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Durable efficacy with MK-6482 in VHL-associated RCC
according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.
MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.
Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.
The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.
The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).
The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
Efficacy and safety
At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.
By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.
The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.
“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.
Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.
In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.
“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.
Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
Remaining questions and next steps
The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.
“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.
While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.
“These are the best response rates reported in non-RCC lesions,” she noted.
However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?
Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.
The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.
SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.
according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.
MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.
Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.
The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.
The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).
The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
Efficacy and safety
At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.
By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.
The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.
“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.
Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.
In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.
“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.
Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
Remaining questions and next steps
The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.
“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.
While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.
“These are the best response rates reported in non-RCC lesions,” she noted.
However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?
Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.
The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.
SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.
according to a presentation at the European Society for Medical Oncology Virtual Congress 2020.
MK-6482 is an oral inhibitor of hypoxia inducible factor-(HIF) 2-alpha. The drug previously showed favorable safety and antitumor activity in advanced RCC, Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute, Bethesda, Md., said when presenting data from the phase 2 trial.
Dr. Srinivasan noted that, in VHL disease, RCC occurs in 25%-60% of individuals and is a key cause of morbidity and shortened life expectancy despite aggressive treatment. HIF-2-alpha accumulation activates genes that drive tumor growth in VHL-associated RCC.
The primary objective of Dr. Srinivasan’s phase 2 study was to evaluate the efficacy of the HIF-2-alpha inhibitor MK-6482 (at 120 mg daily) for the treatment of VHL-associated RCC.
The study included 61 treatment-naive patients with VHL diagnoses based on germline mutations. All subjects had RCC and additional non-RCC lesions, including pancreatic (100%), central nervous system (CNS) hemangioblastoma (70.5%), and retinal lesions (26.2%).
The patients’ median age at baseline was 41 years (range, 19-66), and 52.5% were men. Most (82%) had an European Cooperative Oncology Group performance status of 0.
Efficacy and safety
At a median follow-up of 68.7 weeks, 56 patients were receiving ongoing treatment.
By independent central review, the overall response rate in target RCC lesions was 36.1% (all partial responses), with unconfirmed partial responses in 11.5% and stable disease in 62.3%. There was no progression in target lesions. Decreases in target lesion size were observed in 91.8% of patients.
The median time to response was 31.1 weeks (range, 11.9-62.3 weeks), and the median duration of response was not reached (range, 11.9-62.3 weeks). The 1-year progression-free survival rate was 98.3%.
“Promising clinical activity was observed with MK-6482 in treatment-naive patients with VHL-associated RCC,” Dr. Srinivasan said. He added that efficacy was durable in both RCC and non-renal lesions.
Complete responses were observed in 6.6% (4/61) of pancreatic lesions and 11.6% (5/43) of CNS hemangioblastomas. Partial response and stable disease rates in pancreatic lesions were 57.4% and 34.4%, respectively. Partial response and stable disease rates in CNS hemangioblastomas were 18.6% and 65.1%, respectively.
In the 16 patients with retinal lesions, 68.8% saw an improvement and 25% had stable disease. No progression was reported.
“MK-6482 was well tolerated and has a favorable safety profile,” Dr. Srinivasan noted.
Most patients (98.4%) had treatment-related adverse events (AEs), with anemia being the most common. Grade 3 AEs included anemia (6.6%), fatigue (4.9%), dyspnea (1.6%), and hypoxia (1.6%). One patient (1.6%) discontinued treatment because of grade 1 dizziness. There was one grade 4 AE and one fatal AE, but both were considered unrelated to study treatment.
Remaining questions and next steps
The challenge in managing VHL-associated RCC tumors is finding a balance between the risk of cancer dissemination and renal morbidity, said study discussant Cristina Suárez, MD, PhD, of Hospital Universitari Vall d’Hebron in Barcelona.
“There is no standard of care systemic treatment, and recruitment for clinical trials is challenging,” Dr. Suárez added.
While response rates in RCC lesions with MK-6482 were generally in line with the experience reported for sunitinib and pazopanib, response rates were particularly favorable with MK-6482 in pancreatic lesions and CNS hemangioblastomas, Dr. Suárez said.
“These are the best response rates reported in non-RCC lesions,” she noted.
However, Dr. Suárez said, important questions remain. Specifically, how long should patients continue on treatment, and will lesion rebound occur after treatment discontinuation?
Larger multicenter trials are needed, Dr. Suárez said, pointing out that the current study is the largest to date of systemic therapy for patients with VHL disease.
The study was funded by Merck Sharp & Dohme Corp. Dr. Srinivasan disclosed funding from Merck and Calithera Biosciences. Dr. Suárez disclosed relationships with Astellas, AstraZeneca, Bayer, and many other companies.
SOURCE: Srinivasan R et al. ESMO 2020. Abstract LBA26.
ESMO 2020
Repurposing cardiovascular drugs for serious mental illness
One of the hottest topics now in psychiatry is the possibility of repurposing long-established cardiovascular medications for treatment of patients with serious mental illness, Livia De Picker, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.
The appeal is multifold. A huge unmet need exists in psychiatry for new and better treatments with novel mechanisms of action. Many guideline-recommended cardiovascular medications have a long track record, including a well-established safety profile with no surprises, and are available in generic versions. They can be developed for a new indication at minimal cost, noted Dr. De Picker, a psychiatrist at the University of Antwerp (Belgium).
The idea of psychiatric repurposing of drugs originally developed for nonpsychiatric indications is nothing new, she added. Examples include lithium for gout, valproate for epilepsy, and ketamine for anesthesiology.
One hitch in efforts to repurpose cardiovascular medications is that, when psychiatric patients have been included in randomized trials of the drugs’ cardiovascular effects, the psychiatric outcomes often went untallied.
Indeed, the only high-quality randomized trial evidence of psychiatric benefits for any class of cardiovascular medications is for statins, where a modest-sized meta-analysis of six placebo-controlled trials in 339 patients with schizophrenia showed the lipid-lowering agents had benefit for both positive and negative symptoms (Psychiatry Res. 2018 Apr;262:84-93). But that’s not a body of data of sufficient size to be definitive, in Dr. De Picker’s view.
Much of the recent enthusiasm for exploring the potential of cardiovascular drugs for psychiatric conditions comes from hypothesis-generating big data analyses drawn from Scandinavian national patient registries. Danish investigators scrutinized all 1.6 million Danes exposed to six classes of drugs of interest during 2005-2015 and determined that those on long-term statins, low-dose aspirin, ACE inhibitors, angiotensin receptor blockers, or allopurinol were associated with a decreased rate of new-onset depression, while high-dose aspirin and non-aspirin NSAIDs were associated with an increased rate, compared with a 30% random sample of the country’s population (Acta Psychiatr Scand. 2019 Jan;1391:68-77).
Similarly, the Danish group found that continued use of statins, angiotensin agents, or low-dose aspirin was associated with a decreased rate of new-onset bipolar disorder, while high-dose aspirin and other NSAIDs were linked to increased risk (Bipolar Disord. 2019 Aug;[15]:410-8). What these agents have in common, the investigators observed, is that they act on inflammation and potentially on the stress response system.
Meanwhile, Swedish investigators examined the course of 142,691 Swedes with a diagnosis of bipolar disorder, schizophrenia, or nonaffective psychosis during 2005-2016. They determined that, during periods when those individuals were on a statin, calcium channel blocker, or metformin, they had reduced rates of psychiatric hospitalization and self-harm (JAMA Psychiatry. 2019 Apr 1;76[4]:382-90).
Scottish researchers analyzed the health records of 144,066 patients placed on monotherapy for hypertension and determined that the lowest risk for hospitalization for a mood disorder during follow-up was in those prescribed an ACE inhibitor or angiotensin receptor blocker. The risk was significantly higher in patients on a beta-blocker or calcium channel blocker, and intermediate in those on a thiazide diuretic (Hypertension. 2016 Nov;68[5:1132-8).
“Obviously, this is all at a very macro scale and we have no idea whatsoever what this means for individual patients, number needed to treat, or which type of patients would benefit, but it does provide us with some guidance for future research,” according to Dr. De Picker.
In the meantime, while physicians await definitive evidence of any impact of cardiovascular drugs might have on psychiatric outcomes, abundant data exist underscoring what she called “shockingly high levels” of inadequate management of cardiovascular risk factors in patients with serious mental illness. That problem needs to be addressed, and Dr. De Picker offered her personal recommendations for doing so in a manner consistent with the evidence to date suggestive of potential mental health benefits of some cardiovascular medications.
She advised that, for treatment of hypertension in patients with bipolar disorder or major depression, an ACE inhibitor or angiotensin-converting enzyme inhibitor is preferred as first-line. There is some evidence to suggest lipophilic beta-blockers, which cross the blood-brain barrier, improve anxiety symptoms and panic attacks, and prevent memory consolidation in patients with posttraumatic stress disorder. But the Scottish data suggest that they may worsen mood disorders.
“I would be careful in using beta-blockers as first-line treatment for hypertension. They’re not in the guidelines for anxiety disorders. British guidelines recommend them to prevent memory consolidation in PTSD, but do not use them as first-line in patients with major depressive disorder or bipolar disorder,” she said. As for calcium channel blockers, the jury is still out, with mixed and inconsistent evidence to date as to the impact of this drug class on mental illness outcomes.
She recommended a very low threshold for prescribing statin therapy in patients with serious mental illness in light of the superb risk/benefit ratio for this drug class. In her younger patients, she turns for guidance to an online calculator of an individual’s 10-year risk of a first acute MI or stroke.
Metformin has been shown to be beneficial for addressing the weight gain and other adverse metabolic effects caused by antipsychotic agents, and there is some preliminary evidence of improved psychiatric outcomes in patients with serious mental illness.
Christian Otte, MD, who also spoke at the session, noted that not only do emerging data point to the possibility that cardiovascular drugs might have benefit in terms of psychiatric outcomes, there is also some evidence, albeit mixed, that the converse is true: that is, psychiatric drugs may have cardiovascular benefits. He pointed to a South Korean trial in which 300 patients with a recent acute coronary syndrome and major depression were randomized to 24 weeks of escitalopram or placebo. At median 8.1 years of follow-up, the group that received the SSRI had a 31% relative risk reduction in the primary composite endpoint of all-cause mortality, acute MI, or percutaneous coronary intervention (JAMA. 2018 Jul 24; 320[4]:350–7).
“Potentially independent of their antidepressant effects, some SSRIs’ antiplatelet effects could be beneficial for patients with coronary heart disease, although the jury is still open regarding this question, with evidence in both directions,” said Dr. Otte, professor of psychiatry at Charite University Medical Center in Berlin.
Dr. De Picker offered an example as well: Finnish psychiatrists recently reported that cardiovascular mortality was reduced by an adjusted 38% during periods when 62,250 Finnish schizophrenia patients were on antipsychotic agents, compared with periods of nonuse of the drugs in a national study with a median 14.1 years of follow-up (World Psychiatry. 2020 Feb;19[1]:61-8).
“What they discovered – and this is quite contrary to what we are used to hearing about antipsychotic medication and cardiovascular risk – is that while the number of cardiovascular hospitalizations was not different in periods with or without antipsychotic use, the cardiovascular mortality was quite strikingly reduced when patients were on antipsychotic medication,” she said.
Asked by an audience member whether she personally prescribes metformin, Dr. De Picker replied: “Well, yes, why not? One of the very nice things about metformin is that it is actually a very safe drug, even in the hands of nonspecialists.
“I understand that maybe psychiatrists may not feel very comfortable in starting patients on metformin due to a lack of experience. But there are really only two things you need to take into account. About one-quarter of patients will experience GI side effects – nausea, vomiting, abdominal discomfort – and this can be reduced by gradually uptitrating the dose, dosing at mealtime, and using an extended-release formulation. And the second thing is that metformin can impair vitamin B12 absorption, so I think, especially in psychiatric patients, it would be good to do an annual measurement of vitamin B12 level and, if necessary, administer intramuscular supplements,” Dr. De Picker said.
She reported having no financial conflicts regarding her presentation.
SOURCE: De Picker L. ECNP 2020. Session EDU.05.
One of the hottest topics now in psychiatry is the possibility of repurposing long-established cardiovascular medications for treatment of patients with serious mental illness, Livia De Picker, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.
The appeal is multifold. A huge unmet need exists in psychiatry for new and better treatments with novel mechanisms of action. Many guideline-recommended cardiovascular medications have a long track record, including a well-established safety profile with no surprises, and are available in generic versions. They can be developed for a new indication at minimal cost, noted Dr. De Picker, a psychiatrist at the University of Antwerp (Belgium).
The idea of psychiatric repurposing of drugs originally developed for nonpsychiatric indications is nothing new, she added. Examples include lithium for gout, valproate for epilepsy, and ketamine for anesthesiology.
One hitch in efforts to repurpose cardiovascular medications is that, when psychiatric patients have been included in randomized trials of the drugs’ cardiovascular effects, the psychiatric outcomes often went untallied.
Indeed, the only high-quality randomized trial evidence of psychiatric benefits for any class of cardiovascular medications is for statins, where a modest-sized meta-analysis of six placebo-controlled trials in 339 patients with schizophrenia showed the lipid-lowering agents had benefit for both positive and negative symptoms (Psychiatry Res. 2018 Apr;262:84-93). But that’s not a body of data of sufficient size to be definitive, in Dr. De Picker’s view.
Much of the recent enthusiasm for exploring the potential of cardiovascular drugs for psychiatric conditions comes from hypothesis-generating big data analyses drawn from Scandinavian national patient registries. Danish investigators scrutinized all 1.6 million Danes exposed to six classes of drugs of interest during 2005-2015 and determined that those on long-term statins, low-dose aspirin, ACE inhibitors, angiotensin receptor blockers, or allopurinol were associated with a decreased rate of new-onset depression, while high-dose aspirin and non-aspirin NSAIDs were associated with an increased rate, compared with a 30% random sample of the country’s population (Acta Psychiatr Scand. 2019 Jan;1391:68-77).
Similarly, the Danish group found that continued use of statins, angiotensin agents, or low-dose aspirin was associated with a decreased rate of new-onset bipolar disorder, while high-dose aspirin and other NSAIDs were linked to increased risk (Bipolar Disord. 2019 Aug;[15]:410-8). What these agents have in common, the investigators observed, is that they act on inflammation and potentially on the stress response system.
Meanwhile, Swedish investigators examined the course of 142,691 Swedes with a diagnosis of bipolar disorder, schizophrenia, or nonaffective psychosis during 2005-2016. They determined that, during periods when those individuals were on a statin, calcium channel blocker, or metformin, they had reduced rates of psychiatric hospitalization and self-harm (JAMA Psychiatry. 2019 Apr 1;76[4]:382-90).
Scottish researchers analyzed the health records of 144,066 patients placed on monotherapy for hypertension and determined that the lowest risk for hospitalization for a mood disorder during follow-up was in those prescribed an ACE inhibitor or angiotensin receptor blocker. The risk was significantly higher in patients on a beta-blocker or calcium channel blocker, and intermediate in those on a thiazide diuretic (Hypertension. 2016 Nov;68[5:1132-8).
“Obviously, this is all at a very macro scale and we have no idea whatsoever what this means for individual patients, number needed to treat, or which type of patients would benefit, but it does provide us with some guidance for future research,” according to Dr. De Picker.
In the meantime, while physicians await definitive evidence of any impact of cardiovascular drugs might have on psychiatric outcomes, abundant data exist underscoring what she called “shockingly high levels” of inadequate management of cardiovascular risk factors in patients with serious mental illness. That problem needs to be addressed, and Dr. De Picker offered her personal recommendations for doing so in a manner consistent with the evidence to date suggestive of potential mental health benefits of some cardiovascular medications.
She advised that, for treatment of hypertension in patients with bipolar disorder or major depression, an ACE inhibitor or angiotensin-converting enzyme inhibitor is preferred as first-line. There is some evidence to suggest lipophilic beta-blockers, which cross the blood-brain barrier, improve anxiety symptoms and panic attacks, and prevent memory consolidation in patients with posttraumatic stress disorder. But the Scottish data suggest that they may worsen mood disorders.
“I would be careful in using beta-blockers as first-line treatment for hypertension. They’re not in the guidelines for anxiety disorders. British guidelines recommend them to prevent memory consolidation in PTSD, but do not use them as first-line in patients with major depressive disorder or bipolar disorder,” she said. As for calcium channel blockers, the jury is still out, with mixed and inconsistent evidence to date as to the impact of this drug class on mental illness outcomes.
She recommended a very low threshold for prescribing statin therapy in patients with serious mental illness in light of the superb risk/benefit ratio for this drug class. In her younger patients, she turns for guidance to an online calculator of an individual’s 10-year risk of a first acute MI or stroke.
Metformin has been shown to be beneficial for addressing the weight gain and other adverse metabolic effects caused by antipsychotic agents, and there is some preliminary evidence of improved psychiatric outcomes in patients with serious mental illness.
Christian Otte, MD, who also spoke at the session, noted that not only do emerging data point to the possibility that cardiovascular drugs might have benefit in terms of psychiatric outcomes, there is also some evidence, albeit mixed, that the converse is true: that is, psychiatric drugs may have cardiovascular benefits. He pointed to a South Korean trial in which 300 patients with a recent acute coronary syndrome and major depression were randomized to 24 weeks of escitalopram or placebo. At median 8.1 years of follow-up, the group that received the SSRI had a 31% relative risk reduction in the primary composite endpoint of all-cause mortality, acute MI, or percutaneous coronary intervention (JAMA. 2018 Jul 24; 320[4]:350–7).
