 21 received G-FC and 20 received G-B for up to six cycles of 28 days each. The median age was 60 years, and about one-third of patients had Rai stage III or IV disease. Only one patient had del(17p), and nearly half of patients tested (17 of 38 patients) had unmutated immunoglobulin heavy-chain variable region gene (IGHV). Six patients had del(11q), including four in the G-FC arm and two in the G-B arm.
Both G-FC and G-B had manageable toxicities, with infusion-related reactions being the most common adverse event, occurring in 88% (20% grade 3 or 4), Dr. Brown and her colleagues reported, adding that grade 3 or 4 neutropenia was seen in 48% of the G-FC arm and 55% of the G-B arm.
The objective response rate (ORR) was 62% for G-FC and 90% for GB.
“The ORR in the G-FC arm likely does not reflect the true activity of the regimen, as it is based on an intent-to-treat analysis,” the investigators said.
With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Nine patients in the G-FC arm underwent minimal residual disease (MRD) testing in peripheral blood; 100% had undetectable MRD, according to the report.
“With the caveat of small patient numbers and inevitable differences in patient populations across studies, these results suggest that G-FC may clear residual disease more effectively than rituximab plus FC,” the investigators wrote.
Previous studies of R-FC showed an undetectable MRD rate of 45% or less, they said.
The study was sponsored by Genentech. The investigators reported disclosures related to Genentech/Roche and other companies.
SOURCE: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
Two different obinutuzumab-based chemoimmunotherapy regimens resulted in excellent long-term disease control as front-line therapy for chronic lymphocytic leukemia (CLL), investigators said in a follow-up report on a phase 1b study.
Both obinutuzumab plus fludarabine/cyclophosphamide (G-FC) and obinutuzumab plus bendamustine (G-B) were well tolerated, with adverse events similar to what has been reported in rituximab-containing immunotherapy regimens, they said in the report of final results from the GALTON trial.
Most evaluable patients had B-cell recovery by 36 months in the study, which included a population of CLL patients largely without 17p deletions, said Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, Boston, and her coinvestigators.
“These data support moving forward with these regimens in subsequent trials, which are currently ongoing,” they said in their report on the study, which appears in Blood.
The open-label, parallel-arm, multicenter phase 1b GALTON study included 41 patients with CLL, of whom 21 received G-FC and 20 received G-B for up to six cycles of 28 days each. The median age was 60 years, and about one-third of patients had Rai stage III or IV disease. Only one patient had del(17p), and nearly half of patients tested (17 of 38 patients) had unmutated immunoglobulin heavy-chain variable region gene (IGHV). Six patients had del(11q), including four in the G-FC arm and two in the G-B arm.
Both G-FC and G-B had manageable toxicities, with infusion-related reactions being the most common adverse event, occurring in 88% (20% grade 3 or 4), Dr. Brown and her colleagues reported, adding that grade 3 or 4 neutropenia was seen in 48% of the G-FC arm and 55% of the G-B arm.
The objective response rate (ORR) was 62% for G-FC and 90% for GB.
“The ORR in the G-FC arm likely does not reflect the true activity of the regimen, as it is based on an intent-to-treat analysis,” the investigators said.
With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Nine patients in the G-FC arm underwent minimal residual disease (MRD) testing in peripheral blood; 100% had undetectable MRD, according to the report.
“With the caveat of small patient numbers and inevitable differences in patient populations across studies, these results suggest that G-FC may clear residual disease more effectively than rituximab plus FC,” the investigators wrote.
Previous studies of R-FC showed an undetectable MRD rate of 45% or less, they said.
The study was sponsored by Genentech. The investigators reported disclosures related to Genentech/Roche and other companies.
SOURCE: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
FROM BLOOD
Key clinical point:
Major finding: With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Study details: Long-term follow-up of the phase 1b GALTON trial, including 41 patients with CLL.
Disclosures: The study was sponsored by Genentech. The study authors reported disclosures related to Genentech/Roche and other companies.
Source: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
Host stress response may be a factor in early-stage HCV clearance
The cellular stress response in hepatocytes may play a major role in controlling hepatitis C virus (HCV). This response may be an important host factor for virus clearance during the early stages of HCV infection, according to a review of acute and chronic HCV infection by W. Alfredo Ríos-Ocampo, MD, and his colleagues (Virus Res. 2019. doi: 10.1016/j.virusres.2018.12.013).
The reviewers examined the mechanisms of induction and modulation of oxidative stress and endoplasmic-reticular stress with regard to viral persistence and cell survival. The accumulated research indicates that the activation of the eIF2-alpha/ATF4 pathway and selective autophagy induction are involved in the elimination of harmful viral proteins after oxidative stress induction. This all suggests a negative role of autophagy upon HCV infection or a negative regulation of viral replication.
“We conclude from published studies and our own research that viral protein synthesis activates adaptive responses, including autophagy pathways, that act to limit viral protein load and thereby reduce oxidative stress and cell death. Exploitation of these pathways to reduce viral replication will be the next goal and might be a valuable addition to antiviral therapy,” the reviewers concluded.
The authors reported that they had no conflicts of interest.
SOURCE: Ríos-Ocampo, WA, et al. Virus Res. 2019. doi: 10.1016/j.virusres.2018.12.013).
The cellular stress response in hepatocytes may play a major role in controlling hepatitis C virus (HCV). This response may be an important host factor for virus clearance during the early stages of HCV infection, according to a review of acute and chronic HCV infection by W. Alfredo Ríos-Ocampo, MD, and his colleagues (Virus Res. 2019. doi: 10.1016/j.virusres.2018.12.013).
The reviewers examined the mechanisms of induction and modulation of oxidative stress and endoplasmic-reticular stress with regard to viral persistence and cell survival. The accumulated research indicates that the activation of the eIF2-alpha/ATF4 pathway and selective autophagy induction are involved in the elimination of harmful viral proteins after oxidative stress induction. This all suggests a negative role of autophagy upon HCV infection or a negative regulation of viral replication.
