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Social isolation is associated with an increased risk of a cardiovascular event of more than 40%, and of all-cause mortality approaching 50%, new research suggests. “These results are especially important in the current times of social isolation during the coronavirus crisis,” Janine Gronewold, PhD, University Hospital in Essen, Germany, told a press briefing.

The mechanism by which social isolation may boost risk for stroke, MI, or death is not clear, but other research has shown that loneliness or lack of contact with close friends and family can affect physical health, said Dr. Gronewold.

The findings were presented at the sixth Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual/online meeting because of the COVID-19 pandemic.

For this new study, researchers analyzed data from 4,139 participants, ranging in age from 45 to 75 years (mean 59.1 years), who were recruited into the large community-based Heinz Nixdorf Recall study. The randomly selected study group was representative of an industrial rural area of Germany, said Dr. Gronewold.

Study participants entered the study with no known cardiovascular disease and were followed for a mean of 13.4 years.
 

Social supports

Investigators collected information on three types of social support: instrumental (getting help with everyday activities such as buying food), emotional (provided with comfort), and financial (receiving monetary assistance when needed). They also looked at social integration (or social isolation) using an index with scores for marital status, number of contacts with family and friends, and membership in political, religious, community, sports, or professional associations.

Of the total, 501 participants reported a lack of instrumental support, 659 a lack of emotional support, and 907 a lack of financial support. A total of 309 lacked social integration, defined by the lowest level on the social integration index.

Participants were asked annually about new cardiovascular events, including stroke and MI. Over the follow-up period, there were 339 such events and 530 deaths.

After adjustment for age, sex, and social support, the analysis showed that social isolation was significantly associated with an increased risk of cardiovascular events (hazard ratio, 1.44; 95% confidence interval, 0.97-2.14) and all-cause mortality (HR, 1.47; 95% CI, 1.09-1.97).

The new research also showed that lack of financial support was significantly associated with increased risk for a cardiovascular event (HR, 1.30; 95% CI, 1.01-1.67).
 

Direct effect

Additional models that also adjusted for cardiovascular risk factors, health behaviors, depression, and socioeconomic factors, did not significantly change effect estimates.

“Social relationships protect us from cardiovascular events and mortality, not only via good mood, healthy behavior, and lower cardiovascular risk profile,” Dr. Gronewold said. “They seem to have a direct effect on these outcomes.”

Having strong social relationships is as important to cardiovascular health as classic protective factors such as controlling blood pressure and cholesterol levels, and maintaining a normal weight, said Dr. Gronewold.

The new results are worrying and are particularly important during the current COVID-19 pandemic, as social contact has been restricted in many areas, said Dr. Gronewold.

It is not yet clear why people who are socially isolated have such poor health outcomes, she added.

Dr. Gronewold has reported no relevant financial relationships.

This article first appeared on Medscape.com.

Social isolation is associated with an increased risk of a cardiovascular event of more than 40%, and of all-cause mortality approaching 50%, new research suggests. “These results are especially important in the current times of social isolation during the coronavirus crisis,” Janine Gronewold, PhD, University Hospital in Essen, Germany, told a press briefing.

The mechanism by which social isolation may boost risk for stroke, MI, or death is not clear, but other research has shown that loneliness or lack of contact with close friends and family can affect physical health, said Dr. Gronewold.

The findings were presented at the sixth Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual/online meeting because of the COVID-19 pandemic.

For this new study, researchers analyzed data from 4,139 participants, ranging in age from 45 to 75 years (mean 59.1 years), who were recruited into the large community-based Heinz Nixdorf Recall study. The randomly selected study group was representative of an industrial rural area of Germany, said Dr. Gronewold.

Study participants entered the study with no known cardiovascular disease and were followed for a mean of 13.4 years.
 

Social supports

Investigators collected information on three types of social support: instrumental (getting help with everyday activities such as buying food), emotional (provided with comfort), and financial (receiving monetary assistance when needed). They also looked at social integration (or social isolation) using an index with scores for marital status, number of contacts with family and friends, and membership in political, religious, community, sports, or professional associations.

Of the total, 501 participants reported a lack of instrumental support, 659 a lack of emotional support, and 907 a lack of financial support. A total of 309 lacked social integration, defined by the lowest level on the social integration index.

Participants were asked annually about new cardiovascular events, including stroke and MI. Over the follow-up period, there were 339 such events and 530 deaths.

After adjustment for age, sex, and social support, the analysis showed that social isolation was significantly associated with an increased risk of cardiovascular events (hazard ratio, 1.44; 95% confidence interval, 0.97-2.14) and all-cause mortality (HR, 1.47; 95% CI, 1.09-1.97).

The new research also showed that lack of financial support was significantly associated with increased risk for a cardiovascular event (HR, 1.30; 95% CI, 1.01-1.67).
 

Direct effect

Additional models that also adjusted for cardiovascular risk factors, health behaviors, depression, and socioeconomic factors, did not significantly change effect estimates.