“Potentially independent of their antidepressant effects, some SSRIs’ antiplatelet effects could be beneficial for patients with coronary heart disease, although the jury is still open regarding this question, with evidence in both directions,” said Dr. Otte, professor of psychiatry at Charite University Medical Center in Berlin.
Dr. De Picker offered an example as well: Finnish psychiatrists recently reported that cardiovascular mortality was reduced by an adjusted 38% during periods when 62,250 Finnish schizophrenia patients were on antipsychotic agents, compared with periods of nonuse of the drugs in a national study with a median 14.1 years of follow-up (World Psychiatry. 2020 Feb;19[1]:61-8).
“What they discovered – and this is quite contrary to what we are used to hearing about antipsychotic medication and cardiovascular risk – is that while the number of cardiovascular hospitalizations was not different in periods with or without antipsychotic use, the cardiovascular mortality was quite strikingly reduced when patients were on antipsychotic medication,” she said.
Asked by an audience member whether she personally prescribes metformin, Dr. De Picker replied: “Well, yes, why not? One of the very nice things about metformin is that it is actually a very safe drug, even in the hands of nonspecialists.
“I understand that maybe psychiatrists may not feel very comfortable in starting patients on metformin due to a lack of experience. But there are really only two things you need to take into account. About one-quarter of patients will experience GI side effects – nausea, vomiting, abdominal discomfort – and this can be reduced by gradually uptitrating the dose, dosing at mealtime, and using an extended-release formulation. And the second thing is that metformin can impair vitamin B12 absorption, so I think, especially in psychiatric patients, it would be good to do an annual measurement of vitamin B12 level and, if necessary, administer intramuscular supplements,” Dr. De Picker said.
She reported having no financial conflicts regarding her presentation.
SOURCE: De Picker L. ECNP 2020. Session EDU.05.
One of the hottest topics now in psychiatry is the possibility of repurposing long-established cardiovascular medications for treatment of patients with serious mental illness, Livia De Picker, MD, PhD, said at the virtual congress of the European College of Neuropsychopharmacology.
The appeal is multifold. A huge unmet need exists in psychiatry for new and better treatments with novel mechanisms of action. Many guideline-recommended cardiovascular medications have a long track record, including a well-established safety profile with no surprises, and are available in generic versions. They can be developed for a new indication at minimal cost, noted Dr. De Picker, a psychiatrist at the University of Antwerp (Belgium).
The idea of psychiatric repurposing of drugs originally developed for nonpsychiatric indications is nothing new, she added. Examples include lithium for gout, valproate for epilepsy, and ketamine for anesthesiology.
One hitch in efforts to repurpose cardiovascular medications is that, when psychiatric patients have been included in randomized trials of the drugs’ cardiovascular effects, the psychiatric outcomes often went untallied.
Indeed, the only high-quality randomized trial evidence of psychiatric benefits for any class of cardiovascular medications is for statins, where a modest-sized meta-analysis of six placebo-controlled trials in 339 patients with schizophrenia showed the lipid-lowering agents had benefit for both positive and negative symptoms (Psychiatry Res. 2018 Apr;262:84-93). But that’s not a body of data of sufficient size to be definitive, in Dr. De Picker’s view.
Much of the recent enthusiasm for exploring the potential of cardiovascular drugs for psychiatric conditions comes from hypothesis-generating big data analyses drawn from Scandinavian national patient registries. Danish investigators scrutinized all 1.6 million Danes exposed to six classes of drugs of interest during 2005-2015 and determined that those on long-term statins, low-dose aspirin, ACE inhibitors, angiotensin receptor blockers, or allopurinol were associated with a decreased rate of new-onset depression, while high-dose aspirin and non-aspirin NSAIDs were associated with an increased rate, compared with a 30% random sample of the country’s population (Acta Psychiatr Scand. 2019 Jan;1391:68-77).
Similarly, the Danish group found that continued use of statins, angiotensin agents, or low-dose aspirin was associated with a decreased rate of new-onset bipolar disorder, while high-dose aspirin and other NSAIDs were linked to increased risk (Bipolar Disord. 2019 Aug;[15]:410-8). What these agents have in common, the investigators observed, is that they act on inflammation and potentially on the stress response system.
Meanwhile, Swedish investigators examined the course of 142,691 Swedes with a diagnosis of bipolar disorder, schizophrenia, or nonaffective psychosis during 2005-2016. They determined that, during periods when those individuals were on a statin, calcium channel blocker, or metformin, they had reduced rates of psychiatric hospitalization and self-harm (JAMA Psychiatry. 2019 Apr 1;76[4]:382-90).
Scottish researchers analyzed the health records of 144,066 patients placed on monotherapy for hypertension and determined that the lowest risk for hospitalization for a mood disorder during follow-up was in those prescribed an ACE inhibitor or angiotensin receptor blocker. The risk was significantly higher in patients on a beta-blocker or calcium channel blocker, and intermediate in those on a thiazide diuretic (Hypertension. 2016 Nov;68[5:1132-8).
“Obviously, this is all at a very macro scale and we have no idea whatsoever what this means for individual patients, number needed to treat, or which type of patients would benefit, but it does provide us with some guidance for future research,” according to Dr. De Picker.
In the meantime, while physicians await definitive evidence of any impact of cardiovascular drugs might have on psychiatric outcomes, abundant data exist underscoring what she called “shockingly high levels” of inadequate management of cardiovascular risk factors in patients with serious mental illness. That problem needs to be addressed, and Dr. De Picker offered her personal recommendations for doing so in a manner consistent with the evidence to date suggestive of potential mental health benefits of some cardiovascular medications.
She advised that, for treatment of hypertension in patients with bipolar disorder or major depression, an ACE inhibitor or angiotensin-converting enzyme inhibitor is preferred as first-line. There is some evidence to suggest lipophilic beta-blockers, which cross the blood-brain barrier, improve anxiety symptoms and panic attacks, and prevent memory consolidation in patients with posttraumatic stress disorder. But the Scottish data suggest that they may worsen mood disorders.
“I would be careful in using beta-blockers as first-line treatment for hypertension. They’re not in the guidelines for anxiety disorders. British guidelines recommend them to prevent memory consolidation in PTSD, but do not use them as first-line in patients with major depressive disorder or bipolar disorder,” she said. As for calcium channel blockers, the jury is still out, with mixed and inconsistent evidence to date as to the impact of this drug class on mental illness outcomes.
She recommended a very low threshold for prescribing statin therapy in patients with serious mental illness in light of the superb risk/benefit ratio for this drug class. In her younger patients, she turns for guidance to an online calculator of an individual’s 10-year risk of a first acute MI or stroke.
Metformin has been shown to be beneficial for addressing the weight gain and other adverse metabolic effects caused by antipsychotic agents, and there is some preliminary evidence of improved psychiatric outcomes in patients with serious mental illness.
Christian Otte, MD, who also spoke at the session, noted that not only do emerging data point to the possibility that cardiovascular drugs might have benefit in terms of psychiatric outcomes, there is also some evidence, albeit mixed, that the converse is true: that is, psychiatric drugs may have cardiovascular benefits. He pointed to a South Korean trial in which 300 patients with a recent acute coronary syndrome and major depression were randomized to 24 weeks of escitalopram or placebo. At median 8.1 years of follow-up, the group that received the SSRI had a 31% relative risk reduction in the primary composite endpoint of all-cause mortality, acute MI, or percutaneous coronary intervention (JAMA. 2018 Jul 24; 320[4]:350–7).
“Potentially independent of their antidepressant effects, some SSRIs’ antiplatelet effects could be beneficial for patients with coronary heart disease, although the jury is still open regarding this question, with evidence in both directions,” said Dr. Otte, professor of psychiatry at Charite University Medical Center in Berlin.
Dr. De Picker offered an example as well: Finnish psychiatrists recently reported that cardiovascular mortality was reduced by an adjusted 38% during periods when 62,250 Finnish schizophrenia patients were on antipsychotic agents, compared with periods of nonuse of the drugs in a national study with a median 14.1 years of follow-up (World Psychiatry. 2020 Feb;19[1]:61-8).
“What they discovered – and this is quite contrary to what we are used to hearing about antipsychotic medication and cardiovascular risk – is that while the number of cardiovascular hospitalizations was not different in periods with or without antipsychotic use, the cardiovascular mortality was quite strikingly reduced when patients were on antipsychotic medication,” she said.
Asked by an audience member whether she personally prescribes metformin, Dr. De Picker replied: “Well, yes, why not? One of the very nice things about metformin is that it is actually a very safe drug, even in the hands of nonspecialists.
“I understand that maybe psychiatrists may not feel very comfortable in starting patients on metformin due to a lack of experience. But there are really only two things you need to take into account. About one-quarter of patients will experience GI side effects – nausea, vomiting, abdominal discomfort – and this can be reduced by gradually uptitrating the dose, dosing at mealtime, and using an extended-release formulation. And the second thing is that metformin can impair vitamin B12 absorption, so I think, especially in psychiatric patients, it would be good to do an annual measurement of vitamin B12 level and, if necessary, administer intramuscular supplements,” Dr. De Picker said.
She reported having no financial conflicts regarding her presentation.
SOURCE: De Picker L. ECNP 2020. Session EDU.05.
FROM ECNP 2020
Benefit of rivaroxaban after limb revascularization greatest in those with comorbid CAD
The absolute benefit of adding low-dose rivaroxaban to low-dose aspirin following revascularization for symptomatic lower-extremity peripheral artery disease (PAD) is significantly greater in patients with comorbid coronary artery disease (CAD), according to a new secondary analysis of the VOYAGER PAD trial.
“These findings suggest heterogeneity of prognostic risk for ischemic events in lower-extremity PAD patients, and may support shared decision-making with these patients,” William R. Hiatt, MD, observed in presenting the study results at the virtual annual congress of the European Society of Cardiology.
VOYAGER PAD was a 3-year, 34-country clinical trial in which 6,564 patients with symptomatic PAD who had recently undergone lower-limb revascularization were randomized in double-blind fashion to rivaroxaban (Xarelto) at 2.5 mg twice daily or placebo on top of background standard therapy with low-dose aspirin.
Among the 2,067 participants with baseline comorbid CAD, the primary outcome – a composite comprised of cardiovascular death, acute MI, ischemic stroke, acute limb ischemia, and major amputation – occurred in 18.9% of the rivaroxaban group at 3 years and 24.3% on placebo, for a highly significant 22% relative risk reduction.
In contrast, in the 4,497 patients with PAD only, the primary outcome occurred in 16.1% of those on rivaroxaban and 17.9% of controls, an 11% relative risk reduction which failed to reach statistical significance. The absolute risk reduction achieved with rivaroxaban was 5.4% in patients with PAD plus CAD versus 1.8% in those with PAD alone. Thus, the significant clinical benefit with rivaroxaban plus aspirin previously reported in the overall study population, with a number needed to treat for 3 years of 39 in order to prevent one primary outcome event, was largely driven by the superior outcomes in the dual-diagnosis subgroup, reported Dr. Hiatt, professor of medicine at the University of Colorado at Denver, Aurora.
“A strategy of rivaroxaban at 2.5 mg twice daily plus low-dose aspirin versus low-dose aspirin alone reduces ischemic events of the limb, brain, and heart, but also increases bleeding, with an overall net benefit,” the cardiologist said. “In particular, the benefits of this strategy for MI and ischemic stroke are robust, especially in patients with PAD and CAD.”
Indeed, the MI rate at 3 years in the dual diagnosis subgroup was 7.3% with rivaroxaban and 8.8% with placebo, for a 23% relative risk reduction, compared with rates of 3.3% and 3.7%, respectively, in patients with PAD only. Similarly, ischemic stroke occurred in 2.9% of patients with PAD and CAD in the rivaroxaban group, compared with 3.9% with placebo, whereas the rate in the PAD only group was identical at 2.6% regardless of whether patients were on rivaroxaban or placebo.
In patients without CAD, the clinical benefit of rivaroxaban was driven by reductions in severe limb events. Their rate of acute limb ischemia was 5.2% with rivaroxaban, compared with 8.3% with placebo, for a 37% relative risk reduction. In contrast, the reduction in acute limb ischemia with rivaroxaban in patients with PAD and CAD wasn’t significantly different from placebo.
Thrombolysis in Myocardial Infarction major bleeding occurred in 2.4% of patients with PAD and CAD on rivaroxaban, compared with 1.1% on placebo, and in 1.7% and 1.5% of patients with PAD alone. Of note, rates of ischemic stroke or fatal hemorrhage were low and similar at less than 1% in all four groups, Dr. Hiatt noted.
VOYAGER PAD was sponsored by Bayer and Janssen. Dr. Hiatt reported receiving research grant support from those two companies as well as Amgen.
The absolute benefit of adding low-dose rivaroxaban to low-dose aspirin following revascularization for symptomatic lower-extremity peripheral artery disease (PAD) is significantly greater in patients with comorbid coronary artery disease (CAD), according to a new secondary analysis of the VOYAGER PAD trial.
“These findings suggest heterogeneity of prognostic risk for ischemic events in lower-extremity PAD patients, and may support shared decision-making with these patients,” William R. Hiatt, MD, observed in presenting the study results at the virtual annual congress of the European Society of Cardiology.
VOYAGER PAD was a 3-year, 34-country clinical trial in which 6,564 patients with symptomatic PAD who had recently undergone lower-limb revascularization were randomized in double-blind fashion to rivaroxaban (Xarelto) at 2.5 mg twice daily or placebo on top of background standard therapy with low-dose aspirin.
Among the 2,067 participants with baseline comorbid CAD, the primary outcome – a composite comprised of cardiovascular death, acute MI, ischemic stroke, acute limb ischemia, and major amputation – occurred in 18.9% of the rivaroxaban group at 3 years and 24.3% on placebo, for a highly significant 22% relative risk reduction.
In contrast, in the 4,497 patients with PAD only, the primary outcome occurred in 16.1% of those on rivaroxaban and 17.9% of controls, an 11% relative risk reduction which failed to reach statistical significance. The absolute risk reduction achieved with rivaroxaban was 5.4% in patients with PAD plus CAD versus 1.8% in those with PAD alone. Thus, the significant clinical benefit with rivaroxaban plus aspirin previously reported in the overall study population, with a number needed to treat for 3 years of 39 in order to prevent one primary outcome event, was largely driven by the superior outcomes in the dual-diagnosis subgroup, reported Dr. Hiatt, professor of medicine at the University of Colorado at Denver, Aurora.
“A strategy of rivaroxaban at 2.5 mg twice daily plus low-dose aspirin versus low-dose aspirin alone reduces ischemic events of the limb, brain, and heart, but also increases bleeding, with an overall net benefit,” the cardiologist said. “In particular, the benefits of this strategy for MI and ischemic stroke are robust, especially in patients with PAD and CAD.”
Indeed, the MI rate at 3 years in the dual diagnosis subgroup was 7.3% with rivaroxaban and 8.8% with placebo, for a 23% relative risk reduction, compared with rates of 3.3% and 3.7%, respectively, in patients with PAD only. Similarly, ischemic stroke occurred in 2.9% of patients with PAD and CAD in the rivaroxaban group, compared with 3.9% with placebo, whereas the rate in the PAD only group was identical at 2.6% regardless of whether patients were on rivaroxaban or placebo.
In patients without CAD, the clinical benefit of rivaroxaban was driven by reductions in severe limb events. Their rate of acute limb ischemia was 5.2% with rivaroxaban, compared with 8.3% with placebo, for a 37% relative risk reduction. In contrast, the reduction in acute limb ischemia with rivaroxaban in patients with PAD and CAD wasn’t significantly different from placebo.
Thrombolysis in Myocardial Infarction major bleeding occurred in 2.4% of patients with PAD and CAD on rivaroxaban, compared with 1.1% on placebo, and in 1.7% and 1.5% of patients with PAD alone. Of note, rates of ischemic stroke or fatal hemorrhage were low and similar at less than 1% in all four groups, Dr. Hiatt noted.
VOYAGER PAD was sponsored by Bayer and Janssen. Dr. Hiatt reported receiving research grant support from those two companies as well as Amgen.
The absolute benefit of adding low-dose rivaroxaban to low-dose aspirin following revascularization for symptomatic lower-extremity peripheral artery disease (PAD) is significantly greater in patients with comorbid coronary artery disease (CAD), according to a new secondary analysis of the VOYAGER PAD trial.
“These findings suggest heterogeneity of prognostic risk for ischemic events in lower-extremity PAD patients, and may support shared decision-making with these patients,” William R. Hiatt, MD, observed in presenting the study results at the virtual annual congress of the European Society of Cardiology.
VOYAGER PAD was a 3-year, 34-country clinical trial in which 6,564 patients with symptomatic PAD who had recently undergone lower-limb revascularization were randomized in double-blind fashion to rivaroxaban (Xarelto) at 2.5 mg twice daily or placebo on top of background standard therapy with low-dose aspirin.