“We conclude from published studies and our own research that viral protein synthesis activates adaptive responses, including autophagy pathways, that act to limit viral protein load and thereby reduce oxidative stress and cell death. Exploitation of these pathways to reduce viral replication will be the next goal and might be a valuable addition to antiviral therapy,” the reviewers concluded.
The authors reported that they had no conflicts of interest.
SOURCE: Ríos-Ocampo, WA, et al. Virus Res. 2019. doi: 10.1016/j.virusres.2018.12.013).
The cellular stress response in hepatocytes may play a major role in controlling hepatitis C virus (HCV). This response may be an important host factor for virus clearance during the early stages of HCV infection, according to a review of acute and chronic HCV infection by W. Alfredo Ríos-Ocampo, MD, and his colleagues (Virus Res. 2019. doi: 10.1016/j.virusres.2018.12.013).
The reviewers examined the mechanisms of induction and modulation of oxidative stress and endoplasmic-reticular stress with regard to viral persistence and cell survival. The accumulated research indicates that the activation of the eIF2-alpha/ATF4 pathway and selective autophagy induction are involved in the elimination of harmful viral proteins after oxidative stress induction. This all suggests a negative role of autophagy upon HCV infection or a negative regulation of viral replication.
“We conclude from published studies and our own research that viral protein synthesis activates adaptive responses, including autophagy pathways, that act to limit viral protein load and thereby reduce oxidative stress and cell death. Exploitation of these pathways to reduce viral replication will be the next goal and might be a valuable addition to antiviral therapy,” the reviewers concluded.
The authors reported that they had no conflicts of interest.
SOURCE: Ríos-Ocampo, WA, et al. Virus Res. 2019. doi: 10.1016/j.virusres.2018.12.013).
FROM VIRUS RESEARCH
Treat-to-target approach for CVD risk factors decreased atherosclerosis in RA patients
Researchers from the Netherlands found that a treat-to-target approach for cardiovascular risk factors in patients with rheumatoid arthritis was effective in reducing clinical and subclinical atherosclerosis; however, the researchers noted there was a “considerable” dropout in the study that could have limited the results, according to data recently published in Annals of the Rheumatic Diseases.
Benjamin Burggraaf, MD, and his associates at Franciscus Gasthuis & Vlietland Hospital in Rotterdam, the Netherlands, performed an open-label, randomized, controlled trial of 320 patients with rheumatoid arthritis (RA) who were younger than 70 years old (mean age, 52.4 years) without a prior history of cardiovascular disease (CVD) and diabetes mellitus. The patients received either usual care for traditional CVD risk factors or a treat-to-target approach using a prespecified protocol for treating hypertension, hyperlipidemia and hypertriglyceridemia, as well hemoglobin A1c greater than 48 mmol/mol. A total of 219 patients (68.4%) finished the study after 5 years. The two groups were similar at baseline, but the treat-to-target group had significantly more women (77.2%) compared with the usual care group (62.0%).
The researchers compared the progression of carotid intima media thickness (cIMT) at baseline and 5 years, with secondary outcomes of nonfatal myocardial infarction, nonfatal stroke, coronary artery bypass grafting, percutaneous coronary intervention, peripheral atherosclerotic arterial disease–related amputation, peripheral atherosclerotic arterial disease revascularization, and death due to cardiovascular causes.
“To account for the high dropout, all missing cIMT values after 5 years of follow-up were imputed with all available cIMT values (baseline, years 1-4) and treatment group as covariate,” the researchers said. “Assuming that unobserved cIMT values were missing at random, missing data were imputed with multiple imputation using the fully conditional specification method for seven cycles.”
Dr. Burggraaf and his colleagues found the treat-to-target group had lower mean cIMT progression (0.023 mm; 95% confidence interval, 0.011-0.036) at 5-year follow-up than did the group that received usual care for CVD risk factors (0.045 mm; 95% CI, 0.030-0.059; P = .028). At 5 years, there were no significant differences between treat-to-target and usual care groups regarding mean systolic blood pressure (124.6 mm Hg vs. 124.7 mm Hg, respectively; P = .97), treat-to-target treatment targets for blood pressure (72.4% for usual care vs. 75.9% for treat-to-target; P = .56) and mean HbA1c (37.6 mmol/mol for treat-to-target vs. 37.0 mmol/mol for usual care; P = .39). The treat-to-target group also had fewer cardiovascular events (two events, 1.3%) compared with the usual care group (seven events, 4.7%; P = .048). There were five patients in the treat-to-target group who died during the study (4.7%), compared with seven patients (3.2%) in the usual care group (P = .51).
“Although the difference in cIMT progression between the groups was relatively small in absolute terms, the relative reduction in progression was almost 50% in favor of the treat-to-target group,” they noted. “In light of the reduction of cardiovascular events, these effects are, in our opinion, clinically relevant.”
Other limitations of the study included the use of cIMT as a “soft endpoint” for modern cardiovascular trials and the use of unblinded cIMT progression measurement. In addition, the researchers noted the study was underpowered, and they used data from a type 2 diabetes mellitus cohort to perform the power calculation, which carried a 50% reduction in CVD risk factors. “We had doubts whether this high risk would apply to patients with RA and therefore used a more conservative target of 20% reduction for cIMT progression,” the researchers said.
This study was funded by the Franciscus Gasthuis & Vlietland Hospital, the Foundation for Research and Development of the Department of Internal Medicine, and the Coolsingel Foundation, Rotterdam. One author reported being a consultant for and receiving lecture honoraria from Merck.
SOURCE: Burggraaf B et al. Ann Rheum Dis. 2019 Jan 4. doi: 10.1136/annrheumdis-2018-214075.