“Social relationships protect us from cardiovascular events and mortality, not only via good mood, healthy behavior, and lower cardiovascular risk profile,” Dr. Gronewold said. “They seem to have a direct effect on these outcomes.”

Having strong social relationships is as important to cardiovascular health as classic protective factors such as controlling blood pressure and cholesterol levels, and maintaining a normal weight, said Dr. Gronewold.

The new results are worrying and are particularly important during the current COVID-19 pandemic, as social contact has been restricted in many areas, said Dr. Gronewold.

It is not yet clear why people who are socially isolated have such poor health outcomes, she added.

Dr. Gronewold has reported no relevant financial relationships.

This article first appeared on Medscape.com.

Social isolation is associated with an increased risk of a cardiovascular event of more than 40%, and of all-cause mortality approaching 50%, new research suggests. “These results are especially important in the current times of social isolation during the coronavirus crisis,” Janine Gronewold, PhD, University Hospital in Essen, Germany, told a press briefing.

The mechanism by which social isolation may boost risk for stroke, MI, or death is not clear, but other research has shown that loneliness or lack of contact with close friends and family can affect physical health, said Dr. Gronewold.

The findings were presented at the sixth Congress of the European Academy of Neurology (EAN) 2020, which transitioned to a virtual/online meeting because of the COVID-19 pandemic.

For this new study, researchers analyzed data from 4,139 participants, ranging in age from 45 to 75 years (mean 59.1 years), who were recruited into the large community-based Heinz Nixdorf Recall study. The randomly selected study group was representative of an industrial rural area of Germany, said Dr. Gronewold.

Study participants entered the study with no known cardiovascular disease and were followed for a mean of 13.4 years.
 

Social supports

Investigators collected information on three types of social support: instrumental (getting help with everyday activities such as buying food), emotional (provided with comfort), and financial (receiving monetary assistance when needed). They also looked at social integration (or social isolation) using an index with scores for marital status, number of contacts with family and friends, and membership in political, religious, community, sports, or professional associations.

Of the total, 501 participants reported a lack of instrumental support, 659 a lack of emotional support, and 907 a lack of financial support. A total of 309 lacked social integration, defined by the lowest level on the social integration index.

Participants were asked annually about new cardiovascular events, including stroke and MI. Over the follow-up period, there were 339 such events and 530 deaths.

After adjustment for age, sex, and social support, the analysis showed that social isolation was significantly associated with an increased risk of cardiovascular events (hazard ratio, 1.44; 95% confidence interval, 0.97-2.14) and all-cause mortality (HR, 1.47; 95% CI, 1.09-1.97).

The new research also showed that lack of financial support was significantly associated with increased risk for a cardiovascular event (HR, 1.30; 95% CI, 1.01-1.67).
 

Direct effect

Additional models that also adjusted for cardiovascular risk factors, health behaviors, depression, and socioeconomic factors, did not significantly change effect estimates.

“Social relationships protect us from cardiovascular events and mortality, not only via good mood, healthy behavior, and lower cardiovascular risk profile,” Dr. Gronewold said. “They seem to have a direct effect on these outcomes.”

Having strong social relationships is as important to cardiovascular health as classic protective factors such as controlling blood pressure and cholesterol levels, and maintaining a normal weight, said Dr. Gronewold.

The new results are worrying and are particularly important during the current COVID-19 pandemic, as social contact has been restricted in many areas, said Dr. Gronewold.

It is not yet clear why people who are socially isolated have such poor health outcomes, she added.

Dr. Gronewold has reported no relevant financial relationships.

This article first appeared on Medscape.com.

Angiotensin receptor blocker therapy was not associated with any hint of increased risk of suicide, compared with treatment with an ACE inhibitor, in a large national Veterans Affairs study, Kallisse R. Dent, MPH, reported at the virtual annual meeting of the American Association of Suicidology.

The VA study thus fails to confirm the results of an earlier Canadian, population-based, nested case-control study, which concluded that exposure to an angiotensin receptor blocker (ARB) was independently associated with an adjusted 63% increase risk of death by suicide, compared with ACE inhibitor users. The Canadian study drew considerable attention, noted Ms. Dent, of the VA Office of Mental Health and Suicide Prevention.

The Canadian study included 964 Ontario residents who died by suicide within 100 days of receiving an ACE inhibitor or ARB. They were matched by age, sex, and the presence of hypertension and diabetes to 3,856 controls, all of whom were on an ACE inhibitor or ARB for the 100 days prior to the patient’s suicide. All subjects were aged at least 66 years.

The Canadian investigators recommended that ACE inhibitors should be used instead of ARBs whenever possible, particularly in patients with major mental illness (JAMA Netw Open. 2019 Oct 2;2[10]:e1913304). This was a study that demanded replication because of the enormous potential impact that recommendation could have upon clinical care. ACE inhibitors and ARBs are among the most widely prescribed of all medications, with approved indications for treatment of hypertension, chronic kidney disease, diabetes, and heart failure, Ms. Dent observed.