Among the 2,067 participants with baseline comorbid CAD, the primary outcome – a composite comprised of cardiovascular death, acute MI, ischemic stroke, acute limb ischemia, and major amputation – occurred in 18.9% of the rivaroxaban group at 3 years and 24.3% on placebo, for a highly significant 22% relative risk reduction.
In contrast, in the 4,497 patients with PAD only, the primary outcome occurred in 16.1% of those on rivaroxaban and 17.9% of controls, an 11% relative risk reduction which failed to reach statistical significance. The absolute risk reduction achieved with rivaroxaban was 5.4% in patients with PAD plus CAD versus 1.8% in those with PAD alone. Thus, the significant clinical benefit with rivaroxaban plus aspirin previously reported in the overall study population, with a number needed to treat for 3 years of 39 in order to prevent one primary outcome event, was largely driven by the superior outcomes in the dual-diagnosis subgroup, reported Dr. Hiatt, professor of medicine at the University of Colorado at Denver, Aurora.
“A strategy of rivaroxaban at 2.5 mg twice daily plus low-dose aspirin versus low-dose aspirin alone reduces ischemic events of the limb, brain, and heart, but also increases bleeding, with an overall net benefit,” the cardiologist said. “In particular, the benefits of this strategy for MI and ischemic stroke are robust, especially in patients with PAD and CAD.”
Indeed, the MI rate at 3 years in the dual diagnosis subgroup was 7.3% with rivaroxaban and 8.8% with placebo, for a 23% relative risk reduction, compared with rates of 3.3% and 3.7%, respectively, in patients with PAD only. Similarly, ischemic stroke occurred in 2.9% of patients with PAD and CAD in the rivaroxaban group, compared with 3.9% with placebo, whereas the rate in the PAD only group was identical at 2.6% regardless of whether patients were on rivaroxaban or placebo.
In patients without CAD, the clinical benefit of rivaroxaban was driven by reductions in severe limb events. Their rate of acute limb ischemia was 5.2% with rivaroxaban, compared with 8.3% with placebo, for a 37% relative risk reduction. In contrast, the reduction in acute limb ischemia with rivaroxaban in patients with PAD and CAD wasn’t significantly different from placebo.
Thrombolysis in Myocardial Infarction major bleeding occurred in 2.4% of patients with PAD and CAD on rivaroxaban, compared with 1.1% on placebo, and in 1.7% and 1.5% of patients with PAD alone. Of note, rates of ischemic stroke or fatal hemorrhage were low and similar at less than 1% in all four groups, Dr. Hiatt noted.
VOYAGER PAD was sponsored by Bayer and Janssen. Dr. Hiatt reported receiving research grant support from those two companies as well as Amgen.
FROM ESC CONGRESS 2020
Empagliflozin cut PA pressures in heart failure patients
Elevated pulmonary artery diastolic pressure is “perhaps the best predictor of bad outcomes in patients with heart failure, including hospitalization and death,” and new evidence clearly showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin cuts this metric in patients by a clinically significant amount, Mikhail Kosiborod, MD, said at the virtual annual scientific meeting of the Heart Failure Society of America.
The evidence he collected from a total of 65 heart failure patients with either reduced or preserved ejection fraction is the first documentation from a randomized, controlled study to show a direct effect by a SGLT2 inhibitor on pulmonary artery (PA) pressures.
Other key findings were that the drop in PA diastolic pressure with empagliflozin treatment compared with placebo became discernible early (within the first 4 weeks on treatment), that the pressure-lowering effect steadily grew over time, and that it showed no link to the intensity of loop diuretic treatment, which held steady during 12 weeks on treatment and 13 weeks of overall monitoring.
The study’s primary endpoint was the change from baseline in PA diastolic pressure after 12 weeks on treatment. The 31 patients who completed the full 12-week course had an average drop in their PA diastolic pressure of about 1.5 mm Hg, compared with 28 patients who completed 12 weeks on placebo. Average PA diastolic pressure at baseline was about 21 mm Hg in both treatment arms, and on treatment this fell by more than 0.5 mm Hg among those who received empagliflozin and rose by close to 1 mm Hg among control patients.
“There appears to be a direct effect of empagliflozin on pulmonary artery pressure that’s not been previously demonstrated” by an SGLT2 inhibitor, Dr. Kosiborod said. “I think this is one mechanism of action” for this drug class. “If you control pulmonary artery filling pressures you can prevent hospitalizations and deaths.”
Small reductions matter
“Small pressure differences are particularly important for pulmonary hypertension,” commented Lynne W. Stevenson, MD, professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn., and the report’s designated discussant.
“In the Vanderbilt heart failure database, patients with a pulmonary artery mean pressure of 20-24 mm Hg had 30% higher mortality than patients with lower pressures,” Dr. Stevenson noted. “This has led to a new definition of pulmonary hypertension, a mean pulmonary artery pressure above at or above 20 mm Hg.”
In Dr. Kosiborod’s study, patients began with an average PA mean pressure of about 30 mm Hg, and empagliflozin treatment led to a reduction in this metric with about the same magnitude as its effect on PA diastolic pressure. Empagliflozin also produced a similar reduction in average PA systolic pressure.
A study built on ambulatory PA monitoring
The results “also provide more proof for the concept of ambulatory hemodynamic monitoring” in patients with heart failure to monitor their status, she added. The study enrolled only patients who had already received a CardioMEMS implant as part of their routine care. This device allows for frequent, noninvasive monitoring of PA pressures. Researchers collected PA pressure data from patients twice daily for the entire 13-week study.
The EMBRACE HF (Empagliflozin Impact on Hemodynamics in Patients With Heart Failure) study enrolled patients with established heart failure, a CardioMEMS implant, and New York Heart Association class II-IV symptoms at any of eight U.S. centers. Patients averaged about 65 years old, and slightly more than half had class III disease, which denotes marked limitation of physical activity.
Despite the brief treatment period, patients who received empagliflozin showed other evidence of benefit including a trend toward improved quality of life scores, reduced levels of two different forms of brain natriuretic peptide, and significant weight loss, compared with controls, that averaged 2.4 kg.
The mechanism by which empagliflozin and other drugs in its class might lower PA filling pressures is unclear, but Dr. Kosiborod stressed that the consistent level of loop diuretic use during the study seems to rule out a diuretic effect from the SGLT2 inhibitor as having a role. A pulmonary vasculature effect is “much more likely,” perhaps mediated through modified endothelial function and vasodilation, he suggested.
EMBRACE HF was funded by Boehringer Ingelheim, the company that markets empagliflozin (Jardiance) along with Eli Lilly. Dr. Kosiborod has received research support and honoraria from Boehringer Ingelheim, and he has received honoraria from several other companies. Dr. Stevenson had no disclosures.
Elevated pulmonary artery diastolic pressure is “perhaps the best predictor of bad outcomes in patients with heart failure, including hospitalization and death,” and new evidence clearly showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin cuts this metric in patients by a clinically significant amount, Mikhail Kosiborod, MD, said at the virtual annual scientific meeting of the Heart Failure Society of America.
The evidence he collected from a total of 65 heart failure patients with either reduced or preserved ejection fraction is the first documentation from a randomized, controlled study to show a direct effect by a SGLT2 inhibitor on pulmonary artery (PA) pressures.
Other key findings were that the drop in PA diastolic pressure with empagliflozin treatment compared with placebo became discernible early (within the first 4 weeks on treatment), that the pressure-lowering effect steadily grew over time, and that it showed no link to the intensity of loop diuretic treatment, which held steady during 12 weeks on treatment and 13 weeks of overall monitoring.
The study’s primary endpoint was the change from baseline in PA diastolic pressure after 12 weeks on treatment. The 31 patients who completed the full 12-week course had an average drop in their PA diastolic pressure of about 1.5 mm Hg, compared with 28 patients who completed 12 weeks on placebo. Average PA diastolic pressure at baseline was about 21 mm Hg in both treatment arms, and on treatment this fell by more than 0.5 mm Hg among those who received empagliflozin and rose by close to 1 mm Hg among control patients.
“There appears to be a direct effect of empagliflozin on pulmonary artery pressure that’s not been previously demonstrated” by an SGLT2 inhibitor, Dr. Kosiborod said. “I think this is one mechanism of action” for this drug class. “If you control pulmonary artery filling pressures you can prevent hospitalizations and deaths.”
Small reductions matter
“Small pressure differences are particularly important for pulmonary hypertension,” commented Lynne W. Stevenson, MD, professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn., and the report’s designated discussant.
“In the Vanderbilt heart failure database, patients with a pulmonary artery mean pressure of 20-24 mm Hg had 30% higher mortality than patients with lower pressures,” Dr. Stevenson noted. “This has led to a new definition of pulmonary hypertension, a mean pulmonary artery pressure above at or above 20 mm Hg.”
In Dr. Kosiborod’s study, patients began with an average PA mean pressure of about 30 mm Hg, and empagliflozin treatment led to a reduction in this metric with about the same magnitude as its effect on PA diastolic pressure. Empagliflozin also produced a similar reduction in average PA systolic pressure.
A study built on ambulatory PA monitoring
The results “also provide more proof for the concept of ambulatory hemodynamic monitoring” in patients with heart failure to monitor their status, she added. The study enrolled only patients who had already received a CardioMEMS implant as part of their routine care. This device allows for frequent, noninvasive monitoring of PA pressures. Researchers collected PA pressure data from patients twice daily for the entire 13-week study.
The EMBRACE HF (Empagliflozin Impact on Hemodynamics in Patients With Heart Failure) study enrolled patients with established heart failure, a CardioMEMS implant, and New York Heart Association class II-IV symptoms at any of eight U.S. centers. Patients averaged about 65 years old, and slightly more than half had class III disease, which denotes marked limitation of physical activity.
Despite the brief treatment period, patients who received empagliflozin showed other evidence of benefit including a trend toward improved quality of life scores, reduced levels of two different forms of brain natriuretic peptide, and significant weight loss, compared with controls, that averaged 2.4 kg.
The mechanism by which empagliflozin and other drugs in its class might lower PA filling pressures is unclear, but Dr. Kosiborod stressed that the consistent level of loop diuretic use during the study seems to rule out a diuretic effect from the SGLT2 inhibitor as having a role. A pulmonary vasculature effect is “much more likely,” perhaps mediated through modified endothelial function and vasodilation, he suggested.
EMBRACE HF was funded by Boehringer Ingelheim, the company that markets empagliflozin (Jardiance) along with Eli Lilly. Dr. Kosiborod has received research support and honoraria from Boehringer Ingelheim, and he has received honoraria from several other companies. Dr. Stevenson had no disclosures.
Elevated pulmonary artery diastolic pressure is “perhaps the best predictor of bad outcomes in patients with heart failure, including hospitalization and death,” and new evidence clearly showed that the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin cuts this metric in patients by a clinically significant amount, Mikhail Kosiborod, MD, said at the virtual annual scientific meeting of the Heart Failure Society of America.
The evidence he collected from a total of 65 heart failure patients with either reduced or preserved ejection fraction is the first documentation from a randomized, controlled study to show a direct effect by a SGLT2 inhibitor on pulmonary artery (PA) pressures.
Other key findings were that the drop in PA diastolic pressure with empagliflozin treatment compared with placebo became discernible early (within the first 4 weeks on treatment), that the pressure-lowering effect steadily grew over time, and that it showed no link to the intensity of loop diuretic treatment, which held steady during 12 weeks on treatment and 13 weeks of overall monitoring.
The study’s primary endpoint was the change from baseline in PA diastolic pressure after 12 weeks on treatment. The 31 patients who completed the full 12-week course had an average drop in their PA diastolic pressure of about 1.5 mm Hg, compared with 28 patients who completed 12 weeks on placebo. Average PA diastolic pressure at baseline was about 21 mm Hg in both treatment arms, and on treatment this fell by more than 0.5 mm Hg among those who received empagliflozin and rose by close to 1 mm Hg among control patients.
“There appears to be a direct effect of empagliflozin on pulmonary artery pressure that’s not been previously demonstrated” by an SGLT2 inhibitor, Dr. Kosiborod said. “I think this is one mechanism of action” for this drug class. “If you control pulmonary artery filling pressures you can prevent hospitalizations and deaths.”
Small reductions matter
“Small pressure differences are particularly important for pulmonary hypertension,” commented Lynne W. Stevenson, MD, professor of medicine at Vanderbilt University Medical Center in Nashville, Tenn., and the report’s designated discussant.
“In the Vanderbilt heart failure database, patients with a pulmonary artery mean pressure of 20-24 mm Hg had 30% higher mortality than patients with lower pressures,” Dr. Stevenson noted. “This has led to a new definition of pulmonary hypertension, a mean pulmonary artery pressure above at or above 20 mm Hg.”
In Dr. Kosiborod’s study, patients began with an average PA mean pressure of about 30 mm Hg, and empagliflozin treatment led to a reduction in this metric with about the same magnitude as its effect on PA diastolic pressure. Empagliflozin also produced a similar reduction in average PA systolic pressure.
A study built on ambulatory PA monitoring
The results “also provide more proof for the concept of ambulatory hemodynamic monitoring” in patients with heart failure to monitor their status, she added. The study enrolled only patients who had already received a CardioMEMS implant as part of their routine care. This device allows for frequent, noninvasive monitoring of PA pressures. Researchers collected PA pressure data from patients twice daily for the entire 13-week study.
The EMBRACE HF (Empagliflozin Impact on Hemodynamics in Patients With Heart Failure) study enrolled patients with established heart failure, a CardioMEMS implant, and New York Heart Association class II-IV symptoms at any of eight U.S. centers. Patients averaged about 65 years old, and slightly more than half had class III disease, which denotes marked limitation of physical activity.
Despite the brief treatment period, patients who received empagliflozin showed other evidence of benefit including a trend toward improved quality of life scores, reduced levels of two different forms of brain natriuretic peptide, and significant weight loss, compared with controls, that averaged 2.4 kg.
The mechanism by which empagliflozin and other drugs in its class might lower PA filling pressures is unclear, but Dr. Kosiborod stressed that the consistent level of loop diuretic use during the study seems to rule out a diuretic effect from the SGLT2 inhibitor as having a role. A pulmonary vasculature effect is “much more likely,” perhaps mediated through modified endothelial function and vasodilation, he suggested.
EMBRACE HF was funded by Boehringer Ingelheim, the company that markets empagliflozin (Jardiance) along with Eli Lilly. Dr. Kosiborod has received research support and honoraria from Boehringer Ingelheim, and he has received honoraria from several other companies. Dr. Stevenson had no disclosures.
FROM HFSA 2020
Don’t discount ultrapotent topical corticosteroids for vulvar lichen sclerosus
according to an expert speaking at the virtual conference on diseases of the vulva and vagina.
If needed, intralesional steroid injections or calcineurin inhibitors can be added to a topical corticosteroid regimen, Libby Edwards, MD, suggested at the meeting, hosted by the International Society for the Study of Vulvovaginal Disease. In addition, early reports indicate that newer interventions such as fractional CO2 laser treatments may help patients with refractory disease.
Still, “there is no question, there is no argument: First-, second- and third-line treatment for lichen sclerosus is an ultrapotent or superpotent topical corticosteroid,” she said. Steroids include halobetasol, clobetasol, or betamethasone dipropionate in augmented vehicle ointment once or twice per day. Patients should continue this regimen until the skin texture is normal or the disease is controlled as well as possible, which usually takes several months, said Dr. Edwards, of Southeast Vulvar Clinic in Charlotte, N.C.
Patients then should continue treatment, but less frequently or with a lower potency steroid.
Although corticosteroids are not Food and Drug Administration–approved for the treatment of lichen sclerosus, double-blind, placebo-controlled trials support their use, Dr. Edwards said.
Getting patients to use topical corticosteroids as directed can be a challenge, however, and patient education is crucial.
After about 10 days, many patients start to feel better and stop the medication prematurely, which may lead to recurrence.
“That is such an important counseling point,” Aruna Venkatesan, MD, chief of dermatology and director of the genital dermatology clinic at Santa Clara Valley Medical Center in San Jose, Calif., said during a panel discussion. “Tell them, listen, I may not see you back for a couple months, and you may start feeling better sooner. But I want you to keep using this at this frequency so that when you come back we can make a good decision about whether you’re ready” for a lower potency regimen.
To encourage daily use, Hope K. Haefner, MD, asks patients whether they brush their teeth every night. “When they say yes, I tell them to put the steroid ointment by their toothpaste and use it after brushing,” Dr. Haefner, the Harold A. Furlong Professor of Women’s Health at Michigan Medicine in Ann Arbor, said during the discussion. “But don’t mix up the tubes.”
Once lichen sclerosus is controlled, options include decreasing the superpotent steroid to once, three times per week or changing to a midpotency steroid such as triamcinolone ointment every day, Dr. Edwards said.
Evidence suggests that controlling lichen sclerosus may prevent squamous cell carcinoma and scarring. In a study of more than 500 patients, about 70% complied with treatment instructions, whereas about 30% were considered partially compliant (JAMA Dermatol. 2015 Oct;151[10]:1061-7.). Patients who adhered to their therapy were less likely to have cancer or ongoing scarring during an average of 4.7 years of follow-up.
Beyond topical steroids
“Almost always, topical steroids are all you need,” said Dr. Edwards. “Before I go beyond that, I think of other issues that may be causing symptoms,” such as atrophic vagina, steroid dermatitis, or vulvodynia.