It is well recognized that traditional cardiovascular disease (CVD) risk factors contribute to atherogenesis and CVD events in rheumatoid arthritis (RA) patients at least as much as inflammatory risk factors, and traditional risk factors and inflammatory risk factors may interact (i.e. inflammatory risk factors have a greater impact in the setting of higher number of traditional risk factors).
There is documented reluctance among many rheumatologists to take on the additional burden of screening and managing hyperlipidemia, hypertension, diabetes, weight management, diet, and so on in addition to all the other aspects of managing these patients that take a lot of time. Research is needed on how to efficiently streamline measurement and management of CVD risk in these patients to optimize outcomes.
Jon T. Giles, MD , is a rheumatologist in the division of rheumatology at Columbia University in New York. He was not involved in the study by Burggraaf et al. and reported no relevant conflicts of interest.
It is well recognized that traditional cardiovascular disease (CVD) risk factors contribute to atherogenesis and CVD events in rheumatoid arthritis (RA) patients at least as much as inflammatory risk factors, and traditional risk factors and inflammatory risk factors may interact (i.e. inflammatory risk factors have a greater impact in the setting of higher number of traditional risk factors).
There is documented reluctance among many rheumatologists to take on the additional burden of screening and managing hyperlipidemia, hypertension, diabetes, weight management, diet, and so on in addition to all the other aspects of managing these patients that take a lot of time. Research is needed on how to efficiently streamline measurement and management of CVD risk in these patients to optimize outcomes.
Jon T. Giles, MD , is a rheumatologist in the division of rheumatology at Columbia University in New York. He was not involved in the study by Burggraaf et al. and reported no relevant conflicts of interest.
It is well recognized that traditional cardiovascular disease (CVD) risk factors contribute to atherogenesis and CVD events in rheumatoid arthritis (RA) patients at least as much as inflammatory risk factors, and traditional risk factors and inflammatory risk factors may interact (i.e. inflammatory risk factors have a greater impact in the setting of higher number of traditional risk factors).
There is documented reluctance among many rheumatologists to take on the additional burden of screening and managing hyperlipidemia, hypertension, diabetes, weight management, diet, and so on in addition to all the other aspects of managing these patients that take a lot of time. Research is needed on how to efficiently streamline measurement and management of CVD risk in these patients to optimize outcomes.
Jon T. Giles, MD , is a rheumatologist in the division of rheumatology at Columbia University in New York. He was not involved in the study by Burggraaf et al. and reported no relevant conflicts of interest.
Researchers from the Netherlands found that a treat-to-target approach for cardiovascular risk factors in patients with rheumatoid arthritis was effective in reducing clinical and subclinical atherosclerosis; however, the researchers noted there was a “considerable” dropout in the study that could have limited the results, according to data recently published in Annals of the Rheumatic Diseases.
Benjamin Burggraaf, MD, and his associates at Franciscus Gasthuis & Vlietland Hospital in Rotterdam, the Netherlands, performed an open-label, randomized, controlled trial of 320 patients with rheumatoid arthritis (RA) who were younger than 70 years old (mean age, 52.4 years) without a prior history of cardiovascular disease (CVD) and diabetes mellitus. The patients received either usual care for traditional CVD risk factors or a treat-to-target approach using a prespecified protocol for treating hypertension, hyperlipidemia and hypertriglyceridemia, as well hemoglobin A1c greater than 48 mmol/mol. A total of 219 patients (68.4%) finished the study after 5 years. The two groups were similar at baseline, but the treat-to-target group had significantly more women (77.2%) compared with the usual care group (62.0%).
The researchers compared the progression of carotid intima media thickness (cIMT) at baseline and 5 years, with secondary outcomes of nonfatal myocardial infarction, nonfatal stroke, coronary artery bypass grafting, percutaneous coronary intervention, peripheral atherosclerotic arterial disease–related amputation, peripheral atherosclerotic arterial disease revascularization, and death due to cardiovascular causes.
“To account for the high dropout, all missing cIMT values after 5 years of follow-up were imputed with all available cIMT values (baseline, years 1-4) and treatment group as covariate,” the researchers said. “Assuming that unobserved cIMT values were missing at random, missing data were imputed with multiple imputation using the fully conditional specification method for seven cycles.”
Dr. Burggraaf and his colleagues found the treat-to-target group had lower mean cIMT progression (0.023 mm; 95% confidence interval, 0.011-0.036) at 5-year follow-up than did the group that received usual care for CVD risk factors (0.045 mm; 95% CI, 0.030-0.059; P = .028). At 5 years, there were no significant differences between treat-to-target and usual care groups regarding mean systolic blood pressure (124.6 mm Hg vs. 124.7 mm Hg, respectively; P = .97), treat-to-target treatment targets for blood pressure (72.4% for usual care vs. 75.9% for treat-to-target; P = .56) and mean HbA1c (37.6 mmol/mol for treat-to-target vs. 37.0 mmol/mol for usual care; P = .39). The treat-to-target group also had fewer cardiovascular events (two events, 1.3%) compared with the usual care group (seven events, 4.7%; P = .048). There were five patients in the treat-to-target group who died during the study (4.7%), compared with seven patients (3.2%) in the usual care group (P = .51).
“Although the difference in cIMT progression between the groups was relatively small in absolute terms, the relative reduction in progression was almost 50% in favor of the treat-to-target group,” they noted. “In light of the reduction of cardiovascular events, these effects are, in our opinion, clinically relevant.”
Other limitations of the study included the use of cIMT as a “soft endpoint” for modern cardiovascular trials and the use of unblinded cIMT progression measurement. In addition, the researchers noted the study was underpowered, and they used data from a type 2 diabetes mellitus cohort to perform the power calculation, which carried a 50% reduction in CVD risk factors. “We had doubts whether this high risk would apply to patients with RA and therefore used a more conservative target of 20% reduction for cIMT progression,” the researchers said.