The Canadian investigators noted that a differential effect on suicide risk for the two drug classes was mechanistically plausible. Those drugs can cross the blood-brain barrier to varying extents, where they could conceivably interfere with central angiotensin II activity, which in turn could result in increased activity of substance P, as well as anxiety and stress secondary to increased activity of the hypothalamic-pituitary-adrenal axis.

Ms. Dent and coinvestigators harnessed VA suicide surveillance resources to conduct a nested case-control study that included all 1,311 deaths by suicide during 2015-2017 among patients in the VA system who had an active prescription for an ACE inhibitor or ARB during the 100 days immediately prior to death. As in the Canadian study, these individuals were matched 4:1 to 5,243 controls who did not die by suicide and had an active prescription for an ARB or ACE inhibitor during the 100 days prior to the date of suicide.

Among the veterans who died by suicide, 19.6% were on an ARB and 80.4% were on an ACE inhibitor. Those rates were not significantly different from the rates found in controls, 21.6% of whom were on an ARB and 78.4% were on an ACE inhibitor. In a multivariate analysis adjusted for the same potential confounders included in the Canadian study – including Charlson Comorbidity Index score; drug use; and diagnosis of alcohol use disorder, coronary artery disease, stroke, and chronic liver or kidney disease – being on an ARB was associated with a 9% lower risk of suicide than being on an ACE inhibitor, a nonsignificant difference.

A point of pride for the investigators was that, because of the VA’s sophisticated patient care database and comprehensive suicide analytics, the VA researchers were able to very quickly determine the lack of generalizability of the Canadian findings to a different patient population. Indeed, the entire VA case-control study was completed in less than 2 months.

Ms. Dent reported having no financial conflicts regarding the study, which was sponsored by the Department of Veterans Affairs.

bjancin@mdedge.com

Angiotensin receptor blocker therapy was not associated with any hint of increased risk of suicide, compared with treatment with an ACE inhibitor, in a large national Veterans Affairs study, Kallisse R. Dent, MPH, reported at the virtual annual meeting of the American Association of Suicidology.

The VA study thus fails to confirm the results of an earlier Canadian, population-based, nested case-control study, which concluded that exposure to an angiotensin receptor blocker (ARB) was independently associated with an adjusted 63% increase risk of death by suicide, compared with ACE inhibitor users. The Canadian study drew considerable attention, noted Ms. Dent, of the VA Office of Mental Health and Suicide Prevention.

The Canadian study included 964 Ontario residents who died by suicide within 100 days of receiving an ACE inhibitor or ARB. They were matched by age, sex, and the presence of hypertension and diabetes to 3,856 controls, all of whom were on an ACE inhibitor or ARB for the 100 days prior to the patient’s suicide. All subjects were aged at least 66 years.

The Canadian investigators recommended that ACE inhibitors should be used instead of ARBs whenever possible, particularly in patients with major mental illness (JAMA Netw Open. 2019 Oct 2;2[10]:e1913304). This was a study that demanded replication because of the enormous potential impact that recommendation could have upon clinical care. ACE inhibitors and ARBs are among the most widely prescribed of all medications, with approved indications for treatment of hypertension, chronic kidney disease, diabetes, and heart failure, Ms. Dent observed.

The Canadian investigators noted that a differential effect on suicide risk for the two drug classes was mechanistically plausible. Those drugs can cross the blood-brain barrier to varying extents, where they could conceivably interfere with central angiotensin II activity, which in turn could result in increased activity of substance P, as well as anxiety and stress secondary to increased activity of the hypothalamic-pituitary-adrenal axis.

Ms. Dent and coinvestigators harnessed VA suicide surveillance resources to conduct a nested case-control study that included all 1,311 deaths by suicide during 2015-2017 among patients in the VA system who had an active prescription for an ACE inhibitor or ARB during the 100 days immediately prior to death. As in the Canadian study, these individuals were matched 4:1 to 5,243 controls who did not die by suicide and had an active prescription for an ARB or ACE inhibitor during the 100 days prior to the date of suicide.

Among the veterans who died by suicide, 19.6% were on an ARB and 80.4% were on an ACE inhibitor. Those rates were not significantly different from the rates found in controls, 21.6% of whom were on an ARB and 78.4% were on an ACE inhibitor. In a multivariate analysis adjusted for the same potential confounders included in the Canadian study – including Charlson Comorbidity Index score; drug use; and diagnosis of alcohol use disorder, coronary artery disease, stroke, and chronic liver or kidney disease – being on an ARB was associated with a 9% lower risk of suicide than being on an ACE inhibitor, a nonsignificant difference.

A point of pride for the investigators was that, because of the VA’s sophisticated patient care database and comprehensive suicide analytics, the VA researchers were able to very quickly determine the lack of generalizability of the Canadian findings to a different patient population. Indeed, the entire VA case-control study was completed in less than 2 months.

Ms. Dent reported having no financial conflicts regarding the study, which was sponsored by the Department of Veterans Affairs.

bjancin@mdedge.com

Angiotensin receptor blocker therapy was not associated with any hint of increased risk of suicide, compared with treatment with an ACE inhibitor, in a large national Veterans Affairs study, Kallisse R. Dent, MPH, reported at the virtual annual meeting of the American Association of Suicidology.