For patients with refractory lichen sclerosus, other treatments “can add more oomph to your topical steroid, but they are not better,” she said.
Intralesional corticosteroid injections are one option.
Another option is adding a calcineurin inhibitor such as tacrolimus or pimecrolimus, although these medications can burn with application and irritate. In addition, they carry warnings about rare cases of cancer associated with their use.
Dr. Edwards also uses methotrexate, which is supported by case reports and an open-label study. In a recently published study that included 21 patients with vulvar lichen sclerosus and 24 patients with extragenital lichen sclerosus, about half improved after receiving methotrexate (Dermatol Ther. 2020 Apr 29;e13473.).
What about lasers?
Fractional CO2 laser treatments, which are pulsed to minimize damage from heat, have “a lot of providers very excited,” Dr. Edwards said. In one open-label study of 40 patients, most reported a decrease in symptoms. (J Low Genit Tract Dis. 2020 Apr;24[2]:225-8.)
“We’re awaiting blinded, controlled studies,” Dr. Edwards said. “We don’t have those available yet although they are in progress.”
Ten of Dr. Edwards’ patients who did not improve enough with medication have received laser treatments. One patient stopped laser therapy after one treatment. One did not improve. Two were completely cleared, and six had significant improvement.
If patients who improved stopped steroids against recommendations, lichen sclerosus recurred, Dr. Edwards said.
The ISSVD does not recommend laser for the routine treatment of lichen sclerosus because of a lack of adequate studies and long-term safety data and biologic implausibility, Dr. Edwards noted (J Low Genit Tract Dis. 2019 Apr;23[2]:151-60.) Laser treatments for lichen sclerosus should not be used outside of clinical trials or without special arrangements for clinical governance, consent, and audit, according to a consensus document from the society.
“I mostly agree with that,” Dr. Edwards said. “But I now think that this is a reasonable thing to use when other treatments have been exhausted.”
Dr. Edwards and Dr. Venkatesan had no conflicts of interest. Dr. Haefner is an author for UpToDate.
according to an expert speaking at the virtual conference on diseases of the vulva and vagina.
If needed, intralesional steroid injections or calcineurin inhibitors can be added to a topical corticosteroid regimen, Libby Edwards, MD, suggested at the meeting, hosted by the International Society for the Study of Vulvovaginal Disease. In addition, early reports indicate that newer interventions such as fractional CO2 laser treatments may help patients with refractory disease.
Still, “there is no question, there is no argument: First-, second- and third-line treatment for lichen sclerosus is an ultrapotent or superpotent topical corticosteroid,” she said. Steroids include halobetasol, clobetasol, or betamethasone dipropionate in augmented vehicle ointment once or twice per day. Patients should continue this regimen until the skin texture is normal or the disease is controlled as well as possible, which usually takes several months, said Dr. Edwards, of Southeast Vulvar Clinic in Charlotte, N.C.
Patients then should continue treatment, but less frequently or with a lower potency steroid.
Although corticosteroids are not Food and Drug Administration–approved for the treatment of lichen sclerosus, double-blind, placebo-controlled trials support their use, Dr. Edwards said.
Getting patients to use topical corticosteroids as directed can be a challenge, however, and patient education is crucial.
After about 10 days, many patients start to feel better and stop the medication prematurely, which may lead to recurrence.
“That is such an important counseling point,” Aruna Venkatesan, MD, chief of dermatology and director of the genital dermatology clinic at Santa Clara Valley Medical Center in San Jose, Calif., said during a panel discussion. “Tell them, listen, I may not see you back for a couple months, and you may start feeling better sooner. But I want you to keep using this at this frequency so that when you come back we can make a good decision about whether you’re ready” for a lower potency regimen.
To encourage daily use, Hope K. Haefner, MD, asks patients whether they brush their teeth every night. “When they say yes, I tell them to put the steroid ointment by their toothpaste and use it after brushing,” Dr. Haefner, the Harold A. Furlong Professor of Women’s Health at Michigan Medicine in Ann Arbor, said during the discussion. “But don’t mix up the tubes.”
Once lichen sclerosus is controlled, options include decreasing the superpotent steroid to once, three times per week or changing to a midpotency steroid such as triamcinolone ointment every day, Dr. Edwards said.
Evidence suggests that controlling lichen sclerosus may prevent squamous cell carcinoma and scarring. In a study of more than 500 patients, about 70% complied with treatment instructions, whereas about 30% were considered partially compliant (JAMA Dermatol. 2015 Oct;151[10]:1061-7.). Patients who adhered to their therapy were less likely to have cancer or ongoing scarring during an average of 4.7 years of follow-up.
Beyond topical steroids
“Almost always, topical steroids are all you need,” said Dr. Edwards. “Before I go beyond that, I think of other issues that may be causing symptoms,” such as atrophic vagina, steroid dermatitis, or vulvodynia.
For patients with refractory lichen sclerosus, other treatments “can add more oomph to your topical steroid, but they are not better,” she said.
Intralesional corticosteroid injections are one option.
Another option is adding a calcineurin inhibitor such as tacrolimus or pimecrolimus, although these medications can burn with application and irritate. In addition, they carry warnings about rare cases of cancer associated with their use.
Dr. Edwards also uses methotrexate, which is supported by case reports and an open-label study. In a recently published study that included 21 patients with vulvar lichen sclerosus and 24 patients with extragenital lichen sclerosus, about half improved after receiving methotrexate (Dermatol Ther. 2020 Apr 29;e13473.).
What about lasers?
Fractional CO2 laser treatments, which are pulsed to minimize damage from heat, have “a lot of providers very excited,” Dr. Edwards said. In one open-label study of 40 patients, most reported a decrease in symptoms. (J Low Genit Tract Dis. 2020 Apr;24[2]:225-8.)
“We’re awaiting blinded, controlled studies,” Dr. Edwards said. “We don’t have those available yet although they are in progress.”
Ten of Dr. Edwards’ patients who did not improve enough with medication have received laser treatments. One patient stopped laser therapy after one treatment. One did not improve. Two were completely cleared, and six had significant improvement.
If patients who improved stopped steroids against recommendations, lichen sclerosus recurred, Dr. Edwards said.
The ISSVD does not recommend laser for the routine treatment of lichen sclerosus because of a lack of adequate studies and long-term safety data and biologic implausibility, Dr. Edwards noted (J Low Genit Tract Dis. 2019 Apr;23[2]:151-60.) Laser treatments for lichen sclerosus should not be used outside of clinical trials or without special arrangements for clinical governance, consent, and audit, according to a consensus document from the society.
“I mostly agree with that,” Dr. Edwards said. “But I now think that this is a reasonable thing to use when other treatments have been exhausted.”
Dr. Edwards and Dr. Venkatesan had no conflicts of interest. Dr. Haefner is an author for UpToDate.
according to an expert speaking at the virtual conference on diseases of the vulva and vagina.
If needed, intralesional steroid injections or calcineurin inhibitors can be added to a topical corticosteroid regimen, Libby Edwards, MD, suggested at the meeting, hosted by the International Society for the Study of Vulvovaginal Disease. In addition, early reports indicate that newer interventions such as fractional CO2 laser treatments may help patients with refractory disease.
Still, “there is no question, there is no argument: First-, second- and third-line treatment for lichen sclerosus is an ultrapotent or superpotent topical corticosteroid,” she said. Steroids include halobetasol, clobetasol, or betamethasone dipropionate in augmented vehicle ointment once or twice per day. Patients should continue this regimen until the skin texture is normal or the disease is controlled as well as possible, which usually takes several months, said Dr. Edwards, of Southeast Vulvar Clinic in Charlotte, N.C.
Patients then should continue treatment, but less frequently or with a lower potency steroid.
Although corticosteroids are not Food and Drug Administration–approved for the treatment of lichen sclerosus, double-blind, placebo-controlled trials support their use, Dr. Edwards said.
Getting patients to use topical corticosteroids as directed can be a challenge, however, and patient education is crucial.
After about 10 days, many patients start to feel better and stop the medication prematurely, which may lead to recurrence.
“That is such an important counseling point,” Aruna Venkatesan, MD, chief of dermatology and director of the genital dermatology clinic at Santa Clara Valley Medical Center in San Jose, Calif., said during a panel discussion. “Tell them, listen, I may not see you back for a couple months, and you may start feeling better sooner. But I want you to keep using this at this frequency so that when you come back we can make a good decision about whether you’re ready” for a lower potency regimen.
To encourage daily use, Hope K. Haefner, MD, asks patients whether they brush their teeth every night. “When they say yes, I tell them to put the steroid ointment by their toothpaste and use it after brushing,” Dr. Haefner, the Harold A. Furlong Professor of Women’s Health at Michigan Medicine in Ann Arbor, said during the discussion. “But don’t mix up the tubes.”
Once lichen sclerosus is controlled, options include decreasing the superpotent steroid to once, three times per week or changing to a midpotency steroid such as triamcinolone ointment every day, Dr. Edwards said.
Evidence suggests that controlling lichen sclerosus may prevent squamous cell carcinoma and scarring. In a study of more than 500 patients, about 70% complied with treatment instructions, whereas about 30% were considered partially compliant (JAMA Dermatol. 2015 Oct;151[10]:1061-7.). Patients who adhered to their therapy were less likely to have cancer or ongoing scarring during an average of 4.7 years of follow-up.
Beyond topical steroids
“Almost always, topical steroids are all you need,” said Dr. Edwards. “Before I go beyond that, I think of other issues that may be causing symptoms,” such as atrophic vagina, steroid dermatitis, or vulvodynia.
For patients with refractory lichen sclerosus, other treatments “can add more oomph to your topical steroid, but they are not better,” she said.
Intralesional corticosteroid injections are one option.
Another option is adding a calcineurin inhibitor such as tacrolimus or pimecrolimus, although these medications can burn with application and irritate. In addition, they carry warnings about rare cases of cancer associated with their use.
Dr. Edwards also uses methotrexate, which is supported by case reports and an open-label study. In a recently published study that included 21 patients with vulvar lichen sclerosus and 24 patients with extragenital lichen sclerosus, about half improved after receiving methotrexate (Dermatol Ther. 2020 Apr 29;e13473.).
What about lasers?
Fractional CO2 laser treatments, which are pulsed to minimize damage from heat, have “a lot of providers very excited,” Dr. Edwards said. In one open-label study of 40 patients, most reported a decrease in symptoms. (J Low Genit Tract Dis. 2020 Apr;24[2]:225-8.)
“We’re awaiting blinded, controlled studies,” Dr. Edwards said. “We don’t have those available yet although they are in progress.”
Ten of Dr. Edwards’ patients who did not improve enough with medication have received laser treatments. One patient stopped laser therapy after one treatment. One did not improve. Two were completely cleared, and six had significant improvement.
If patients who improved stopped steroids against recommendations, lichen sclerosus recurred, Dr. Edwards said.
The ISSVD does not recommend laser for the routine treatment of lichen sclerosus because of a lack of adequate studies and long-term safety data and biologic implausibility, Dr. Edwards noted (J Low Genit Tract Dis. 2019 Apr;23[2]:151-60.) Laser treatments for lichen sclerosus should not be used outside of clinical trials or without special arrangements for clinical governance, consent, and audit, according to a consensus document from the society.
“I mostly agree with that,” Dr. Edwards said. “But I now think that this is a reasonable thing to use when other treatments have been exhausted.”
Dr. Edwards and Dr. Venkatesan had no conflicts of interest. Dr. Haefner is an author for UpToDate.
EXPERT ANALYSIS FROM THE ISSVD BIENNIAL CONFERENCE
Spine fractures more common at trampoline parks, study shows
Across the United States, an explosive growth in recreational facilities boasting trampolines coincides with alarming growth in trampoline-related injuries in children, including those to the spine, according to new research.
Among youths, the risk for trampoline park–related fractures is about three times higher than for home-based trampoline fractures, said study author Serena Freiman, MD, of Washington University, St. Louis.
Recreational sports facilities with trampolines “pose a public health hazard,” Dr. Freiman said during a presentation at the virtual American Academy of Pediatrics 2020 National Conference.
“There aren’t any set regulations for these parks, so the American Society for Testing and Materials released a set of standards, but only Michigan and Arizona enforced those,” Dr. Freiman explained.
“Hopefully, since we’re showing a significant increased risk of injuries, the federal government will enforce regulations throughout the United States,” she said in an interview.
The first trampoline park in the United States opened in 2004, Dr. Freiman said. By 2018, there were more than 800 recreational facilities with trampolines across the country. This rapid growth coincided with a 45% increase in ED visits for trampoline-related injuries, from 61,509 in 2014 to more than 89,000 in 2017.
“There’s been exponential growth since their founding,” she said, “and with that we’ve also seen an exponential growth in injuries, whereas home injuries [from trampolines] remained stable during that time period.”
To assess the rates of trampoline-related injuries, Dr. Freiman and colleague analyzed data from the National Electronic Injury Surveillance System (NEISS). They included all patients whose records include a code for trampoline injury and who presented to a hospital ED between 1998 and 2017. They compared home trampoline injuries with those sustained at recreational facilities.
During the study period, more than 1.37 million patients presented to the ED for trampoline-related injuries. Of those, 125,473 occurred at recreational facilities, and 1.22 million occurred at home. Injuries at trampoline parks increased 90-fold between 2004 and 2017 (0.04 per 10,000 ED visits in 2004 to 0.9 per 10,000 in 2017), with 69% of those injuries occurring between 2012 and 2017.
Home-based trampoline injuries dropped during the study period, from 2.8 per 10,000 ED visits in 2014 to 1.6 in 2017.
Patients injured at trampoline facilities tended to present at large hospitals, Dr. Freiman noted, likely because of these parks being located in more populated regions.
The type of injury differed between locations. Severe injuries, such as spine fractures, occurred three times as often at trampoline parks than at home (2.7% vs. 0.9%; P = .016).
Internal organ injuries occurred more frequently on home-based trampolines (20.1% vs. 2.3% ; P < .001), whereas strains and sprains were more common at trampoline parks (32% vs. 51%; P < .001).
“Since home trampolines are often off the ground, I would speculate that you’re more likely to hit the edge of the trampoline or fall from it,” she said, “whereas at recreational sports facilities, there are often multiple jumpers, and you’re not falling off ― you’re falling in general or colliding with other jumpers.”
The authors noted that lower-extremity fractures occurred more often in trampoline parks (35.6% home vs. 51.7% parks; P < .0001), and upper-extremity fractures were more prevalent from home trampolines (60.2% vs. 42.5%; P < .0001). Also, a larger proportion of trampoline park injuries occurred among adolescents and young adults aged 15-34 years in comparison with home-based injuries (28.2% vs. 13.6%). No race or gender differences were noted.
Dr. Freiman noted one possible study limitation. The NEISS data only included patients tagged as being injured on trampolines, so “it may be incomplete,” she said. “Also, anyone presenting to their personal physician or urgent care centers weren’t included, so there’s likely an underestimation of cases.
“We hope people gain a better understanding of risks associated with these facilities and dive further into research and [to] identify areas that can be improved within these facilities,” Dr. Freiman added.
To drive home the importance of caution, physicians should relay data about trampoline injuries to parents and children, said Amber Hardeman, MD, MPH, MBA, of Tulane University, New Orleans.
Because most injuries at trampoline parks occur among people aged 15-34 years, Dr. Hardeman said, babysitters or parents may also “be indulging as well” when they take their young charges there to jump.
“They need to understand how to set a good example and teach kids proper safety precautions, such as not jumping too close together or maybe not doing things like splits,” she said.
Dr. Hardeman said in an interview that “there’s a lot of truth” to the study’s conclusion that recreational sports facilities with trampolines pose a public health hazard. Additional research should focus on what types of safety measures trampoline parks may be taking. Such measures could include increased padding, hiring more staff, or placing firmer limits on how many people can jump in each area at a time.
“Some centers don’t have as much padding around as others, and some allow multiple children to jump in the same area at the same time,” she said. “What exact scenarios are kids encountering more so than being on a trampoline at home?
“Trampoline centers are exciting and fun, but they are a hazard, and the fact that such an aggregate population being impacted by increasing numbers shows it’s definitely an issue right now,” Dr. Hardeman added.
Dr. Freiman and Dr. Hardeman have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Across the United States, an explosive growth in recreational facilities boasting trampolines coincides with alarming growth in trampoline-related injuries in children, including those to the spine, according to new research.
Among youths, the risk for trampoline park–related fractures is about three times higher than for home-based trampoline fractures, said study author Serena Freiman, MD, of Washington University, St. Louis.
Recreational sports facilities with trampolines “pose a public health hazard,” Dr. Freiman said during a presentation at the virtual American Academy of Pediatrics 2020 National Conference.
“There aren’t any set regulations for these parks, so the American Society for Testing and Materials released a set of standards, but only Michigan and Arizona enforced those,” Dr. Freiman explained.
“Hopefully, since we’re showing a significant increased risk of injuries, the federal government will enforce regulations throughout the United States,” she said in an interview.
The first trampoline park in the United States opened in 2004, Dr. Freiman said. By 2018, there were more than 800 recreational facilities with trampolines across the country. This rapid growth coincided with a 45% increase in ED visits for trampoline-related injuries, from 61,509 in 2014 to more than 89,000 in 2017.