This study was funded by the Franciscus Gasthuis & Vlietland Hospital, the Foundation for Research and Development of the Department of Internal Medicine, and the Coolsingel Foundation, Rotterdam. One author reported being a consultant for and receiving lecture honoraria from Merck.
SOURCE: Burggraaf B et al. Ann Rheum Dis. 2019 Jan 4. doi: 10.1136/annrheumdis-2018-214075.
Researchers from the Netherlands found that a treat-to-target approach for cardiovascular risk factors in patients with rheumatoid arthritis was effective in reducing clinical and subclinical atherosclerosis; however, the researchers noted there was a “considerable” dropout in the study that could have limited the results, according to data recently published in Annals of the Rheumatic Diseases.
Benjamin Burggraaf, MD, and his associates at Franciscus Gasthuis & Vlietland Hospital in Rotterdam, the Netherlands, performed an open-label, randomized, controlled trial of 320 patients with rheumatoid arthritis (RA) who were younger than 70 years old (mean age, 52.4 years) without a prior history of cardiovascular disease (CVD) and diabetes mellitus. The patients received either usual care for traditional CVD risk factors or a treat-to-target approach using a prespecified protocol for treating hypertension, hyperlipidemia and hypertriglyceridemia, as well hemoglobin A1c greater than 48 mmol/mol. A total of 219 patients (68.4%) finished the study after 5 years. The two groups were similar at baseline, but the treat-to-target group had significantly more women (77.2%) compared with the usual care group (62.0%).
The researchers compared the progression of carotid intima media thickness (cIMT) at baseline and 5 years, with secondary outcomes of nonfatal myocardial infarction, nonfatal stroke, coronary artery bypass grafting, percutaneous coronary intervention, peripheral atherosclerotic arterial disease–related amputation, peripheral atherosclerotic arterial disease revascularization, and death due to cardiovascular causes.
“To account for the high dropout, all missing cIMT values after 5 years of follow-up were imputed with all available cIMT values (baseline, years 1-4) and treatment group as covariate,” the researchers said. “Assuming that unobserved cIMT values were missing at random, missing data were imputed with multiple imputation using the fully conditional specification method for seven cycles.”
Dr. Burggraaf and his colleagues found the treat-to-target group had lower mean cIMT progression (0.023 mm; 95% confidence interval, 0.011-0.036) at 5-year follow-up than did the group that received usual care for CVD risk factors (0.045 mm; 95% CI, 0.030-0.059; P = .028). At 5 years, there were no significant differences between treat-to-target and usual care groups regarding mean systolic blood pressure (124.6 mm Hg vs. 124.7 mm Hg, respectively; P = .97), treat-to-target treatment targets for blood pressure (72.4% for usual care vs. 75.9% for treat-to-target; P = .56) and mean HbA1c (37.6 mmol/mol for treat-to-target vs. 37.0 mmol/mol for usual care; P = .39). The treat-to-target group also had fewer cardiovascular events (two events, 1.3%) compared with the usual care group (seven events, 4.7%; P = .048). There were five patients in the treat-to-target group who died during the study (4.7%), compared with seven patients (3.2%) in the usual care group (P = .51).
“Although the difference in cIMT progression between the groups was relatively small in absolute terms, the relative reduction in progression was almost 50% in favor of the treat-to-target group,” they noted. “In light of the reduction of cardiovascular events, these effects are, in our opinion, clinically relevant.”
Other limitations of the study included the use of cIMT as a “soft endpoint” for modern cardiovascular trials and the use of unblinded cIMT progression measurement. In addition, the researchers noted the study was underpowered, and they used data from a type 2 diabetes mellitus cohort to perform the power calculation, which carried a 50% reduction in CVD risk factors. “We had doubts whether this high risk would apply to patients with RA and therefore used a more conservative target of 20% reduction for cIMT progression,” the researchers said.
This study was funded by the Franciscus Gasthuis & Vlietland Hospital, the Foundation for Research and Development of the Department of Internal Medicine, and the Coolsingel Foundation, Rotterdam. One author reported being a consultant for and receiving lecture honoraria from Merck.
SOURCE: Burggraaf B et al. Ann Rheum Dis. 2019 Jan 4. doi: 10.1136/annrheumdis-2018-214075.
FROM ANNALS OF THE RHEUMATIC DISEASES
Key clinical point:
Major finding: The treat-to-target group had greater mean carotid intima media thickness progression (0.023 mm; 95% confidence interval, 0.011-0.036) at 5-year follow-up compared with the group that received usual care for cardiovascular disease risk factors (0.045 mm; 95% CI, 0.030-0.059; P = .028).
Study details: An open-label, randomized, controlled trial of 320 RA patients who received a treat-to-target intervention or usual care for cardiovascular disease risk factors.
Disclosures: This study was funded by the Franciscus Gasthuis & Vlietland Hospital, the Foundation for Research and Development of the Department of Internal Medicine, and the Coolsingel Foundation, Rotterdam. One author reported being a consultant for and receiving lecture honoraria from Merck.
Source: Burggraaf B et al. Ann Rheum Dis. 2019 Jan 4. doi: 10.1136/annrheumdis-2018-214075.
Prescription puppy, China’s commode hospital, Hall of Fame diuretics
Prescription puppies
I’d like a script for a golden retriever who loves fetch and has a super sniffer, please. Turns out, man’s best friend can be especially friendly for patients with type 1 diabetes mellitus.
Dogs have been trained to detect seizures, lead the blind, and even call 9-1-1, and now they are increasingly being used as glycemia monitors for people with diabetes. Obviously, people don’t get a prescription for their helpful furry friends, but one can dream about an all-puppy pharmacy, right?
A recently published study took a look at how glycemia-alert dogs improve the quality of life of people living with type 1 diabetes, and assessed the reliability of the dogs to respond to hypo- and hyperglycemic episodes.