The VA study thus fails to confirm the results of an earlier Canadian, population-based, nested case-control study, which concluded that exposure to an angiotensin receptor blocker (ARB) was independently associated with an adjusted 63% increase risk of death by suicide, compared with ACE inhibitor users. The Canadian study drew considerable attention, noted Ms. Dent, of the VA Office of Mental Health and Suicide Prevention.

The Canadian study included 964 Ontario residents who died by suicide within 100 days of receiving an ACE inhibitor or ARB. They were matched by age, sex, and the presence of hypertension and diabetes to 3,856 controls, all of whom were on an ACE inhibitor or ARB for the 100 days prior to the patient’s suicide. All subjects were aged at least 66 years.

The Canadian investigators recommended that ACE inhibitors should be used instead of ARBs whenever possible, particularly in patients with major mental illness (JAMA Netw Open. 2019 Oct 2;2[10]:e1913304). This was a study that demanded replication because of the enormous potential impact that recommendation could have upon clinical care. ACE inhibitors and ARBs are among the most widely prescribed of all medications, with approved indications for treatment of hypertension, chronic kidney disease, diabetes, and heart failure, Ms. Dent observed.

The Canadian investigators noted that a differential effect on suicide risk for the two drug classes was mechanistically plausible. Those drugs can cross the blood-brain barrier to varying extents, where they could conceivably interfere with central angiotensin II activity, which in turn could result in increased activity of substance P, as well as anxiety and stress secondary to increased activity of the hypothalamic-pituitary-adrenal axis.

Ms. Dent and coinvestigators harnessed VA suicide surveillance resources to conduct a nested case-control study that included all 1,311 deaths by suicide during 2015-2017 among patients in the VA system who had an active prescription for an ACE inhibitor or ARB during the 100 days immediately prior to death. As in the Canadian study, these individuals were matched 4:1 to 5,243 controls who did not die by suicide and had an active prescription for an ARB or ACE inhibitor during the 100 days prior to the date of suicide.

Among the veterans who died by suicide, 19.6% were on an ARB and 80.4% were on an ACE inhibitor. Those rates were not significantly different from the rates found in controls, 21.6% of whom were on an ARB and 78.4% were on an ACE inhibitor. In a multivariate analysis adjusted for the same potential confounders included in the Canadian study – including Charlson Comorbidity Index score; drug use; and diagnosis of alcohol use disorder, coronary artery disease, stroke, and chronic liver or kidney disease – being on an ARB was associated with a 9% lower risk of suicide than being on an ACE inhibitor, a nonsignificant difference.

A point of pride for the investigators was that, because of the VA’s sophisticated patient care database and comprehensive suicide analytics, the VA researchers were able to very quickly determine the lack of generalizability of the Canadian findings to a different patient population. Indeed, the entire VA case-control study was completed in less than 2 months.

Ms. Dent reported having no financial conflicts regarding the study, which was sponsored by the Department of Veterans Affairs.

bjancin@mdedge.com

Daily low-dose aspirin for primary disease prevention in apparently healthy older people increased their risk of serious gastrointestinal bleeding by 60% in a new analysis from the large randomized ASPREE trial released as part of the annual Digestive Disease Week^.

David Sucsy/iStockphoto

The analysis identified several independent risk factors for major GI bleeding – advanced age, hypertension, obesity, smoking, and chronic kidney disease – according to Suzanne E. Mahady, MBBS, PhD, a gastroenterologist and clinical epidemiologist at Monash University in Melbourne.

“To date, there [are] no comparable data assessing aspirin-related bleeding in older healthy people from a large randomized, controlled trial. Previous data [have] been observational, with variable definitions of significant bleeding, and retrospective. We derived a standard definition for bleeding, used physicians to adjudicate bleeding endpoints, and followed older people for 5 years,” she explained in an interview.

“Our data on bleeding [are] novel,” Dr. Mahady added. “It will help clinicians assess who is most at risk of bleeding with aspirin and target modifiable bleeding risk factors where possible.”

ASPREE was a double-blind trial including 19,114 apparently healthy Australian and American adults age 70 or older, or age 65-plus for blacks and Hispanics in the United States. Participants were randomized to 100 mg/day of enteric-coated aspirin or placebo. At a median 4.7 years of follow-up, there was no between-group difference in major adverse cardiovascular events, a lack of benefit accompanied by a 38% greater risk of major hemorrhage risk and a statistically significant 14% increase in all-cause mortality in the aspirin group. (N Engl J Med. 2018 Oct 18;379[16]:1509-18). The chief contributor to the excess mortality in the aspirin group was their 31% greater risk of cancer-related death (N Engl J Med. 2018 Oct 18;379[16]:1519-28).

The new analysis of severe GI bleeding documented an absolute 5-year risk of 0.2% for 70-year-olds and 0.4% in 80-year-olds on aspirin. In 80-year-olds with additional GI bleeding risk factors as identified in the study, the rate reached up to 5.5%. The risk of major upper GI bleeding events was 87% greater in the aspirin group, compared with placebo-treated controls, and the risk of serious lower GI bleeding was increased 36%.