“There’s been exponential growth since their founding,” she said, “and with that we’ve also seen an exponential growth in injuries, whereas home injuries [from trampolines] remained stable during that time period.”
To assess the rates of trampoline-related injuries, Dr. Freiman and colleague analyzed data from the National Electronic Injury Surveillance System (NEISS). They included all patients whose records include a code for trampoline injury and who presented to a hospital ED between 1998 and 2017. They compared home trampoline injuries with those sustained at recreational facilities.
During the study period, more than 1.37 million patients presented to the ED for trampoline-related injuries. Of those, 125,473 occurred at recreational facilities, and 1.22 million occurred at home. Injuries at trampoline parks increased 90-fold between 2004 and 2017 (0.04 per 10,000 ED visits in 2004 to 0.9 per 10,000 in 2017), with 69% of those injuries occurring between 2012 and 2017.
Home-based trampoline injuries dropped during the study period, from 2.8 per 10,000 ED visits in 2014 to 1.6 in 2017.
Patients injured at trampoline facilities tended to present at large hospitals, Dr. Freiman noted, likely because of these parks being located in more populated regions.
The type of injury differed between locations. Severe injuries, such as spine fractures, occurred three times as often at trampoline parks than at home (2.7% vs. 0.9%; P = .016).
Internal organ injuries occurred more frequently on home-based trampolines (20.1% vs. 2.3% ; P < .001), whereas strains and sprains were more common at trampoline parks (32% vs. 51%; P < .001).
“Since home trampolines are often off the ground, I would speculate that you’re more likely to hit the edge of the trampoline or fall from it,” she said, “whereas at recreational sports facilities, there are often multiple jumpers, and you’re not falling off ― you’re falling in general or colliding with other jumpers.”
The authors noted that lower-extremity fractures occurred more often in trampoline parks (35.6% home vs. 51.7% parks; P < .0001), and upper-extremity fractures were more prevalent from home trampolines (60.2% vs. 42.5%; P < .0001). Also, a larger proportion of trampoline park injuries occurred among adolescents and young adults aged 15-34 years in comparison with home-based injuries (28.2% vs. 13.6%). No race or gender differences were noted.
Dr. Freiman noted one possible study limitation. The NEISS data only included patients tagged as being injured on trampolines, so “it may be incomplete,” she said. “Also, anyone presenting to their personal physician or urgent care centers weren’t included, so there’s likely an underestimation of cases.
“We hope people gain a better understanding of risks associated with these facilities and dive further into research and [to] identify areas that can be improved within these facilities,” Dr. Freiman added.
To drive home the importance of caution, physicians should relay data about trampoline injuries to parents and children, said Amber Hardeman, MD, MPH, MBA, of Tulane University, New Orleans.
Because most injuries at trampoline parks occur among people aged 15-34 years, Dr. Hardeman said, babysitters or parents may also “be indulging as well” when they take their young charges there to jump.
“They need to understand how to set a good example and teach kids proper safety precautions, such as not jumping too close together or maybe not doing things like splits,” she said.
Dr. Hardeman said in an interview that “there’s a lot of truth” to the study’s conclusion that recreational sports facilities with trampolines pose a public health hazard. Additional research should focus on what types of safety measures trampoline parks may be taking. Such measures could include increased padding, hiring more staff, or placing firmer limits on how many people can jump in each area at a time.
“Some centers don’t have as much padding around as others, and some allow multiple children to jump in the same area at the same time,” she said. “What exact scenarios are kids encountering more so than being on a trampoline at home?
“Trampoline centers are exciting and fun, but they are a hazard, and the fact that such an aggregate population being impacted by increasing numbers shows it’s definitely an issue right now,” Dr. Hardeman added.
Dr. Freiman and Dr. Hardeman have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Across the United States, an explosive growth in recreational facilities boasting trampolines coincides with alarming growth in trampoline-related injuries in children, including those to the spine, according to new research.
Among youths, the risk for trampoline park–related fractures is about three times higher than for home-based trampoline fractures, said study author Serena Freiman, MD, of Washington University, St. Louis.
Recreational sports facilities with trampolines “pose a public health hazard,” Dr. Freiman said during a presentation at the virtual American Academy of Pediatrics 2020 National Conference.
“There aren’t any set regulations for these parks, so the American Society for Testing and Materials released a set of standards, but only Michigan and Arizona enforced those,” Dr. Freiman explained.
“Hopefully, since we’re showing a significant increased risk of injuries, the federal government will enforce regulations throughout the United States,” she said in an interview.
The first trampoline park in the United States opened in 2004, Dr. Freiman said. By 2018, there were more than 800 recreational facilities with trampolines across the country. This rapid growth coincided with a 45% increase in ED visits for trampoline-related injuries, from 61,509 in 2014 to more than 89,000 in 2017.
“There’s been exponential growth since their founding,” she said, “and with that we’ve also seen an exponential growth in injuries, whereas home injuries [from trampolines] remained stable during that time period.”
To assess the rates of trampoline-related injuries, Dr. Freiman and colleague analyzed data from the National Electronic Injury Surveillance System (NEISS). They included all patients whose records include a code for trampoline injury and who presented to a hospital ED between 1998 and 2017. They compared home trampoline injuries with those sustained at recreational facilities.
During the study period, more than 1.37 million patients presented to the ED for trampoline-related injuries. Of those, 125,473 occurred at recreational facilities, and 1.22 million occurred at home. Injuries at trampoline parks increased 90-fold between 2004 and 2017 (0.04 per 10,000 ED visits in 2004 to 0.9 per 10,000 in 2017), with 69% of those injuries occurring between 2012 and 2017.
Home-based trampoline injuries dropped during the study period, from 2.8 per 10,000 ED visits in 2014 to 1.6 in 2017.
Patients injured at trampoline facilities tended to present at large hospitals, Dr. Freiman noted, likely because of these parks being located in more populated regions.
The type of injury differed between locations. Severe injuries, such as spine fractures, occurred three times as often at trampoline parks than at home (2.7% vs. 0.9%; P = .016).
Internal organ injuries occurred more frequently on home-based trampolines (20.1% vs. 2.3% ; P < .001), whereas strains and sprains were more common at trampoline parks (32% vs. 51%; P < .001).
“Since home trampolines are often off the ground, I would speculate that you’re more likely to hit the edge of the trampoline or fall from it,” she said, “whereas at recreational sports facilities, there are often multiple jumpers, and you’re not falling off ― you’re falling in general or colliding with other jumpers.”
The authors noted that lower-extremity fractures occurred more often in trampoline parks (35.6% home vs. 51.7% parks; P < .0001), and upper-extremity fractures were more prevalent from home trampolines (60.2% vs. 42.5%; P < .0001). Also, a larger proportion of trampoline park injuries occurred among adolescents and young adults aged 15-34 years in comparison with home-based injuries (28.2% vs. 13.6%). No race or gender differences were noted.
Dr. Freiman noted one possible study limitation. The NEISS data only included patients tagged as being injured on trampolines, so “it may be incomplete,” she said. “Also, anyone presenting to their personal physician or urgent care centers weren’t included, so there’s likely an underestimation of cases.
“We hope people gain a better understanding of risks associated with these facilities and dive further into research and [to] identify areas that can be improved within these facilities,” Dr. Freiman added.
To drive home the importance of caution, physicians should relay data about trampoline injuries to parents and children, said Amber Hardeman, MD, MPH, MBA, of Tulane University, New Orleans.
Because most injuries at trampoline parks occur among people aged 15-34 years, Dr. Hardeman said, babysitters or parents may also “be indulging as well” when they take their young charges there to jump.
“They need to understand how to set a good example and teach kids proper safety precautions, such as not jumping too close together or maybe not doing things like splits,” she said.
Dr. Hardeman said in an interview that “there’s a lot of truth” to the study’s conclusion that recreational sports facilities with trampolines pose a public health hazard. Additional research should focus on what types of safety measures trampoline parks may be taking. Such measures could include increased padding, hiring more staff, or placing firmer limits on how many people can jump in each area at a time.
“Some centers don’t have as much padding around as others, and some allow multiple children to jump in the same area at the same time,” she said. “What exact scenarios are kids encountering more so than being on a trampoline at home?
“Trampoline centers are exciting and fun, but they are a hazard, and the fact that such an aggregate population being impacted by increasing numbers shows it’s definitely an issue right now,” Dr. Hardeman added.
Dr. Freiman and Dr. Hardeman have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Chemoradiation boosts glioblastoma survival in real-world setting
A comparison of U.S. and European treatment patterns for glioblastomas provides further evidence that adding systemic chemotherapy with temozolomide to radiotherapy offers a significant survival benefit over radiotherapy alone, and wider uptake of chemoradiation in Europe would extend the benefit to more patients.
That conclusion comes from a study of registry data from both sides of the Atlantic. The study showed a doubling in 2-year survival rates for patients with glioblastomas treated with radiotherapy plus chemotherapy compared with radiotherapy alone, a practice change that was prompted by a phase 3 trial published in The New England Journal of Medicine in 2005.
“Using population data from cancer registries, we observed a huge increase in radiotherapy plus chemotherapy between 1999 and 2013 in Europe and the U.S.,” said Francesco Giusti, PhD, of the European Commission Joint Research Center in Ispra, Italy.
“Data from 1999 to 2005 was already showing a clear survival advantage for patients treated with chemotherapy plus radiotherapy compared with radiotherapy alone,” he added.
However, when Dr. Giusti and colleagues compared practice patterns from before and after the publication of the practice-changing trial, they found that about 10% more patients in the United States were receiving combined chemotherapy and radiation, a difference reflected in superior survival rates in the U.S., he said.
Dr. Giusti presented these findings at the European Society for Medical Oncology Virtual Congress 2020.
He and his colleagues looked at data from cancer registries contributing to the European Cancer Information System and the U.S. National Cancer Institute’s Surveillance Epidemiology and End Results data.
The data set included patients diagnosed from 1999 through 2013 with glioblastoma as a first tumor.
During that time, results from the aforementioned phase 3 trial were published. They showed that, at a median follow-up of 28 months, the median survival was 14.6 months for the 287 patients assigned to radiotherapy plus temozolomide, compared with 12.1 months for the 286 patients randomized to radiotherapy alone.
The unadjusted hazard ratio for death in the combination therapy group was 0.63 (P < .001). The 2-year survival rate was 26.5% for chemoradiation and 10.4% for radiation alone.
Adding temozolomide to radiotherapy in the trial also appeared to be safe. The incidence of grade 3 or 4 hematologic adverse events was 7%.
Registry data study
To see how practice patterns changed in the United States and Europe after publication of the trial, Dr. Giusti and colleagues used registry data to calculate the proportion of cases by treatment type and overall survival during 1999-2005 (pre-study) and 2009-2013 (post-study).
The data included 34,229 cases from 11 countries in Europe and 36,925 cases from the United States.
The percentage of patients receiving both chemotherapy and radiation increased steadily over the study period. For example, among 18- to 49-year-olds, the percentage receiving the combined modalities in Europe increased from 20% in 1999-2001 to 70% in 2010-2013. In the United States, 40% of the same age group received combination therapy in 1999-2001, and this percentage grew to 80% in 2010-2013.
Overall survival rates in the general population were similar to those seen in the clinical trial during 1999-2005, when 2-year overall survival rates for patients treated with radiation alone were 11% in Europe and 12% in the United States. For patients treated with combined therapy, the respective 2-year survival rates in Europe and the United States were 24% and 25%.
“In the period after the trial, we observed a increasing 2-year survival rate to 28% in Europe and 29% in the U.S. for patients with radiotherapy plus chemotherapy,” Dr. Giusti said.
Real-world results
Invited discussant Matthias Preusser, MD, of the Medical University of Vienna in Austria, said the study shows that “population-based investigations are very valuable and should be further developed so that we can see how treatment patterns vary between countries and what the regional variations are, and whether new treatment standards actually reach clinical practice, and also to see whether there’s an effect on a population basis that is different from what is seen in controlled clinical trials.”
Dr. Preusser said it’s clear from the study that survival is increased with the addition of chemotherapy to radiotherapy, and more patients in the United States than in Europe received the combination during the study period.
Pointing to a treatment algorithm from the European Association of Neuro-oncology published in 2017, Dr. Preusser noted that radiotherapy alone may still be recommended for patients with unfavorable prognostic factors or patients 70 years and older with methylguanine-DNA methyltransferase promoter non-methylated tumors.
“It seems the differences in the age distribution between the U.S. and European populations that were analyzed could be one explanation why the radiochemotherapy combination was applied more often in the U.S. population,” Dr. Preusser said.
No outside funding was used to support the study. Dr. Giusti and coauthors reported having no conflicts of interest. Dr. Preusser disclosed relationships with multiple companies, including Merck, which markets temozolomide under the name Temodar.
SOURCE: Giusti F et al. ESMO 2020. Abstract 365MO.
A comparison of U.S. and European treatment patterns for glioblastomas provides further evidence that adding systemic chemotherapy with temozolomide to radiotherapy offers a significant survival benefit over radiotherapy alone, and wider uptake of chemoradiation in Europe would extend the benefit to more patients.
That conclusion comes from a study of registry data from both sides of the Atlantic. The study showed a doubling in 2-year survival rates for patients with glioblastomas treated with radiotherapy plus chemotherapy compared with radiotherapy alone, a practice change that was prompted by a phase 3 trial published in The New England Journal of Medicine in 2005.
“Using population data from cancer registries, we observed a huge increase in radiotherapy plus chemotherapy between 1999 and 2013 in Europe and the U.S.,” said Francesco Giusti, PhD, of the European Commission Joint Research Center in Ispra, Italy.
“Data from 1999 to 2005 was already showing a clear survival advantage for patients treated with chemotherapy plus radiotherapy compared with radiotherapy alone,” he added.
However, when Dr. Giusti and colleagues compared practice patterns from before and after the publication of the practice-changing trial, they found that about 10% more patients in the United States were receiving combined chemotherapy and radiation, a difference reflected in superior survival rates in the U.S., he said.
Dr. Giusti presented these findings at the European Society for Medical Oncology Virtual Congress 2020.
He and his colleagues looked at data from cancer registries contributing to the European Cancer Information System and the U.S. National Cancer Institute’s Surveillance Epidemiology and End Results data.
The data set included patients diagnosed from 1999 through 2013 with glioblastoma as a first tumor.
During that time, results from the aforementioned phase 3 trial were published. They showed that, at a median follow-up of 28 months, the median survival was 14.6 months for the 287 patients assigned to radiotherapy plus temozolomide, compared with 12.1 months for the 286 patients randomized to radiotherapy alone.
The unadjusted hazard ratio for death in the combination therapy group was 0.63 (P < .001). The 2-year survival rate was 26.5% for chemoradiation and 10.4% for radiation alone.
Adding temozolomide to radiotherapy in the trial also appeared to be safe. The incidence of grade 3 or 4 hematologic adverse events was 7%.
Registry data study
To see how practice patterns changed in the United States and Europe after publication of the trial, Dr. Giusti and colleagues used registry data to calculate the proportion of cases by treatment type and overall survival during 1999-2005 (pre-study) and 2009-2013 (post-study).
The data included 34,229 cases from 11 countries in Europe and 36,925 cases from the United States.
The percentage of patients receiving both chemotherapy and radiation increased steadily over the study period. For example, among 18- to 49-year-olds, the percentage receiving the combined modalities in Europe increased from 20% in 1999-2001 to 70% in 2010-2013. In the United States, 40% of the same age group received combination therapy in 1999-2001, and this percentage grew to 80% in 2010-2013.
Overall survival rates in the general population were similar to those seen in the clinical trial during 1999-2005, when 2-year overall survival rates for patients treated with radiation alone were 11% in Europe and 12% in the United States. For patients treated with combined therapy, the respective 2-year survival rates in Europe and the United States were 24% and 25%.
“In the period after the trial, we observed a increasing 2-year survival rate to 28% in Europe and 29% in the U.S. for patients with radiotherapy plus chemotherapy,” Dr. Giusti said.
Real-world results
Invited discussant Matthias Preusser, MD, of the Medical University of Vienna in Austria, said the study shows that “population-based investigations are very valuable and should be further developed so that we can see how treatment patterns vary between countries and what the regional variations are, and whether new treatment standards actually reach clinical practice, and also to see whether there’s an effect on a population basis that is different from what is seen in controlled clinical trials.”
Dr. Preusser said it’s clear from the study that survival is increased with the addition of chemotherapy to radiotherapy, and more patients in the United States than in Europe received the combination during the study period.
Pointing to a treatment algorithm from the European Association of Neuro-oncology published in 2017, Dr. Preusser noted that radiotherapy alone may still be recommended for patients with unfavorable prognostic factors or patients 70 years and older with methylguanine-DNA methyltransferase promoter non-methylated tumors.
“It seems the differences in the age distribution between the U.S. and European populations that were analyzed could be one explanation why the radiochemotherapy combination was applied more often in the U.S. population,” Dr. Preusser said.
No outside funding was used to support the study. Dr. Giusti and coauthors reported having no conflicts of interest. Dr. Preusser disclosed relationships with multiple companies, including Merck, which markets temozolomide under the name Temodar.
SOURCE: Giusti F et al. ESMO 2020. Abstract 365MO.