Researchers concluded that, overall, a trained pup’s response to these episodes is more sensitive than previously thought. In addition, researchers also found that 100% of the study participants were extremely good dogs.
Really selective hearing loss
A woman in China is experiencing something straight out of a movie – she woke up one morning and couldn’t hear men’s voices anymore. Some might say this is a tragic loss. Others might contend that she is living the dream.
The woman was diagnosed with reverse-slope hearing loss, a very rare type of hearing loss that makes the patient unable able to hear low-frequency sounds, such as a man’s voice. Only 1 in every 12,000 people with hearing loss has this kind, and it is most often caused by genetics.
In this case, the woman’s stress and extreme fatigue appear to be contributing factors to her newfound superpower. Her doctor expects her to make a full recovery, but I’d milk it for as long as possible: “What’s that? Something about the dishes, honey? Sorry I can’t hear what you’re saying!”
The epitome of crappy design
Here at MDedge News, we approve of all scatologically related humor, and the Guangxi International Zhuangyi Hospital in Nanning, China, certainly fits the bill. In an ode to the digestive system, the Chinese have built a hospital that bears an undeniable resemblance to a toilet.
The building is huge, spread out over 42 acres. The patients are contained in the multistory tank, while the medical departments line the outside of the massive bowl.
According to a local citizen, the hospital was designed this way so patients could go from the main section to the departments without carrying an umbrella. We hope it’s because they have an excellent gastroenterology department they want to show off.
Leaking the news: Hall of Fame edition
Can you name the ultimate prize for a life-saving achievement in medicine? You’re right, it is induction into the National Inventors Hall of Fame!
And that’s just what’s about to happen to the inventors of thiazide diuretics. The NIHF just announced its class of 2019, and it includes pharmacologists John Baer and Karl H. Beyer Jr. and organic chemists Frederick Novello and James Sprague, who developed Diuril (chlorothiazide) while at Merck Sharp & Dohme in the 1950s. (Is it just us, or do you get the feeling that Don Draper and the rest of the Sterling Cooper crew must have handled the Diuril account?)
The honor is, unfortunately, posthumous for all four men, but they were around for the Lasker Foundation Special Public Health Award they received in 1975.
We here at LOTME can’t top either of these commendations, but there’s at least one hypertensive on the staff who will be thinking of these men and their achievement when he experiences his next forced diuresis.
Prescription puppies
I’d like a script for a golden retriever who loves fetch and has a super sniffer, please. Turns out, man’s best friend can be especially friendly for patients with type 1 diabetes mellitus.
Dogs have been trained to detect seizures, lead the blind, and even call 9-1-1, and now they are increasingly being used as glycemia monitors for people with diabetes. Obviously, people don’t get a prescription for their helpful furry friends, but one can dream about an all-puppy pharmacy, right?
A recently published study took a look at how glycemia-alert dogs improve the quality of life of people living with type 1 diabetes, and assessed the reliability of the dogs to respond to hypo- and hyperglycemic episodes.
Researchers concluded that, overall, a trained pup’s response to these episodes is more sensitive than previously thought. In addition, researchers also found that 100% of the study participants were extremely good dogs.
Really selective hearing loss
A woman in China is experiencing something straight out of a movie – she woke up one morning and couldn’t hear men’s voices anymore. Some might say this is a tragic loss. Others might contend that she is living the dream.
The woman was diagnosed with reverse-slope hearing loss, a very rare type of hearing loss that makes the patient unable able to hear low-frequency sounds, such as a man’s voice. Only 1 in every 12,000 people with hearing loss has this kind, and it is most often caused by genetics.
In this case, the woman’s stress and extreme fatigue appear to be contributing factors to her newfound superpower. Her doctor expects her to make a full recovery, but I’d milk it for as long as possible: “What’s that? Something about the dishes, honey? Sorry I can’t hear what you’re saying!”
The epitome of crappy design
Here at MDedge News, we approve of all scatologically related humor, and the Guangxi International Zhuangyi Hospital in Nanning, China, certainly fits the bill. In an ode to the digestive system, the Chinese have built a hospital that bears an undeniable resemblance to a toilet.
The building is huge, spread out over 42 acres. The patients are contained in the multistory tank, while the medical departments line the outside of the massive bowl.
According to a local citizen, the hospital was designed this way so patients could go from the main section to the departments without carrying an umbrella. We hope it’s because they have an excellent gastroenterology department they want to show off.
Leaking the news: Hall of Fame edition
Can you name the ultimate prize for a life-saving achievement in medicine? You’re right, it is induction into the National Inventors Hall of Fame!
And that’s just what’s about to happen to the inventors of thiazide diuretics. The NIHF just announced its class of 2019, and it includes pharmacologists John Baer and Karl H. Beyer Jr. and organic chemists Frederick Novello and James Sprague, who developed Diuril (chlorothiazide) while at Merck Sharp & Dohme in the 1950s. (Is it just us, or do you get the feeling that Don Draper and the rest of the Sterling Cooper crew must have handled the Diuril account?)
The honor is, unfortunately, posthumous for all four men, but they were around for the Lasker Foundation Special Public Health Award they received in 1975.
We here at LOTME can’t top either of these commendations, but there’s at least one hypertensive on the staff who will be thinking of these men and their achievement when he experiences his next forced diuresis.
Prescription puppies
I’d like a script for a golden retriever who loves fetch and has a super sniffer, please. Turns out, man’s best friend can be especially friendly for patients with type 1 diabetes mellitus.
Dogs have been trained to detect seizures, lead the blind, and even call 9-1-1, and now they are increasingly being used as glycemia monitors for people with diabetes. Obviously, people don’t get a prescription for their helpful furry friends, but one can dream about an all-puppy pharmacy, right?
A recently published study took a look at how glycemia-alert dogs improve the quality of life of people living with type 1 diabetes, and assessed the reliability of the dogs to respond to hypo- and hyperglycemic episodes.