ASPREE coinvestigator Andrew T. Chan, MD, said that the bleeding data should prove useful in future efforts to appropriately weight the risks and benefits of low-dose aspirin treatment.

“We need to better understand how to incorporate bleeding risk in clinical decision making about how to use aspirin among older adults because aspirin has many potential benefits, including prevention of colorectal cancer,” said Dr. Chan, a gastroenterologist and professor of medicine at Harvard Medical School and director for cancer epidemiology at Massachusetts General Hospital, both in Boston.

However, ASPREE has soured cardiologists on the decades-long practice of recommending aspirin for primary prevention of cardiovascular disease in older individuals. In response to the publication of primary outcomes in ASPREE, which was closely bracketed by publication of the largely negative results of the randomized ARRIVE and ASCEND trials in a collective 47,000-plus randomized patients, the American College of Cardiology/American Heart Association clipped aspirin’s role for primary prevention of atherosclerotic cardiovascular disease. The current recommendation is that low-dose aspirin should not be administered on a routine basis for primary cardiovascular prevention in people above age 70, nor in adults at any age at increased bleeding risk, although the practice “might be considered” for primary prevention in select higher atherosclerotic cardiovascular disease–risk 40- to 70-year-olds, provided they are not at increased bleeding risk (J Am Coll Cardiol. 2019 Sep. doi: 10.1016/j.jacc.2019.03.010).

Dr. Mahady reported having no financial conflicts of interest. Dr. Chan serves as a consultant to Bayer Pharma, Janssen, and Pfizer.

bjancin@mdedge.com

Daily low-dose aspirin for primary disease prevention in apparently healthy older people increased their risk of serious gastrointestinal bleeding by 60% in a new analysis from the large randomized ASPREE trial released as part of the annual Digestive Disease Week^.

David Sucsy/iStockphoto

The analysis identified several independent risk factors for major GI bleeding – advanced age, hypertension, obesity, smoking, and chronic kidney disease – according to Suzanne E. Mahady, MBBS, PhD, a gastroenterologist and clinical epidemiologist at Monash University in Melbourne.

“To date, there [are] no comparable data assessing aspirin-related bleeding in older healthy people from a large randomized, controlled trial. Previous data [have] been observational, with variable definitions of significant bleeding, and retrospective. We derived a standard definition for bleeding, used physicians to adjudicate bleeding endpoints, and followed older people for 5 years,” she explained in an interview.

“Our data on bleeding [are] novel,” Dr. Mahady added. “It will help clinicians assess who is most at risk of bleeding with aspirin and target modifiable bleeding risk factors where possible.”

ASPREE was a double-blind trial including 19,114 apparently healthy Australian and American adults age 70 or older, or age 65-plus for blacks and Hispanics in the United States. Participants were randomized to 100 mg/day of enteric-coated aspirin or placebo. At a median 4.7 years of follow-up, there was no between-group difference in major adverse cardiovascular events, a lack of benefit accompanied by a 38% greater risk of major hemorrhage risk and a statistically significant 14% increase in all-cause mortality in the aspirin group. (N Engl J Med. 2018 Oct 18;379[16]:1509-18). The chief contributor to the excess mortality in the aspirin group was their 31% greater risk of cancer-related death (N Engl J Med. 2018 Oct 18;379[16]:1519-28).

The new analysis of severe GI bleeding documented an absolute 5-year risk of 0.2% for 70-year-olds and 0.4% in 80-year-olds on aspirin. In 80-year-olds with additional GI bleeding risk factors as identified in the study, the rate reached up to 5.5%. The risk of major upper GI bleeding events was 87% greater in the aspirin group, compared with placebo-treated controls, and the risk of serious lower GI bleeding was increased 36%.

ASPREE coinvestigator Andrew T. Chan, MD, said that the bleeding data should prove useful in future efforts to appropriately weight the risks and benefits of low-dose aspirin treatment.

“We need to better understand how to incorporate bleeding risk in clinical decision making about how to use aspirin among older adults because aspirin has many potential benefits, including prevention of colorectal cancer,” said Dr. Chan, a gastroenterologist and professor of medicine at Harvard Medical School and director for cancer epidemiology at Massachusetts General Hospital, both in Boston.

However, ASPREE has soured cardiologists on the decades-long practice of recommending aspirin for primary prevention of cardiovascular disease in older individuals. In response to the publication of primary outcomes in ASPREE, which was closely bracketed by publication of the largely negative results of the randomized ARRIVE and ASCEND trials in a collective 47,000-plus randomized patients, the American College of Cardiology/American Heart Association clipped aspirin’s role for primary prevention of atherosclerotic cardiovascular disease. The current recommendation is that low-dose aspirin should not be administered on a routine basis for primary cardiovascular prevention in people above age 70, nor in adults at any age at increased bleeding risk, although the practice “might be considered” for primary prevention in select higher atherosclerotic cardiovascular disease–risk 40- to 70-year-olds, provided they are not at increased bleeding risk (J Am Coll Cardiol. 2019 Sep. doi: 10.1016/j.jacc.2019.03.010).