A comparison of U.S. and European treatment patterns for glioblastomas provides further evidence that adding systemic chemotherapy with temozolomide to radiotherapy offers a significant survival benefit over radiotherapy alone, and wider uptake of chemoradiation in Europe would extend the benefit to more patients.
That conclusion comes from a study of registry data from both sides of the Atlantic. The study showed a doubling in 2-year survival rates for patients with glioblastomas treated with radiotherapy plus chemotherapy compared with radiotherapy alone, a practice change that was prompted by a phase 3 trial published in The New England Journal of Medicine in 2005.
“Using population data from cancer registries, we observed a huge increase in radiotherapy plus chemotherapy between 1999 and 2013 in Europe and the U.S.,” said Francesco Giusti, PhD, of the European Commission Joint Research Center in Ispra, Italy.
“Data from 1999 to 2005 was already showing a clear survival advantage for patients treated with chemotherapy plus radiotherapy compared with radiotherapy alone,” he added.
However, when Dr. Giusti and colleagues compared practice patterns from before and after the publication of the practice-changing trial, they found that about 10% more patients in the United States were receiving combined chemotherapy and radiation, a difference reflected in superior survival rates in the U.S., he said.
Dr. Giusti presented these findings at the European Society for Medical Oncology Virtual Congress 2020.
He and his colleagues looked at data from cancer registries contributing to the European Cancer Information System and the U.S. National Cancer Institute’s Surveillance Epidemiology and End Results data.
The data set included patients diagnosed from 1999 through 2013 with glioblastoma as a first tumor.
During that time, results from the aforementioned phase 3 trial were published. They showed that, at a median follow-up of 28 months, the median survival was 14.6 months for the 287 patients assigned to radiotherapy plus temozolomide, compared with 12.1 months for the 286 patients randomized to radiotherapy alone.
The unadjusted hazard ratio for death in the combination therapy group was 0.63 (P < .001). The 2-year survival rate was 26.5% for chemoradiation and 10.4% for radiation alone.
Adding temozolomide to radiotherapy in the trial also appeared to be safe. The incidence of grade 3 or 4 hematologic adverse events was 7%.
Registry data study
To see how practice patterns changed in the United States and Europe after publication of the trial, Dr. Giusti and colleagues used registry data to calculate the proportion of cases by treatment type and overall survival during 1999-2005 (pre-study) and 2009-2013 (post-study).
The data included 34,229 cases from 11 countries in Europe and 36,925 cases from the United States.
The percentage of patients receiving both chemotherapy and radiation increased steadily over the study period. For example, among 18- to 49-year-olds, the percentage receiving the combined modalities in Europe increased from 20% in 1999-2001 to 70% in 2010-2013. In the United States, 40% of the same age group received combination therapy in 1999-2001, and this percentage grew to 80% in 2010-2013.
Overall survival rates in the general population were similar to those seen in the clinical trial during 1999-2005, when 2-year overall survival rates for patients treated with radiation alone were 11% in Europe and 12% in the United States. For patients treated with combined therapy, the respective 2-year survival rates in Europe and the United States were 24% and 25%.
“In the period after the trial, we observed a increasing 2-year survival rate to 28% in Europe and 29% in the U.S. for patients with radiotherapy plus chemotherapy,” Dr. Giusti said.
Real-world results
Invited discussant Matthias Preusser, MD, of the Medical University of Vienna in Austria, said the study shows that “population-based investigations are very valuable and should be further developed so that we can see how treatment patterns vary between countries and what the regional variations are, and whether new treatment standards actually reach clinical practice, and also to see whether there’s an effect on a population basis that is different from what is seen in controlled clinical trials.”
Dr. Preusser said it’s clear from the study that survival is increased with the addition of chemotherapy to radiotherapy, and more patients in the United States than in Europe received the combination during the study period.
Pointing to a treatment algorithm from the European Association of Neuro-oncology published in 2017, Dr. Preusser noted that radiotherapy alone may still be recommended for patients with unfavorable prognostic factors or patients 70 years and older with methylguanine-DNA methyltransferase promoter non-methylated tumors.
“It seems the differences in the age distribution between the U.S. and European populations that were analyzed could be one explanation why the radiochemotherapy combination was applied more often in the U.S. population,” Dr. Preusser said.
No outside funding was used to support the study. Dr. Giusti and coauthors reported having no conflicts of interest. Dr. Preusser disclosed relationships with multiple companies, including Merck, which markets temozolomide under the name Temodar.
SOURCE: Giusti F et al. ESMO 2020. Abstract 365MO.
FROM ESMO 2020
Assault- and sports-related concussions may differ in kids
Concussions resulting from assaults and sports may not be entirely similar in children and youth, researchers report. For example, more than twice as many children who experience assault-related concussions report declines in school grades, compared with those with sports-related concussions.
The researchers also saw trends suggesting there are clinically meaningful differences between the groups in terms of longer periods before return to school, symptom resolution, and full physician clearance after injury. Patients with assault-related concussion were also less likely to be referred to specialists and to receive initial visio-vestibular testing.
The research, conducted over a 2-year period with 124 children and adolescents aged 8-18 years, stands out by focusing on lesser-understood outcomes of concussions related to assault, said study author Margaret Means, MD, of Children’s Hospital of Philadelphia.
“From my standpoint as a pediatrician and training to be a pediatric neurologist, I want to make sure I come into each patient encounter with as much understanding as I can and to treat all the associated factors adequately,” Dr. Means said.
“It’s so important to recognize that one disease process, as we categorize it, such as concussion, doesn’t mean all your patients are going to have the same needs or outcomes,” Dr. Means said in an interview. “We focus a lot on sports-related concussion, and that’s very important, but unless we recognize [that] a child who presents to the emergency department after assault could have a concussion, they are much less likely to be screened for certain concussion aspects.”
The research was presented at the virtual American Academy of Pediatrics National Conference.
Dr. Means and her colleagues undertook a retrospective chart review comparing 62 patients with assault-related concussions to the same number with sports- and recreation-related concussion between 2012 and 2014.
Patients with assault-related concussion were more likely to be Black, publicly insured, and to initially present to the emergency department. Markedly fewer patients with assault-related concussions received visio-vestibular testing at their first visit, compared with sports concussion patients (25% vs. 75%; P < .001).
Although the total number of reported physical, cognitive, emotional, and sleep symptoms didn’t differ between the groups during their recovery period, (47% vs. 20%; P = .012).
“The decline in grades in this group suggests it takes longer for children to become asymptomatic from concussion related to an assault,” Dr. Means explained. “We need to investigate that further to hopefully address that difference and help kids to not experience that decline in grades.”
Clinically meaningful but not statistically significant differences were revealed in the rate of specialist referral for those with assault-related vs. sports-related concussions (53% vs. 40%; P = .086). Patients with assault-related concussions also tended to take longer to return to school than patients with sports-related concussions (11 days vs. 8 days; P = .252); to experience symptom resolution (13.5 days vs. 11.5 days; P = .389); and to receive full physician clearance (35 days vs. 24 days; P = .332).
“With a child experiencing interpersonal assault, obviously there are a lot of different factors that need to be addressed in terms of the emotional and physical response to the trauma,” Dr. Means said. “But in terms of to-dos – and I’d love for the medical community to recognize this more readily – maybe we could develop some type of screening tool for the population experiencing assault so we might be more aware they’ve also experienced concussion.
“As a clinician, it’s important to understand research like this so you see some nuances to how each patient experiences this,” she added, “and tailor your approach to them for the best treatment and outcomes.”
Carrie Esopenko, PhD, of Rutgers University in Newark, N.J., agreed with Dr. Means that focusing on youth concussions that are not the result of sports has been largely neglected.
“We haven’t really realized concussion is occurring more on a milder scale of abusive head injuries,” said Dr. Esopenko, who conducts research on intimate partner violence but wasn’t involved in the new study.
“Head injury is the key phrase in sports right now, and I think we’re just starting to realize how prevalent the issue is in interpersonal and intimate partner violence,” Dr. Esopenko said in an interview.
“Clinicians need to do a full concussion battery on kids coming in and be aware these symptoms can be treated similarly even if they’re from a different mechanism,” she added. “It’s still the same organ impacted. These kids are still struggling, even though they’re not injured on a sports field.”
Dr. Means and Dr. Esopenko have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Concussions resulting from assaults and sports may not be entirely similar in children and youth, researchers report. For example, more than twice as many children who experience assault-related concussions report declines in school grades, compared with those with sports-related concussions.
The researchers also saw trends suggesting there are clinically meaningful differences between the groups in terms of longer periods before return to school, symptom resolution, and full physician clearance after injury. Patients with assault-related concussion were also less likely to be referred to specialists and to receive initial visio-vestibular testing.
The research, conducted over a 2-year period with 124 children and adolescents aged 8-18 years, stands out by focusing on lesser-understood outcomes of concussions related to assault, said study author Margaret Means, MD, of Children’s Hospital of Philadelphia.
“From my standpoint as a pediatrician and training to be a pediatric neurologist, I want to make sure I come into each patient encounter with as much understanding as I can and to treat all the associated factors adequately,” Dr. Means said.
“It’s so important to recognize that one disease process, as we categorize it, such as concussion, doesn’t mean all your patients are going to have the same needs or outcomes,” Dr. Means said in an interview. “We focus a lot on sports-related concussion, and that’s very important, but unless we recognize [that] a child who presents to the emergency department after assault could have a concussion, they are much less likely to be screened for certain concussion aspects.”
The research was presented at the virtual American Academy of Pediatrics National Conference.
Dr. Means and her colleagues undertook a retrospective chart review comparing 62 patients with assault-related concussions to the same number with sports- and recreation-related concussion between 2012 and 2014.
Patients with assault-related concussion were more likely to be Black, publicly insured, and to initially present to the emergency department. Markedly fewer patients with assault-related concussions received visio-vestibular testing at their first visit, compared with sports concussion patients (25% vs. 75%; P < .001).
Although the total number of reported physical, cognitive, emotional, and sleep symptoms didn’t differ between the groups during their recovery period, (47% vs. 20%; P = .012).
“The decline in grades in this group suggests it takes longer for children to become asymptomatic from concussion related to an assault,” Dr. Means explained. “We need to investigate that further to hopefully address that difference and help kids to not experience that decline in grades.”
Clinically meaningful but not statistically significant differences were revealed in the rate of specialist referral for those with assault-related vs. sports-related concussions (53% vs. 40%; P = .086). Patients with assault-related concussions also tended to take longer to return to school than patients with sports-related concussions (11 days vs. 8 days; P = .252); to experience symptom resolution (13.5 days vs. 11.5 days; P = .389); and to receive full physician clearance (35 days vs. 24 days; P = .332).
“With a child experiencing interpersonal assault, obviously there are a lot of different factors that need to be addressed in terms of the emotional and physical response to the trauma,” Dr. Means said. “But in terms of to-dos – and I’d love for the medical community to recognize this more readily – maybe we could develop some type of screening tool for the population experiencing assault so we might be more aware they’ve also experienced concussion.
“As a clinician, it’s important to understand research like this so you see some nuances to how each patient experiences this,” she added, “and tailor your approach to them for the best treatment and outcomes.”
Carrie Esopenko, PhD, of Rutgers University in Newark, N.J., agreed with Dr. Means that focusing on youth concussions that are not the result of sports has been largely neglected.
“We haven’t really realized concussion is occurring more on a milder scale of abusive head injuries,” said Dr. Esopenko, who conducts research on intimate partner violence but wasn’t involved in the new study.
“Head injury is the key phrase in sports right now, and I think we’re just starting to realize how prevalent the issue is in interpersonal and intimate partner violence,” Dr. Esopenko said in an interview.
“Clinicians need to do a full concussion battery on kids coming in and be aware these symptoms can be treated similarly even if they’re from a different mechanism,” she added. “It’s still the same organ impacted. These kids are still struggling, even though they’re not injured on a sports field.”
Dr. Means and Dr. Esopenko have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Concussions resulting from assaults and sports may not be entirely similar in children and youth, researchers report. For example, more than twice as many children who experience assault-related concussions report declines in school grades, compared with those with sports-related concussions.
The researchers also saw trends suggesting there are clinically meaningful differences between the groups in terms of longer periods before return to school, symptom resolution, and full physician clearance after injury. Patients with assault-related concussion were also less likely to be referred to specialists and to receive initial visio-vestibular testing.
The research, conducted over a 2-year period with 124 children and adolescents aged 8-18 years, stands out by focusing on lesser-understood outcomes of concussions related to assault, said study author Margaret Means, MD, of Children’s Hospital of Philadelphia.
“From my standpoint as a pediatrician and training to be a pediatric neurologist, I want to make sure I come into each patient encounter with as much understanding as I can and to treat all the associated factors adequately,” Dr. Means said.
“It’s so important to recognize that one disease process, as we categorize it, such as concussion, doesn’t mean all your patients are going to have the same needs or outcomes,” Dr. Means said in an interview. “We focus a lot on sports-related concussion, and that’s very important, but unless we recognize [that] a child who presents to the emergency department after assault could have a concussion, they are much less likely to be screened for certain concussion aspects.”
The research was presented at the virtual American Academy of Pediatrics National Conference.
Dr. Means and her colleagues undertook a retrospective chart review comparing 62 patients with assault-related concussions to the same number with sports- and recreation-related concussion between 2012 and 2014.
Patients with assault-related concussion were more likely to be Black, publicly insured, and to initially present to the emergency department. Markedly fewer patients with assault-related concussions received visio-vestibular testing at their first visit, compared with sports concussion patients (25% vs. 75%; P < .001).
Although the total number of reported physical, cognitive, emotional, and sleep symptoms didn’t differ between the groups during their recovery period, (47% vs. 20%; P = .012).
“The decline in grades in this group suggests it takes longer for children to become asymptomatic from concussion related to an assault,” Dr. Means explained. “We need to investigate that further to hopefully address that difference and help kids to not experience that decline in grades.”
Clinically meaningful but not statistically significant differences were revealed in the rate of specialist referral for those with assault-related vs. sports-related concussions (53% vs. 40%; P = .086). Patients with assault-related concussions also tended to take longer to return to school than patients with sports-related concussions (11 days vs. 8 days; P = .252); to experience symptom resolution (13.5 days vs. 11.5 days; P = .389); and to receive full physician clearance (35 days vs. 24 days; P = .332).
“With a child experiencing interpersonal assault, obviously there are a lot of different factors that need to be addressed in terms of the emotional and physical response to the trauma,” Dr. Means said. “But in terms of to-dos – and I’d love for the medical community to recognize this more readily – maybe we could develop some type of screening tool for the population experiencing assault so we might be more aware they’ve also experienced concussion.
“As a clinician, it’s important to understand research like this so you see some nuances to how each patient experiences this,” she added, “and tailor your approach to them for the best treatment and outcomes.”
Carrie Esopenko, PhD, of Rutgers University in Newark, N.J., agreed with Dr. Means that focusing on youth concussions that are not the result of sports has been largely neglected.
“We haven’t really realized concussion is occurring more on a milder scale of abusive head injuries,” said Dr. Esopenko, who conducts research on intimate partner violence but wasn’t involved in the new study.
“Head injury is the key phrase in sports right now, and I think we’re just starting to realize how prevalent the issue is in interpersonal and intimate partner violence,” Dr. Esopenko said in an interview.
“Clinicians need to do a full concussion battery on kids coming in and be aware these symptoms can be treated similarly even if they’re from a different mechanism,” she added. “It’s still the same organ impacted. These kids are still struggling, even though they’re not injured on a sports field.”
Dr. Means and Dr. Esopenko have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Study advances personalized treatment for older breast cancer patients
Findings from the study were reported at the 12th European Breast Cancer Conference.
“Primary endocrine therapy is usually reserved for older, less fit, and frail women. Rates of use vary widely,” noted investigator Lynda Wyld, MBChB, PhD, of the University of Sheffield (England).
“Although there is no set threshold for who is suitable, some women are undoubtedly over- and undertreated for their breast cancer,” she added.
Dr. Wyld and colleagues undertook the Age Gap study among women older than 70 years with breast cancer recruited from 56 U.K. breast units during 2013-2018.
The main goals were to determine which women can be safely offered primary endocrine therapy as nonstandard care and to develop and test a tool to help women in this age group make treatment decisions.
The first component of the study was a multicenter, prospective cohort study of women with ER+ disease who were eligible for surgery. Results showed that breast cancer–specific mortality was greater with primary endocrine therapy than with surgery in the entire cohort. However, breast cancer–specific mortality was lower with primary endocrine therapy than with surgery in a cohort matched with propensity scores to achieve similar age, fitness, and frailty.
The second component of the study was a cluster-randomized controlled trial of women with operable breast cancer, most of whom had ER+ disease. Results showed that a decision support tool increased awareness of treatment options and readiness to decide. The tool also altered treatment choices, prompting a larger share of patients with ER+ disease to choose primary endocrine therapy.
Prospective cohort study
The prospective observational study was conducted in 2,854 women with ER+ disease who were eligible for surgery and treated in usual practice. Most women (n = 2,354) were treated with surgery (followed by antiestrogen therapy), while the rest received primary endocrine therapy (n = 500).