Researchers concluded that, overall, a trained pup’s response to these episodes is more sensitive than previously thought. In addition, researchers also found that 100% of the study participants were extremely good dogs.
Really selective hearing loss
A woman in China is experiencing something straight out of a movie – she woke up one morning and couldn’t hear men’s voices anymore. Some might say this is a tragic loss. Others might contend that she is living the dream.
The woman was diagnosed with reverse-slope hearing loss, a very rare type of hearing loss that makes the patient unable able to hear low-frequency sounds, such as a man’s voice. Only 1 in every 12,000 people with hearing loss has this kind, and it is most often caused by genetics.
In this case, the woman’s stress and extreme fatigue appear to be contributing factors to her newfound superpower. Her doctor expects her to make a full recovery, but I’d milk it for as long as possible: “What’s that? Something about the dishes, honey? Sorry I can’t hear what you’re saying!”
The epitome of crappy design
Here at MDedge News, we approve of all scatologically related humor, and the Guangxi International Zhuangyi Hospital in Nanning, China, certainly fits the bill. In an ode to the digestive system, the Chinese have built a hospital that bears an undeniable resemblance to a toilet.
The building is huge, spread out over 42 acres. The patients are contained in the multistory tank, while the medical departments line the outside of the massive bowl.
According to a local citizen, the hospital was designed this way so patients could go from the main section to the departments without carrying an umbrella. We hope it’s because they have an excellent gastroenterology department they want to show off.
Leaking the news: Hall of Fame edition
Can you name the ultimate prize for a life-saving achievement in medicine? You’re right, it is induction into the National Inventors Hall of Fame!
And that’s just what’s about to happen to the inventors of thiazide diuretics. The NIHF just announced its class of 2019, and it includes pharmacologists John Baer and Karl H. Beyer Jr. and organic chemists Frederick Novello and James Sprague, who developed Diuril (chlorothiazide) while at Merck Sharp & Dohme in the 1950s. (Is it just us, or do you get the feeling that Don Draper and the rest of the Sterling Cooper crew must have handled the Diuril account?)
The honor is, unfortunately, posthumous for all four men, but they were around for the Lasker Foundation Special Public Health Award they received in 1975.
We here at LOTME can’t top either of these commendations, but there’s at least one hypertensive on the staff who will be thinking of these men and their achievement when he experiences his next forced diuresis.
New guidance: Preventing steroid-induced osteoporosis in ITP
The British Society for Haematology has released new recommendations on the clinical management of osteoporosis secondary to glucocorticoid use in patients with immune thrombocytopenia.
The “good practice paper” was published in the British Journal of Haematology.
“Glucocorticoids are a standard first-line treatment for immune thrombocytopenia and are an important risk factor for osteoporosis,” wrote Quentin A. Hill, MBChB, of the University of Leeds (England), and his colleagues.
When given for extended periods of time, glucocorticoids have been shown to trigger substantial reductions in bone mineral density, which has been linked with an increased risk for bone fractures. The researchers reported that fracture risk is not exclusively dependent on steroid use but is also affected by other factors, such as patient age, duration of glucocorticoid use, and treatment dose.
“Some studies have found that fracture risk is not significantly elevated in patients receiving oral glucocorticoids for [less than] 3 months,” the researches wrote. “Most guidelines are for patients with an intended duration of treatment [greater than] 3 months.”
In adult patients treated with glucocorticoids, the authors recommended that appropriate educational information be provided on how to enhance bone health. Additionally, they stated that patients should obtain sufficient calcium and vitamin D, defined as 700-1,200 mg and 800 IU daily, respectively, which can be achieved through diet or supplementation.
“Patients at high risk of fracture should be considered for oral alendronate or risedronate,” they wrote. “If contraindicated or poorly tolerated, zoledronic acid, denosumab, or teriparatide are appropriate alternatives.”
With respect to the use of glucocorticoids for relapse, the experts recommended starting on the lowest effective dose and providing steroid-sparing agents when appropriate. Treatment with bisphosphonates may benefit children and patients aged less than 40 years.
The authors also reported that glucocorticoid cessation may reduce some degree of fracture risk; however, an elevated risk does remain, even after withdrawal of therapy, warranting ongoing clinical assessment and follow-up.
Dr. Hill and several coauthors reported financial affiliations with Amgen, Novartis, Ono Pharmaceuticals, Shire, and others.
SOURCE: Hill QA et al. Br J Haematol. 2019 Jan 4. doi: 10.1111/bjh.15735.
The British Society for Haematology has released new recommendations on the clinical management of osteoporosis secondary to glucocorticoid use in patients with immune thrombocytopenia.
The “good practice paper” was published in the British Journal of Haematology.
“Glucocorticoids are a standard first-line treatment for immune thrombocytopenia and are an important risk factor for osteoporosis,” wrote Quentin A. Hill, MBChB, of the University of Leeds (England), and his colleagues.
When given for extended periods of time, glucocorticoids have been shown to trigger substantial reductions in bone mineral density, which has been linked with an increased risk for bone fractures. The researchers reported that fracture risk is not exclusively dependent on steroid use but is also affected by other factors, such as patient age, duration of glucocorticoid use, and treatment dose.
“Some studies have found that fracture risk is not significantly elevated in patients receiving oral glucocorticoids for [less than] 3 months,” the researches wrote. “Most guidelines are for patients with an intended duration of treatment [greater than] 3 months.”
In adult patients treated with glucocorticoids, the authors recommended that appropriate educational information be provided on how to enhance bone health. Additionally, they stated that patients should obtain sufficient calcium and vitamin D, defined as 700-1,200 mg and 800 IU daily, respectively, which can be achieved through diet or supplementation.
“Patients at high risk of fracture should be considered for oral alendronate or risedronate,” they wrote. “If contraindicated or poorly tolerated, zoledronic acid, denosumab, or teriparatide are appropriate alternatives.”