Dr. Mahady reported having no financial conflicts of interest. Dr. Chan serves as a consultant to Bayer Pharma, Janssen, and Pfizer.

bjancin@mdedge.com

Daily low-dose aspirin for primary disease prevention in apparently healthy older people increased their risk of serious gastrointestinal bleeding by 60% in a new analysis from the large randomized ASPREE trial released as part of the annual Digestive Disease Week^.

David Sucsy/iStockphoto

The analysis identified several independent risk factors for major GI bleeding – advanced age, hypertension, obesity, smoking, and chronic kidney disease – according to Suzanne E. Mahady, MBBS, PhD, a gastroenterologist and clinical epidemiologist at Monash University in Melbourne.

“To date, there [are] no comparable data assessing aspirin-related bleeding in older healthy people from a large randomized, controlled trial. Previous data [have] been observational, with variable definitions of significant bleeding, and retrospective. We derived a standard definition for bleeding, used physicians to adjudicate bleeding endpoints, and followed older people for 5 years,” she explained in an interview.

“Our data on bleeding [are] novel,” Dr. Mahady added. “It will help clinicians assess who is most at risk of bleeding with aspirin and target modifiable bleeding risk factors where possible.”

ASPREE was a double-blind trial including 19,114 apparently healthy Australian and American adults age 70 or older, or age 65-plus for blacks and Hispanics in the United States. Participants were randomized to 100 mg/day of enteric-coated aspirin or placebo. At a median 4.7 years of follow-up, there was no between-group difference in major adverse cardiovascular events, a lack of benefit accompanied by a 38% greater risk of major hemorrhage risk and a statistically significant 14% increase in all-cause mortality in the aspirin group. (N Engl J Med. 2018 Oct 18;379[16]:1509-18). The chief contributor to the excess mortality in the aspirin group was their 31% greater risk of cancer-related death (N Engl J Med. 2018 Oct 18;379[16]:1519-28).

The new analysis of severe GI bleeding documented an absolute 5-year risk of 0.2% for 70-year-olds and 0.4% in 80-year-olds on aspirin. In 80-year-olds with additional GI bleeding risk factors as identified in the study, the rate reached up to 5.5%. The risk of major upper GI bleeding events was 87% greater in the aspirin group, compared with placebo-treated controls, and the risk of serious lower GI bleeding was increased 36%.

ASPREE coinvestigator Andrew T. Chan, MD, said that the bleeding data should prove useful in future efforts to appropriately weight the risks and benefits of low-dose aspirin treatment.

“We need to better understand how to incorporate bleeding risk in clinical decision making about how to use aspirin among older adults because aspirin has many potential benefits, including prevention of colorectal cancer,” said Dr. Chan, a gastroenterologist and professor of medicine at Harvard Medical School and director for cancer epidemiology at Massachusetts General Hospital, both in Boston.

However, ASPREE has soured cardiologists on the decades-long practice of recommending aspirin for primary prevention of cardiovascular disease in older individuals. In response to the publication of primary outcomes in ASPREE, which was closely bracketed by publication of the largely negative results of the randomized ARRIVE and ASCEND trials in a collective 47,000-plus randomized patients, the American College of Cardiology/American Heart Association clipped aspirin’s role for primary prevention of atherosclerotic cardiovascular disease. The current recommendation is that low-dose aspirin should not be administered on a routine basis for primary cardiovascular prevention in people above age 70, nor in adults at any age at increased bleeding risk, although the practice “might be considered” for primary prevention in select higher atherosclerotic cardiovascular disease–risk 40- to 70-year-olds, provided they are not at increased bleeding risk (J Am Coll Cardiol. 2019 Sep. doi: 10.1016/j.jacc.2019.03.010).

Dr. Mahady reported having no financial conflicts of interest. Dr. Chan serves as a consultant to Bayer Pharma, Janssen, and Pfizer.

bjancin@mdedge.com

A novel penclomedine shows promising safety and efficacy in some adolescent and young adult patients with cancers involving the central nervous system, according to phase 1/2 clinical trial findings.

The trial included 15 patients, aged 15-39 years, with measurable cancer involving the CNS who were treated with the agent 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN).

Two of these patients were “in their 59th month of survival and doing well” as of April, when the data were presented at the AACR virtual meeting I.

One of the patients with long-term survival benefit had non–small cell lung cancer, and one had astrocytoma, Lee Roy Morgan, MD, PhD, chief executive officer of Dekk-Tec Inc., New Orleans, reported during a poster presentation.

Patients with glioblastoma, however, “did not do well,” said Dr. Morgan, an adjunct professor at Tulane University in New Orleans. He noted that none of the five glioblastoma patients experienced a long-term response.
 

Safety

Study subjects were treated with the maximum tolerated dose (MTD) of DM-CHOC-PEN as identified in an earlier study. Patients with liver involvement received 75 mg/m², and those without liver involvement received up to 98.7 mg/m². Dosing was by 3-hour intravenous administration once every 21 days as lab tests and subject status allowed.