In the entire cohort, patients undergoing surgery were younger, had a lower level of comorbidity, and were less often frail. But these characteristics were generally similar in a propensity-matched cohort of 672 patients.
At a median follow-up of 52 months, overall and breast cancer–specific survival were significantly poorer with primary endocrine therapy versus surgery in the entire cohort but not in the propensity-matched cohort.
In the entire cohort, the breast cancer–specific mortality was 9.5% with primary endocrine therapy and 4.9% with surgery. In the propensity-matched cohort, breast cancer–specific mortality was 3.1% and 6.6%, respectively.
The overall mortality was 41.8% with primary endocrine therapy and 14.6% with surgery in the entire cohort, but the gap narrowed to 34.5% and 25.6%, respectively, in the propensity-matched cohort.
In the latter, “although there is a slight divergence in overall survival and it’s likely that with longer-term follow-up this will become significant, at the moment, it isn’t,” Dr. Wyld commented.
Curves for breast cancer–specific survival basically overlapped until 5 years, when surgery started to show an advantage. The rate of locoregional recurrence or progression was low and not significantly different by treatment.
None of the women in the entire cohort died from surgery. “But it’s worth bearing in mind that these were all women selected for surgery, who were thought to be fit for it by their surgeons. The least fit women in this cohort will have obviously been offered primary endocrine therapy,” Dr. Wyld cautioned.
Although 19% of patients had a surgical complication, only 2.1% had a systemic surgical complication.
Cluster-randomized controlled trial
In the cluster-randomized controlled trial, researchers compared a decision support tool to usual care. The tool was developed using U.K. registry data from almost 30,000 older women and input from women in this age group on their preferred format and method of presentation, according to Dr. Wyld.
The tool consists of an algorithm available to clinicians online (for input of tumor stage and biology, comorbidities, and functional status) plus a booklet and outcome sheets for patients to take home after discussions that can be personalized to their particulars.
Intention-to-treat analyses were based on 1,339 patients with operable breast cancer, 1,161 of whom had ER+ disease. Per-protocol analyses were based on the subset of 449 patients who were offered a choice between surgery and primary endocrine therapy, presumably because they were less fit and frailer.
Results showed that, at 6 months, mean scores for global quality of life on the EORTC questionnaire did not differ between decision support and usual care in the intention-to-treat population (69.0 vs. 68.9; P = .900), but scores were more favorable with decision support in the per-protocol population (70.7 vs. 66.8; P = .044).
The tool also altered treatment choices, with a larger share of ER+ patients choosing primary endocrine therapy (21.0% vs. 15.4%; P = .029) but still having similar disease outcomes.
Although ER+ patients in the decision support group more often selected primary endocrine therapy, at a median follow-up of 36 months, the groups did not differ significantly on overall survival, cause-specific survival, or time to recurrence in either intention-to-treat or per-protocol analyses.
Larger shares of women in the decision support group reported that they had adequate knowledge about the treatment options available to them (94% vs. 74%), were aware of the advantages and disadvantages of each option (91% vs. 76%), knew which option they preferred (96% vs. 91%), and were ready to make a decision (99% vs. 90%).
Applying results to practice
“Most women over the age of 70 are relatively fit, and the aim should be to treat them with surgery,” Dr. Wyld said. “For the less fit, a point is reached where the oncology benefits of surgery disappear and surgery may just cause harm. This threshold appears to be for women in their mid-80s with moderate to poor health.”
“Use of the Age Gap online tool may enhance shared decision-making for these women while increasing knowledge. And whilst it does seem to increase the use of primary endocrine therapy, this does not seem to have an adverse impact on survival at 36 months of follow-up,” she added.
“The study by Dr. Wyld and colleagues adds to the available literature regarding the scenarios in which some treatments may be omitted without impacting overall survival in older women with breast cancer,” Lesly A. Dossett, MD, of Michigan Medicine in Ann Arbor, commented in an interview.
In her own practice, Dr. Dossett emphasizes the generally favorable prognosis for older women with hormone receptor–positive breast cancer, she said. However, tools that help communicate risk and clarify the value of various therapies are welcome.
“The decision support tool appears to be a promising tool in helping to avoid treatments that are unlikely to benefit older women with breast cancer,” Dr. Dossett said. “The results will be widely applicable, as there is growing recognition that this patient population is at risk for overtreatment.”
The study was funded by the U.K. National Institute for Health Research programme grant for applied research. Dr. Wyld and Dr. Dossett said they had no relevant conflicts of interest.
SOURCES: Wyld L et al. EBCC-12 Virtual Congress. Abstract 8A and Abstract 8B.
Findings from the study were reported at the 12th European Breast Cancer Conference.
“Primary endocrine therapy is usually reserved for older, less fit, and frail women. Rates of use vary widely,” noted investigator Lynda Wyld, MBChB, PhD, of the University of Sheffield (England).
“Although there is no set threshold for who is suitable, some women are undoubtedly over- and undertreated for their breast cancer,” she added.
Dr. Wyld and colleagues undertook the Age Gap study among women older than 70 years with breast cancer recruited from 56 U.K. breast units during 2013-2018.
The main goals were to determine which women can be safely offered primary endocrine therapy as nonstandard care and to develop and test a tool to help women in this age group make treatment decisions.
The first component of the study was a multicenter, prospective cohort study of women with ER+ disease who were eligible for surgery. Results showed that breast cancer–specific mortality was greater with primary endocrine therapy than with surgery in the entire cohort. However, breast cancer–specific mortality was lower with primary endocrine therapy than with surgery in a cohort matched with propensity scores to achieve similar age, fitness, and frailty.
The second component of the study was a cluster-randomized controlled trial of women with operable breast cancer, most of whom had ER+ disease. Results showed that a decision support tool increased awareness of treatment options and readiness to decide. The tool also altered treatment choices, prompting a larger share of patients with ER+ disease to choose primary endocrine therapy.
Prospective cohort study
The prospective observational study was conducted in 2,854 women with ER+ disease who were eligible for surgery and treated in usual practice. Most women (n = 2,354) were treated with surgery (followed by antiestrogen therapy), while the rest received primary endocrine therapy (n = 500).
In the entire cohort, patients undergoing surgery were younger, had a lower level of comorbidity, and were less often frail. But these characteristics were generally similar in a propensity-matched cohort of 672 patients.
At a median follow-up of 52 months, overall and breast cancer–specific survival were significantly poorer with primary endocrine therapy versus surgery in the entire cohort but not in the propensity-matched cohort.
In the entire cohort, the breast cancer–specific mortality was 9.5% with primary endocrine therapy and 4.9% with surgery. In the propensity-matched cohort, breast cancer–specific mortality was 3.1% and 6.6%, respectively.
The overall mortality was 41.8% with primary endocrine therapy and 14.6% with surgery in the entire cohort, but the gap narrowed to 34.5% and 25.6%, respectively, in the propensity-matched cohort.
In the latter, “although there is a slight divergence in overall survival and it’s likely that with longer-term follow-up this will become significant, at the moment, it isn’t,” Dr. Wyld commented.
Curves for breast cancer–specific survival basically overlapped until 5 years, when surgery started to show an advantage. The rate of locoregional recurrence or progression was low and not significantly different by treatment.
None of the women in the entire cohort died from surgery. “But it’s worth bearing in mind that these were all women selected for surgery, who were thought to be fit for it by their surgeons. The least fit women in this cohort will have obviously been offered primary endocrine therapy,” Dr. Wyld cautioned.
Although 19% of patients had a surgical complication, only 2.1% had a systemic surgical complication.
Cluster-randomized controlled trial
In the cluster-randomized controlled trial, researchers compared a decision support tool to usual care. The tool was developed using U.K. registry data from almost 30,000 older women and input from women in this age group on their preferred format and method of presentation, according to Dr. Wyld.
The tool consists of an algorithm available to clinicians online (for input of tumor stage and biology, comorbidities, and functional status) plus a booklet and outcome sheets for patients to take home after discussions that can be personalized to their particulars.
Intention-to-treat analyses were based on 1,339 patients with operable breast cancer, 1,161 of whom had ER+ disease. Per-protocol analyses were based on the subset of 449 patients who were offered a choice between surgery and primary endocrine therapy, presumably because they were less fit and frailer.
Results showed that, at 6 months, mean scores for global quality of life on the EORTC questionnaire did not differ between decision support and usual care in the intention-to-treat population (69.0 vs. 68.9; P = .900), but scores were more favorable with decision support in the per-protocol population (70.7 vs. 66.8; P = .044).
The tool also altered treatment choices, with a larger share of ER+ patients choosing primary endocrine therapy (21.0% vs. 15.4%; P = .029) but still having similar disease outcomes.
Although ER+ patients in the decision support group more often selected primary endocrine therapy, at a median follow-up of 36 months, the groups did not differ significantly on overall survival, cause-specific survival, or time to recurrence in either intention-to-treat or per-protocol analyses.
Larger shares of women in the decision support group reported that they had adequate knowledge about the treatment options available to them (94% vs. 74%), were aware of the advantages and disadvantages of each option (91% vs. 76%), knew which option they preferred (96% vs. 91%), and were ready to make a decision (99% vs. 90%).
Applying results to practice
“Most women over the age of 70 are relatively fit, and the aim should be to treat them with surgery,” Dr. Wyld said. “For the less fit, a point is reached where the oncology benefits of surgery disappear and surgery may just cause harm. This threshold appears to be for women in their mid-80s with moderate to poor health.”
“Use of the Age Gap online tool may enhance shared decision-making for these women while increasing knowledge. And whilst it does seem to increase the use of primary endocrine therapy, this does not seem to have an adverse impact on survival at 36 months of follow-up,” she added.
“The study by Dr. Wyld and colleagues adds to the available literature regarding the scenarios in which some treatments may be omitted without impacting overall survival in older women with breast cancer,” Lesly A. Dossett, MD, of Michigan Medicine in Ann Arbor, commented in an interview.
In her own practice, Dr. Dossett emphasizes the generally favorable prognosis for older women with hormone receptor–positive breast cancer, she said. However, tools that help communicate risk and clarify the value of various therapies are welcome.
“The decision support tool appears to be a promising tool in helping to avoid treatments that are unlikely to benefit older women with breast cancer,” Dr. Dossett said. “The results will be widely applicable, as there is growing recognition that this patient population is at risk for overtreatment.”
The study was funded by the U.K. National Institute for Health Research programme grant for applied research. Dr. Wyld and Dr. Dossett said they had no relevant conflicts of interest.
SOURCES: Wyld L et al. EBCC-12 Virtual Congress. Abstract 8A and Abstract 8B.
Findings from the study were reported at the 12th European Breast Cancer Conference.
“Primary endocrine therapy is usually reserved for older, less fit, and frail women. Rates of use vary widely,” noted investigator Lynda Wyld, MBChB, PhD, of the University of Sheffield (England).
“Although there is no set threshold for who is suitable, some women are undoubtedly over- and undertreated for their breast cancer,” she added.
Dr. Wyld and colleagues undertook the Age Gap study among women older than 70 years with breast cancer recruited from 56 U.K. breast units during 2013-2018.
The main goals were to determine which women can be safely offered primary endocrine therapy as nonstandard care and to develop and test a tool to help women in this age group make treatment decisions.
The first component of the study was a multicenter, prospective cohort study of women with ER+ disease who were eligible for surgery. Results showed that breast cancer–specific mortality was greater with primary endocrine therapy than with surgery in the entire cohort. However, breast cancer–specific mortality was lower with primary endocrine therapy than with surgery in a cohort matched with propensity scores to achieve similar age, fitness, and frailty.
The second component of the study was a cluster-randomized controlled trial of women with operable breast cancer, most of whom had ER+ disease. Results showed that a decision support tool increased awareness of treatment options and readiness to decide. The tool also altered treatment choices, prompting a larger share of patients with ER+ disease to choose primary endocrine therapy.
Prospective cohort study
The prospective observational study was conducted in 2,854 women with ER+ disease who were eligible for surgery and treated in usual practice. Most women (n = 2,354) were treated with surgery (followed by antiestrogen therapy), while the rest received primary endocrine therapy (n = 500).
In the entire cohort, patients undergoing surgery were younger, had a lower level of comorbidity, and were less often frail. But these characteristics were generally similar in a propensity-matched cohort of 672 patients.
At a median follow-up of 52 months, overall and breast cancer–specific survival were significantly poorer with primary endocrine therapy versus surgery in the entire cohort but not in the propensity-matched cohort.
In the entire cohort, the breast cancer–specific mortality was 9.5% with primary endocrine therapy and 4.9% with surgery. In the propensity-matched cohort, breast cancer–specific mortality was 3.1% and 6.6%, respectively.
The overall mortality was 41.8% with primary endocrine therapy and 14.6% with surgery in the entire cohort, but the gap narrowed to 34.5% and 25.6%, respectively, in the propensity-matched cohort.
In the latter, “although there is a slight divergence in overall survival and it’s likely that with longer-term follow-up this will become significant, at the moment, it isn’t,” Dr. Wyld commented.
Curves for breast cancer–specific survival basically overlapped until 5 years, when surgery started to show an advantage. The rate of locoregional recurrence or progression was low and not significantly different by treatment.
None of the women in the entire cohort died from surgery. “But it’s worth bearing in mind that these were all women selected for surgery, who were thought to be fit for it by their surgeons. The least fit women in this cohort will have obviously been offered primary endocrine therapy,” Dr. Wyld cautioned.
Although 19% of patients had a surgical complication, only 2.1% had a systemic surgical complication.
Cluster-randomized controlled trial
In the cluster-randomized controlled trial, researchers compared a decision support tool to usual care. The tool was developed using U.K. registry data from almost 30,000 older women and input from women in this age group on their preferred format and method of presentation, according to Dr. Wyld.
The tool consists of an algorithm available to clinicians online (for input of tumor stage and biology, comorbidities, and functional status) plus a booklet and outcome sheets for patients to take home after discussions that can be personalized to their particulars.
Intention-to-treat analyses were based on 1,339 patients with operable breast cancer, 1,161 of whom had ER+ disease. Per-protocol analyses were based on the subset of 449 patients who were offered a choice between surgery and primary endocrine therapy, presumably because they were less fit and frailer.
Results showed that, at 6 months, mean scores for global quality of life on the EORTC questionnaire did not differ between decision support and usual care in the intention-to-treat population (69.0 vs. 68.9; P = .900), but scores were more favorable with decision support in the per-protocol population (70.7 vs. 66.8; P = .044).
The tool also altered treatment choices, with a larger share of ER+ patients choosing primary endocrine therapy (21.0% vs. 15.4%; P = .029) but still having similar disease outcomes.
Although ER+ patients in the decision support group more often selected primary endocrine therapy, at a median follow-up of 36 months, the groups did not differ significantly on overall survival, cause-specific survival, or time to recurrence in either intention-to-treat or per-protocol analyses.
Larger shares of women in the decision support group reported that they had adequate knowledge about the treatment options available to them (94% vs. 74%), were aware of the advantages and disadvantages of each option (91% vs. 76%), knew which option they preferred (96% vs. 91%), and were ready to make a decision (99% vs. 90%).
Applying results to practice
“Most women over the age of 70 are relatively fit, and the aim should be to treat them with surgery,” Dr. Wyld said. “For the less fit, a point is reached where the oncology benefits of surgery disappear and surgery may just cause harm. This threshold appears to be for women in their mid-80s with moderate to poor health.”
“Use of the Age Gap online tool may enhance shared decision-making for these women while increasing knowledge. And whilst it does seem to increase the use of primary endocrine therapy, this does not seem to have an adverse impact on survival at 36 months of follow-up,” she added.
“The study by Dr. Wyld and colleagues adds to the available literature regarding the scenarios in which some treatments may be omitted without impacting overall survival in older women with breast cancer,” Lesly A. Dossett, MD, of Michigan Medicine in Ann Arbor, commented in an interview.
In her own practice, Dr. Dossett emphasizes the generally favorable prognosis for older women with hormone receptor–positive breast cancer, she said. However, tools that help communicate risk and clarify the value of various therapies are welcome.
“The decision support tool appears to be a promising tool in helping to avoid treatments that are unlikely to benefit older women with breast cancer,” Dr. Dossett said. “The results will be widely applicable, as there is growing recognition that this patient population is at risk for overtreatment.”
The study was funded by the U.K. National Institute for Health Research programme grant for applied research. Dr. Wyld and Dr. Dossett said they had no relevant conflicts of interest.
SOURCES: Wyld L et al. EBCC-12 Virtual Congress. Abstract 8A and Abstract 8B.
FROM EBCC-12 VIRTUAL CONFERENCE
LSD microdosing to boost attention: Too soon to tell?
Microdosing with lysergic acid diethylamide (LSD) is associated with improved mood and increased attention, early research suggests. However, at least one expert believes it’s far too soon to tell and warns against endorsing patient microdosing.
In a dose-finding exploratory study, three low doses of LSD were compared with placebo in healthy volunteers who were all recreational drug users. Adjusted results showed that the highest dose boosted attention and mood, although participants were aware of psychedelic effects, prompting researchers to conclude the results demonstrated “selective, beneficial effects.”
“The majority of participants have improved attention,” study investigator Nadia Hutten, PhD, Department of Neuropsychology and Psychopharmacology, Maastricht University, the Netherlands, told Medscape Medical News.