With respect to the use of glucocorticoids for relapse, the experts recommended starting on the lowest effective dose and providing steroid-sparing agents when appropriate. Treatment with bisphosphonates may benefit children and patients aged less than 40 years.
The authors also reported that glucocorticoid cessation may reduce some degree of fracture risk; however, an elevated risk does remain, even after withdrawal of therapy, warranting ongoing clinical assessment and follow-up.
Dr. Hill and several coauthors reported financial affiliations with Amgen, Novartis, Ono Pharmaceuticals, Shire, and others.
SOURCE: Hill QA et al. Br J Haematol. 2019 Jan 4. doi: 10.1111/bjh.15735.
The British Society for Haematology has released new recommendations on the clinical management of osteoporosis secondary to glucocorticoid use in patients with immune thrombocytopenia.
The “good practice paper” was published in the British Journal of Haematology.
“Glucocorticoids are a standard first-line treatment for immune thrombocytopenia and are an important risk factor for osteoporosis,” wrote Quentin A. Hill, MBChB, of the University of Leeds (England), and his colleagues.
When given for extended periods of time, glucocorticoids have been shown to trigger substantial reductions in bone mineral density, which has been linked with an increased risk for bone fractures. The researchers reported that fracture risk is not exclusively dependent on steroid use but is also affected by other factors, such as patient age, duration of glucocorticoid use, and treatment dose.
“Some studies have found that fracture risk is not significantly elevated in patients receiving oral glucocorticoids for [less than] 3 months,” the researches wrote. “Most guidelines are for patients with an intended duration of treatment [greater than] 3 months.”
In adult patients treated with glucocorticoids, the authors recommended that appropriate educational information be provided on how to enhance bone health. Additionally, they stated that patients should obtain sufficient calcium and vitamin D, defined as 700-1,200 mg and 800 IU daily, respectively, which can be achieved through diet or supplementation.
“Patients at high risk of fracture should be considered for oral alendronate or risedronate,” they wrote. “If contraindicated or poorly tolerated, zoledronic acid, denosumab, or teriparatide are appropriate alternatives.”
With respect to the use of glucocorticoids for relapse, the experts recommended starting on the lowest effective dose and providing steroid-sparing agents when appropriate. Treatment with bisphosphonates may benefit children and patients aged less than 40 years.
The authors also reported that glucocorticoid cessation may reduce some degree of fracture risk; however, an elevated risk does remain, even after withdrawal of therapy, warranting ongoing clinical assessment and follow-up.
Dr. Hill and several coauthors reported financial affiliations with Amgen, Novartis, Ono Pharmaceuticals, Shire, and others.
SOURCE: Hill QA et al. Br J Haematol. 2019 Jan 4. doi: 10.1111/bjh.15735.
FROM THE BRITISH JOURNAL OF HAEMATOLOGY
Key clinical point:
Major finding: In patients with relapsed immune thrombocytopenia, use the lowest effective glucocorticoid dose and administer steroid-sparing agents when appropriate.
Study details: An expert review focused on the prevention of steroid-induced osteoporosis in patients with immune thrombocytopenia.
Disclosures: Dr. Hill and several coauthors reported financial affiliations with Amgen, Novartis, Ono Pharmaceuticals, Shire, and others.
Source: Hill QA et al. Br J Haematol. 2019 Jan 4. doi: 10.1111/bjh.15735.
Online tools support hemophilia A prophylaxis changes
Online applications designed to facilitate tailoring of hemophilia A prophylaxis supported a regimen change in nearly half of patients enrolled in a recent study, investigators report.
The development of individualized pharmacokinetic profiles using those online tools may have contributed to improved adherence and decreased bleeding, according to Azusa Nagao, MD, a researcher in the department of blood coagulation at Ogikubo Hospital, Tokyo, and colleagues.
Dr. Nagao and colleagues calculated individual pharmacokinetic profiles for the 39 patients using myPKFiT for those patients receiving antihemophilic factor (recombinant) and the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) for those using other factor concentrates.
Based on profiling results, changes to prophylaxis regimens were warranted for 20 of the 39 patients, Dr. Nagao and coresearchers reported in Thrombosis Research.
Those changes included a higher dosage of factor concentrate in eight patients, a shorter infusion interval in five patients, a change from a standard half-life product to an extended half-life product in five patients, and a reduction in prophylaxis dose for two patients.
Adherence stayed the same in patients who had a dose increase and improved for those who switched to a shorter infusion interval and for those who switched to an extended half-life product, according to the researchers.
Annualized bleeding rate significantly decreased for patients who switched to an extended half-life product (P less than .05), and there was a trend toward decrease in annualized joint bleeding rate in this group, the researchers reported.
The annualized joint bleeding rate did significantly decrease in patients without end-stage arthropathy (P less than .05), with no significant change in this outcome for those with end-stage arthropathy.
“The impact of adopting population pharmacokinetics-based treatment as measured by changes in treatment adherence and bleeding rate was modest, but the study power was limited by the characteristics of the study population,” the researchers wrote.
The myPKFiT and WAPPS-Hemo tools are designed to simplify the development of individual pharmacokinetic profiles to guide prophylaxis dosing in patients with hemophilia A, according to the researchers.
“Full [pharmacokinetic] analysis poses a big burden, especially on children and their families,” they wrote.
A full pharmacokinetic study requires a 72-hour washout period and sample collection at 10 time points over the course of about 48 hours, along with associated hospital admissions or outpatient clinic visits, they noted.
The myPKFiT application, cleared by the Food and Drug Administration for use in hemophilia A patients being treated with antihemophilic factor (recombinant), can generate an individual’s pharmacokinetic profile based on as few as two blood samples, according to a news release from Shire.
Nagao reported receiving a research grant from Shire unrelated to this study. One coauthor also reported disclosures related to Shire, Bayer, Pfizer, Novo Nordisk, CSL Behring, and others.