DM-CHOC-PEN was generally well tolerated. One patient experienced grade 2 vasogenic edema, and another experienced seizures. Both were secondary to tumor swelling, and both resolved with tumor regression.

No grade 3 toxicities occurred at the MTD, and “no renal, hematological, hepatic, or pulmonary toxicities were noted using the MTD in this trial,” Dr. Morgan said.
 

Mechanism

DM-CHOC-PEN is a polychlorinated pyridine with a cholesteryl carbonate attachment that induces lipophilicity, which potentiates the drug’s penetration of the blood-brain barrier and its entry into the brain and brain cancers, Dr. Morgan explained.

He added that DM-CHOC-PEN is a bis-alkylator that binds to DNA’s cytosine/guanine nucleotides. The agent does not require hepatic activation, it crosses the blood-brain barrier intact, and accumulates in CNS tumors but not normal CNS tissue, he said.

Further, it “is not a substrate for [p-glycoprotein] transport; thus, it doesn’t easily get out of the brain,” Dr. Morgan said. He noted that DM-CHOC-PEN can be used with other agents, such as temozolomide and bis-chloroethylnitrosourea, because of the difference in mechanisms of action.

This study was supported by Louisiana state grants, the National Cancer Institute, the National Institute of General Medical Sciences, and the Small Business Innovation Research program. Dr. Morgan reported having no disclosures, but he is chief executive officer of Dekk-Tec Inc., which is developing DM-CHOC-PEN.

sworcester@mdedge.com

SOURCE: Morgan L et al. AACR 2020, Abstract CT181.

A novel penclomedine shows promising safety and efficacy in some adolescent and young adult patients with cancers involving the central nervous system, according to phase 1/2 clinical trial findings.

The trial included 15 patients, aged 15-39 years, with measurable cancer involving the CNS who were treated with the agent 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN).

Two of these patients were “in their 59th month of survival and doing well” as of April, when the data were presented at the AACR virtual meeting I.

One of the patients with long-term survival benefit had non–small cell lung cancer, and one had astrocytoma, Lee Roy Morgan, MD, PhD, chief executive officer of Dekk-Tec Inc., New Orleans, reported during a poster presentation.

Patients with glioblastoma, however, “did not do well,” said Dr. Morgan, an adjunct professor at Tulane University in New Orleans. He noted that none of the five glioblastoma patients experienced a long-term response.
 

Safety

Study subjects were treated with the maximum tolerated dose (MTD) of DM-CHOC-PEN as identified in an earlier study. Patients with liver involvement received 75 mg/m², and those without liver involvement received up to 98.7 mg/m². Dosing was by 3-hour intravenous administration once every 21 days as lab tests and subject status allowed.

DM-CHOC-PEN was generally well tolerated. One patient experienced grade 2 vasogenic edema, and another experienced seizures. Both were secondary to tumor swelling, and both resolved with tumor regression.

No grade 3 toxicities occurred at the MTD, and “no renal, hematological, hepatic, or pulmonary toxicities were noted using the MTD in this trial,” Dr. Morgan said.
 

Mechanism

DM-CHOC-PEN is a polychlorinated pyridine with a cholesteryl carbonate attachment that induces lipophilicity, which potentiates the drug’s penetration of the blood-brain barrier and its entry into the brain and brain cancers, Dr. Morgan explained.

He added that DM-CHOC-PEN is a bis-alkylator that binds to DNA’s cytosine/guanine nucleotides. The agent does not require hepatic activation, it crosses the blood-brain barrier intact, and accumulates in CNS tumors but not normal CNS tissue, he said.

Further, it “is not a substrate for [p-glycoprotein] transport; thus, it doesn’t easily get out of the brain,” Dr. Morgan said. He noted that DM-CHOC-PEN can be used with other agents, such as temozolomide and bis-chloroethylnitrosourea, because of the difference in mechanisms of action.

This study was supported by Louisiana state grants, the National Cancer Institute, the National Institute of General Medical Sciences, and the Small Business Innovation Research program. Dr. Morgan reported having no disclosures, but he is chief executive officer of Dekk-Tec Inc., which is developing DM-CHOC-PEN.

sworcester@mdedge.com

SOURCE: Morgan L et al. AACR 2020, Abstract CT181.

A novel penclomedine shows promising safety and efficacy in some adolescent and young adult patients with cancers involving the central nervous system, according to phase 1/2 clinical trial findings.

The trial included 15 patients, aged 15-39 years, with measurable cancer involving the CNS who were treated with the agent 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN).

Two of these patients were “in their 59th month of survival and doing well” as of April, when the data were presented at the AACR virtual meeting I.

One of the patients with long-term survival benefit had non–small cell lung cancer, and one had astrocytoma, Lee Roy Morgan, MD, PhD, chief executive officer of Dekk-Tec Inc., New Orleans, reported during a poster presentation.

Patients with glioblastoma, however, “did not do well,” said Dr. Morgan, an adjunct professor at Tulane University in New Orleans. He noted that none of the five glioblastoma patients experienced a long-term response.
 