“So we think that patients with attention deficits might have more beneficial effects,” she added, noting her team plans to study LSD microdosing in patients with attention deficit hyperactivity disorder.
The study was presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress, which was held online this year because of the COVID-19 pandemic.
Growing interest
Over the past 10 years there has been growing interest in psychedelic microdosing, which is defined as a dose that aims to enhance mood and/or performance but does not affect perception.
However, there has been considerable debate over what constitutes a “microdose.” One tenth of a “full” psychedelic dose is typically suggested, but users report a much wider dose range in practice, suggesting potential “individual variation in response to low doses,” the researchers note.
In the current dose-finding study, the researchers explored whether the effects of LSD on cognition and subjective measures differed between individuals.
The study included 24 healthy recreational drug users and compared the acute effects of 5 mcg, 20 mcg, and 20 mcg LSD with placebo on a computer-based psychomotor vigilance task (PVT) that measured attention and on a Digit Symbol Substitution Test (DSST).
Participants also completed the 72-item Profile of Mood States (POMS) questionnaire, a visual analog scale (VAS) on mood, and the 94-item 5-Dimensional Altered States of Consciousness Rating scales (5D-ASC).
Unadjusted results showed that the 20-mcg LSD dose significantly reduced correct substitutions on the DSST vs placebo (P < .05), but had no effect on attentional lapses on the PCT or on positive mood on the POMS.
Correcting the DSST score for the number of total responses revealed no dose effect of LSD. This suggested that participants were no less accurate when under the influence of LSD, even though they encoded fewer digits, the researchers note.
Participants also reported that both the 10-mcg and 20-mcg dose of LSD increased subjective experiences on the VAS and alternated states of consciousness on the 5D-ASC compared with placebo.
After stratifying the results by dose and participant, the effect of LSD differed between individuals. For example, both the 5-mcg and 20-mcg doses were associated with improvement in attention on the PVT (P < .05), but not the 10-mcg dose.
These results also indicated that the 20-mcg dose was associated with a significant increase in the correct number of substitutions on the DSST and with a significant increase in positive mood on the POMS (P < .05 for both outcomes).
The findings suggest that future studies in patient populations with impaired attention are needed, “including biological parameters involved in LSD receptor-binding and metabolism, in order to understand the inter-individual variation in response to LSD,” the investigators note.
In an educational session at the meeting, the study’s lead researcher, Kim Kuypers, PhD, associate professor at Maastricht University, said research shows individuals are already self-medicating with psychedelic microdosing to treat a wide range of mental health problems, and rated it as significantly more effective than conventional therapy at alleviating symptoms and improving quality of life.
Nevertheless, Kuypers noted there have been fewer than 20 published placebo-controlled studies examining psychedelic microdosing in humans – and much of the current evidence is anecdotal.
However, there is some clinical research suggesting that low-dose LSD is associated with improved mood and cognitive performance and that it also has an effect on resting-state amygdala functional connectivity and acutely increases brain-derived neurotrophic factor plasma levels.
Furthermore, said Kuypers, the evidence in healthy volunteers thus far suggests microdosing is “safe.”
Jumping ahead of the science?
Commenting on the study for Medscape Medical News, Jeffrey A. Lieberman, MD, professor and chair of psychiatry at Columbia University, New York City, said he “gives the investigators credit for doing such a study” but does not believe anything can be gleaned from the findings.
He said he is also concerned that the resurgence of psychedelic research is not congruent with “the methodologic rigor and scientific thinking that accompanies treatment development in other disease areas.”
Lieberman, who is also psychiatrist-in-chief at the NewYork–Presbyterian Hospital Columbia Medical Center and was not involved with the study, added that some of the research is also being conducted in individuals who are “true believers and not sufficiently dispassionate and objective.”
“ But because these are such notorious and interesting compounds, they have attracted a lot of peripheral interest to promote and to disseminate; and the risk is that it will be done in the wrong way and there may be consequences,” he said.
Moreover, Lieberman noted that the psychedelic drugs may be used in practice ahead of strong evidence of safety and efficacy. As an example, he pointed to ketamine, a drug that was identified as a treatment for people with depression who had not responded to standard treatments, he noted.
“But before you knew it, there were clinics being opened up all over the place by anesthesiologists or other people that were trying to make a quick buck,” he said.
“That was alarming because they were stretching the criteria for whom the treatment was appropriate; there were no protocols for dosing, for frequency of administration, and there was inadequate psychiatric follow-up,” Lieberman added.
Preliminary but promising
He agreed with Kuypers that cases of microdosing with psychedelics are largely anecdotal.
“So in that context, when these investigators tried to put it to a test, which is commendable, the results in no way tell you whether it’s good, bad, or indifferent,” Lieberman said. In fact, the results are “disappointing in terms of suggesting any beneficial effect.”
Lieberman said more and larger studies are needed in order to determine whether LSD microdosing is beneficial.
In response to Lieberman’s comments, Kuypers told Medscape Medical News that the investigators tried to base their placebo-controlled research on previous anecdotal research.
She emphasized that the “whole field is still in its infancy,” including research on the use of “full” doses of psychedelics.
“I sometimes think that the message is too positive. We should never forget to communicate that not a lot of research has been done.” In addition, she agreed that researchers should “keep a balanced message.”
“All the data to date is preliminary, in my view, but promising,” she stressed, “and the evidence is growing.”
The study received financial support from the Beckley Foundation. The study authors and Lieberman have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Microdosing with lysergic acid diethylamide (LSD) is associated with improved mood and increased attention, early research suggests. However, at least one expert believes it’s far too soon to tell and warns against endorsing patient microdosing.
In a dose-finding exploratory study, three low doses of LSD were compared with placebo in healthy volunteers who were all recreational drug users. Adjusted results showed that the highest dose boosted attention and mood, although participants were aware of psychedelic effects, prompting researchers to conclude the results demonstrated “selective, beneficial effects.”
“The majority of participants have improved attention,” study investigator Nadia Hutten, PhD, Department of Neuropsychology and Psychopharmacology, Maastricht University, the Netherlands, told Medscape Medical News.
“So we think that patients with attention deficits might have more beneficial effects,” she added, noting her team plans to study LSD microdosing in patients with attention deficit hyperactivity disorder.
The study was presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress, which was held online this year because of the COVID-19 pandemic.
Growing interest
Over the past 10 years there has been growing interest in psychedelic microdosing, which is defined as a dose that aims to enhance mood and/or performance but does not affect perception.
However, there has been considerable debate over what constitutes a “microdose.” One tenth of a “full” psychedelic dose is typically suggested, but users report a much wider dose range in practice, suggesting potential “individual variation in response to low doses,” the researchers note.
In the current dose-finding study, the researchers explored whether the effects of LSD on cognition and subjective measures differed between individuals.
The study included 24 healthy recreational drug users and compared the acute effects of 5 mcg, 20 mcg, and 20 mcg LSD with placebo on a computer-based psychomotor vigilance task (PVT) that measured attention and on a Digit Symbol Substitution Test (DSST).
Participants also completed the 72-item Profile of Mood States (POMS) questionnaire, a visual analog scale (VAS) on mood, and the 94-item 5-Dimensional Altered States of Consciousness Rating scales (5D-ASC).
Unadjusted results showed that the 20-mcg LSD dose significantly reduced correct substitutions on the DSST vs placebo (P < .05), but had no effect on attentional lapses on the PCT or on positive mood on the POMS.
Correcting the DSST score for the number of total responses revealed no dose effect of LSD. This suggested that participants were no less accurate when under the influence of LSD, even though they encoded fewer digits, the researchers note.
Participants also reported that both the 10-mcg and 20-mcg dose of LSD increased subjective experiences on the VAS and alternated states of consciousness on the 5D-ASC compared with placebo.
After stratifying the results by dose and participant, the effect of LSD differed between individuals. For example, both the 5-mcg and 20-mcg doses were associated with improvement in attention on the PVT (P < .05), but not the 10-mcg dose.
These results also indicated that the 20-mcg dose was associated with a significant increase in the correct number of substitutions on the DSST and with a significant increase in positive mood on the POMS (P < .05 for both outcomes).
The findings suggest that future studies in patient populations with impaired attention are needed, “including biological parameters involved in LSD receptor-binding and metabolism, in order to understand the inter-individual variation in response to LSD,” the investigators note.
In an educational session at the meeting, the study’s lead researcher, Kim Kuypers, PhD, associate professor at Maastricht University, said research shows individuals are already self-medicating with psychedelic microdosing to treat a wide range of mental health problems, and rated it as significantly more effective than conventional therapy at alleviating symptoms and improving quality of life.
Nevertheless, Kuypers noted there have been fewer than 20 published placebo-controlled studies examining psychedelic microdosing in humans – and much of the current evidence is anecdotal.
However, there is some clinical research suggesting that low-dose LSD is associated with improved mood and cognitive performance and that it also has an effect on resting-state amygdala functional connectivity and acutely increases brain-derived neurotrophic factor plasma levels.
Furthermore, said Kuypers, the evidence in healthy volunteers thus far suggests microdosing is “safe.”
Jumping ahead of the science?
Commenting on the study for Medscape Medical News, Jeffrey A. Lieberman, MD, professor and chair of psychiatry at Columbia University, New York City, said he “gives the investigators credit for doing such a study” but does not believe anything can be gleaned from the findings.
He said he is also concerned that the resurgence of psychedelic research is not congruent with “the methodologic rigor and scientific thinking that accompanies treatment development in other disease areas.”
Lieberman, who is also psychiatrist-in-chief at the NewYork–Presbyterian Hospital Columbia Medical Center and was not involved with the study, added that some of the research is also being conducted in individuals who are “true believers and not sufficiently dispassionate and objective.”
“ But because these are such notorious and interesting compounds, they have attracted a lot of peripheral interest to promote and to disseminate; and the risk is that it will be done in the wrong way and there may be consequences,” he said.
Moreover, Lieberman noted that the psychedelic drugs may be used in practice ahead of strong evidence of safety and efficacy. As an example, he pointed to ketamine, a drug that was identified as a treatment for people with depression who had not responded to standard treatments, he noted.
“But before you knew it, there were clinics being opened up all over the place by anesthesiologists or other people that were trying to make a quick buck,” he said.
“That was alarming because they were stretching the criteria for whom the treatment was appropriate; there were no protocols for dosing, for frequency of administration, and there was inadequate psychiatric follow-up,” Lieberman added.
Preliminary but promising
He agreed with Kuypers that cases of microdosing with psychedelics are largely anecdotal.
“So in that context, when these investigators tried to put it to a test, which is commendable, the results in no way tell you whether it’s good, bad, or indifferent,” Lieberman said. In fact, the results are “disappointing in terms of suggesting any beneficial effect.”
Lieberman said more and larger studies are needed in order to determine whether LSD microdosing is beneficial.
In response to Lieberman’s comments, Kuypers told Medscape Medical News that the investigators tried to base their placebo-controlled research on previous anecdotal research.
She emphasized that the “whole field is still in its infancy,” including research on the use of “full” doses of psychedelics.
“I sometimes think that the message is too positive. We should never forget to communicate that not a lot of research has been done.” In addition, she agreed that researchers should “keep a balanced message.”
“All the data to date is preliminary, in my view, but promising,” she stressed, “and the evidence is growing.”
The study received financial support from the Beckley Foundation. The study authors and Lieberman have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Microdosing with lysergic acid diethylamide (LSD) is associated with improved mood and increased attention, early research suggests. However, at least one expert believes it’s far too soon to tell and warns against endorsing patient microdosing.
In a dose-finding exploratory study, three low doses of LSD were compared with placebo in healthy volunteers who were all recreational drug users. Adjusted results showed that the highest dose boosted attention and mood, although participants were aware of psychedelic effects, prompting researchers to conclude the results demonstrated “selective, beneficial effects.”
“The majority of participants have improved attention,” study investigator Nadia Hutten, PhD, Department of Neuropsychology and Psychopharmacology, Maastricht University, the Netherlands, told Medscape Medical News.
“So we think that patients with attention deficits might have more beneficial effects,” she added, noting her team plans to study LSD microdosing in patients with attention deficit hyperactivity disorder.
The study was presented at the 33rd European College of Neuropsychopharmacology (ECNP) Congress, which was held online this year because of the COVID-19 pandemic.
Growing interest
Over the past 10 years there has been growing interest in psychedelic microdosing, which is defined as a dose that aims to enhance mood and/or performance but does not affect perception.
However, there has been considerable debate over what constitutes a “microdose.” One tenth of a “full” psychedelic dose is typically suggested, but users report a much wider dose range in practice, suggesting potential “individual variation in response to low doses,” the researchers note.
In the current dose-finding study, the researchers explored whether the effects of LSD on cognition and subjective measures differed between individuals.
The study included 24 healthy recreational drug users and compared the acute effects of 5 mcg, 20 mcg, and 20 mcg LSD with placebo on a computer-based psychomotor vigilance task (PVT) that measured attention and on a Digit Symbol Substitution Test (DSST).
Participants also completed the 72-item Profile of Mood States (POMS) questionnaire, a visual analog scale (VAS) on mood, and the 94-item 5-Dimensional Altered States of Consciousness Rating scales (5D-ASC).
Unadjusted results showed that the 20-mcg LSD dose significantly reduced correct substitutions on the DSST vs placebo (P < .05), but had no effect on attentional lapses on the PCT or on positive mood on the POMS.
Correcting the DSST score for the number of total responses revealed no dose effect of LSD. This suggested that participants were no less accurate when under the influence of LSD, even though they encoded fewer digits, the researchers note.
Participants also reported that both the 10-mcg and 20-mcg dose of LSD increased subjective experiences on the VAS and alternated states of consciousness on the 5D-ASC compared with placebo.
After stratifying the results by dose and participant, the effect of LSD differed between individuals. For example, both the 5-mcg and 20-mcg doses were associated with improvement in attention on the PVT (P < .05), but not the 10-mcg dose.
These results also indicated that the 20-mcg dose was associated with a significant increase in the correct number of substitutions on the DSST and with a significant increase in positive mood on the POMS (P < .05 for both outcomes).
The findings suggest that future studies in patient populations with impaired attention are needed, “including biological parameters involved in LSD receptor-binding and metabolism, in order to understand the inter-individual variation in response to LSD,” the investigators note.
In an educational session at the meeting, the study’s lead researcher, Kim Kuypers, PhD, associate professor at Maastricht University, said research shows individuals are already self-medicating with psychedelic microdosing to treat a wide range of mental health problems, and rated it as significantly more effective than conventional therapy at alleviating symptoms and improving quality of life.
Nevertheless, Kuypers noted there have been fewer than 20 published placebo-controlled studies examining psychedelic microdosing in humans – and much of the current evidence is anecdotal.
However, there is some clinical research suggesting that low-dose LSD is associated with improved mood and cognitive performance and that it also has an effect on resting-state amygdala functional connectivity and acutely increases brain-derived neurotrophic factor plasma levels.
Furthermore, said Kuypers, the evidence in healthy volunteers thus far suggests microdosing is “safe.”
Jumping ahead of the science?
Commenting on the study for Medscape Medical News, Jeffrey A. Lieberman, MD, professor and chair of psychiatry at Columbia University, New York City, said he “gives the investigators credit for doing such a study” but does not believe anything can be gleaned from the findings.
He said he is also concerned that the resurgence of psychedelic research is not congruent with “the methodologic rigor and scientific thinking that accompanies treatment development in other disease areas.”
Lieberman, who is also psychiatrist-in-chief at the NewYork–Presbyterian Hospital Columbia Medical Center and was not involved with the study, added that some of the research is also being conducted in individuals who are “true believers and not sufficiently dispassionate and objective.”
“ But because these are such notorious and interesting compounds, they have attracted a lot of peripheral interest to promote and to disseminate; and the risk is that it will be done in the wrong way and there may be consequences,” he said.
Moreover, Lieberman noted that the psychedelic drugs may be used in practice ahead of strong evidence of safety and efficacy. As an example, he pointed to ketamine, a drug that was identified as a treatment for people with depression who had not responded to standard treatments, he noted.
“But before you knew it, there were clinics being opened up all over the place by anesthesiologists or other people that were trying to make a quick buck,” he said.
“That was alarming because they were stretching the criteria for whom the treatment was appropriate; there were no protocols for dosing, for frequency of administration, and there was inadequate psychiatric follow-up,” Lieberman added.
Preliminary but promising
He agreed with Kuypers that cases of microdosing with psychedelics are largely anecdotal.
“So in that context, when these investigators tried to put it to a test, which is commendable, the results in no way tell you whether it’s good, bad, or indifferent,” Lieberman said. In fact, the results are “disappointing in terms of suggesting any beneficial effect.”
Lieberman said more and larger studies are needed in order to determine whether LSD microdosing is beneficial.
In response to Lieberman’s comments, Kuypers told Medscape Medical News that the investigators tried to base their placebo-controlled research on previous anecdotal research.
She emphasized that the “whole field is still in its infancy,” including research on the use of “full” doses of psychedelics.
“I sometimes think that the message is too positive. We should never forget to communicate that not a lot of research has been done.” In addition, she agreed that researchers should “keep a balanced message.”
“All the data to date is preliminary, in my view, but promising,” she stressed, “and the evidence is growing.”
The study received financial support from the Beckley Foundation. The study authors and Lieberman have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.