SOURCE: Nagao A et al. Thromb Res. 2019 Jan;173:79-84.
Online applications designed to facilitate tailoring of hemophilia A prophylaxis supported a regimen change in nearly half of patients enrolled in a recent study, investigators report.
The development of individualized pharmacokinetic profiles using those online tools may have contributed to improved adherence and decreased bleeding, according to Azusa Nagao, MD, a researcher in the department of blood coagulation at Ogikubo Hospital, Tokyo, and colleagues.
Dr. Nagao and colleagues calculated individual pharmacokinetic profiles for the 39 patients using myPKFiT for those patients receiving antihemophilic factor (recombinant) and the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) for those using other factor concentrates.
Based on profiling results, changes to prophylaxis regimens were warranted for 20 of the 39 patients, Dr. Nagao and coresearchers reported in Thrombosis Research.
Those changes included a higher dosage of factor concentrate in eight patients, a shorter infusion interval in five patients, a change from a standard half-life product to an extended half-life product in five patients, and a reduction in prophylaxis dose for two patients.
Adherence stayed the same in patients who had a dose increase and improved for those who switched to a shorter infusion interval and for those who switched to an extended half-life product, according to the researchers.
Annualized bleeding rate significantly decreased for patients who switched to an extended half-life product (P less than .05), and there was a trend toward decrease in annualized joint bleeding rate in this group, the researchers reported.
The annualized joint bleeding rate did significantly decrease in patients without end-stage arthropathy (P less than .05), with no significant change in this outcome for those with end-stage arthropathy.
“The impact of adopting population pharmacokinetics-based treatment as measured by changes in treatment adherence and bleeding rate was modest, but the study power was limited by the characteristics of the study population,” the researchers wrote.
The myPKFiT and WAPPS-Hemo tools are designed to simplify the development of individual pharmacokinetic profiles to guide prophylaxis dosing in patients with hemophilia A, according to the researchers.
“Full [pharmacokinetic] analysis poses a big burden, especially on children and their families,” they wrote.
A full pharmacokinetic study requires a 72-hour washout period and sample collection at 10 time points over the course of about 48 hours, along with associated hospital admissions or outpatient clinic visits, they noted.
The myPKFiT application, cleared by the Food and Drug Administration for use in hemophilia A patients being treated with antihemophilic factor (recombinant), can generate an individual’s pharmacokinetic profile based on as few as two blood samples, according to a news release from Shire.
Nagao reported receiving a research grant from Shire unrelated to this study. One coauthor also reported disclosures related to Shire, Bayer, Pfizer, Novo Nordisk, CSL Behring, and others.
SOURCE: Nagao A et al. Thromb Res. 2019 Jan;173:79-84.
Online applications designed to facilitate tailoring of hemophilia A prophylaxis supported a regimen change in nearly half of patients enrolled in a recent study, investigators report.
The development of individualized pharmacokinetic profiles using those online tools may have contributed to improved adherence and decreased bleeding, according to Azusa Nagao, MD, a researcher in the department of blood coagulation at Ogikubo Hospital, Tokyo, and colleagues.
Dr. Nagao and colleagues calculated individual pharmacokinetic profiles for the 39 patients using myPKFiT for those patients receiving antihemophilic factor (recombinant) and the Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) for those using other factor concentrates.
Based on profiling results, changes to prophylaxis regimens were warranted for 20 of the 39 patients, Dr. Nagao and coresearchers reported in Thrombosis Research.
Those changes included a higher dosage of factor concentrate in eight patients, a shorter infusion interval in five patients, a change from a standard half-life product to an extended half-life product in five patients, and a reduction in prophylaxis dose for two patients.
Adherence stayed the same in patients who had a dose increase and improved for those who switched to a shorter infusion interval and for those who switched to an extended half-life product, according to the researchers.
Annualized bleeding rate significantly decreased for patients who switched to an extended half-life product (P less than .05), and there was a trend toward decrease in annualized joint bleeding rate in this group, the researchers reported.
The annualized joint bleeding rate did significantly decrease in patients without end-stage arthropathy (P less than .05), with no significant change in this outcome for those with end-stage arthropathy.
“The impact of adopting population pharmacokinetics-based treatment as measured by changes in treatment adherence and bleeding rate was modest, but the study power was limited by the characteristics of the study population,” the researchers wrote.
The myPKFiT and WAPPS-Hemo tools are designed to simplify the development of individual pharmacokinetic profiles to guide prophylaxis dosing in patients with hemophilia A, according to the researchers.
“Full [pharmacokinetic] analysis poses a big burden, especially on children and their families,” they wrote.
A full pharmacokinetic study requires a 72-hour washout period and sample collection at 10 time points over the course of about 48 hours, along with associated hospital admissions or outpatient clinic visits, they noted.
The myPKFiT application, cleared by the Food and Drug Administration for use in hemophilia A patients being treated with antihemophilic factor (recombinant), can generate an individual’s pharmacokinetic profile based on as few as two blood samples, according to a news release from Shire.
Nagao reported receiving a research grant from Shire unrelated to this study. One coauthor also reported disclosures related to Shire, Bayer, Pfizer, Novo Nordisk, CSL Behring, and others.
SOURCE: Nagao A et al. Thromb Res. 2019 Jan;173:79-84.
FROM THROMBOSIS RESEARCH
Key clinical point:
Major finding: Adherence stayed the same or improved in patients whose prophylaxis regimens were changed based on the tool results, while bleeding rates improved for specific patient subsets.
Study details: Prospective study including 39 patients receiving hemophilia A prophylaxis.
Disclosures: Study authors reported disclosures related to Shire, Bayer, Pfizer, Novo Nordisk, CSL Behring, and others.
Source: Nagao A et al. Thromb Res. 2019 Jan;173:79-84.