Safety

Study subjects were treated with the maximum tolerated dose (MTD) of DM-CHOC-PEN as identified in an earlier study. Patients with liver involvement received 75 mg/m², and those without liver involvement received up to 98.7 mg/m². Dosing was by 3-hour intravenous administration once every 21 days as lab tests and subject status allowed.

DM-CHOC-PEN was generally well tolerated. One patient experienced grade 2 vasogenic edema, and another experienced seizures. Both were secondary to tumor swelling, and both resolved with tumor regression.

No grade 3 toxicities occurred at the MTD, and “no renal, hematological, hepatic, or pulmonary toxicities were noted using the MTD in this trial,” Dr. Morgan said.
 

Mechanism

DM-CHOC-PEN is a polychlorinated pyridine with a cholesteryl carbonate attachment that induces lipophilicity, which potentiates the drug’s penetration of the blood-brain barrier and its entry into the brain and brain cancers, Dr. Morgan explained.

He added that DM-CHOC-PEN is a bis-alkylator that binds to DNA’s cytosine/guanine nucleotides. The agent does not require hepatic activation, it crosses the blood-brain barrier intact, and accumulates in CNS tumors but not normal CNS tissue, he said.

Further, it “is not a substrate for [p-glycoprotein] transport; thus, it doesn’t easily get out of the brain,” Dr. Morgan said. He noted that DM-CHOC-PEN can be used with other agents, such as temozolomide and bis-chloroethylnitrosourea, because of the difference in mechanisms of action.

This study was supported by Louisiana state grants, the National Cancer Institute, the National Institute of General Medical Sciences, and the Small Business Innovation Research program. Dr. Morgan reported having no disclosures, but he is chief executive officer of Dekk-Tec Inc., which is developing DM-CHOC-PEN.

sworcester@mdedge.com

SOURCE: Morgan L et al. AACR 2020, Abstract CT181.

A successful vaccine for prevention of SARS-CoV-2 infection will probably need to incorporate T-cell epitopes to induce a long-term memory T-cell immune response to the virus, Mehrdad Matloubian, MD, PhD, predicted at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

Vaccine-induced neutralizing antibodies may not be sufficient to reliably provide sustained protection against infection. In mouse studies, T-cell immunity has protected against reinfection with the novel coronaviruses. And in some but not all studies of patients infected with the SARS virus, which shares 80% genetic overlap with the SARS-CoV-2 virus responsible for the COVID-19 pandemic, neutralizing antibodies have waned over time.

“In one study, 20 of 26 patients with SARS had lost their antibody response by 6 years post infection. And they had no B-cell immunity against the SARS antigens. The good news is they did have T-cell memory against SARS virus, and people with more severe disease tended to have more T-cell memory against SARS. All of this has really important implications for vaccine development,” observed Dr. Matloubian, a rheumatologist at the University of California, San Francisco.

Dr. Matloubian is among those who are convinced that the ongoing massive global accelerated effort to develop a safe and effective vaccine affords the best opportunity to gain the upper hand in the COVID-19 pandemic. A large array of vaccines are in development.

A key safety concern to watch for in the coming months is whether a vaccine candidate is able to sidestep the issue of antibody-dependent enhancement, whereby prior infection with a non-SARS coronavirus, such as those that cause the common cold, might result in creation of rogue subneutralizing coronavirus antibodies in response to vaccination. There is concern that these nonneutralizing antibodies could facilitate entry of the virus into monocytes and other cells lacking the ACE2 receptor, its usual portal of entry. This in turn could trigger expanded viral replication, a hyperinflammatory response, and viral spread to sites beyond the lung, such as the heart or kidneys.
 

Little optimism about antivirals’ impact

Dr. Matloubian predicted that antiviral medications, including the much-ballyhooed remdesivir, are unlikely to be a game changer in the COVID-19 pandemic. That’s because most patients who become symptomatic don’t do so until at least 2 days post infection. By that point, their viral load has already peaked and is waning and the B- and T-cell immune responses are starting to gear up.

“Timing seems to be everything when it comes to treatment with antivirals,” he observed. “The virus titer is usually declining by the time people present with severe COVID-19, suggesting that at this time antiviral therapy might be of little use to change the course of the disease, especially if it’s mainly immune-mediated by then. Even with influenza virus, there’s a really short window where Tamiflu [oseltamivir] is effective. It’s going to be the same case for antivirals used for treatment of COVID-19.”

He noted that in a placebo-controlled, randomized trial of remdesivir in 236 Chinese patients with severe COVID-19, intravenous remdesivir wasn’t associated with a significantly shorter time to clinical improvement, although there was a trend in that direction in the subgroup with symptom duration of 10 days or less at initiation of treatment.

A National Institutes of Health press release announcing that remdesivir had a positive impact on duration of hospitalization in a separate randomized trial drew enormous attention from a public desperate for good news. However, the full study has yet to be published, and it’s unclear when during the disease course the antiviral agent was started.

“We need a blockbuster antiviral that’s oral, highly effective, and doesn’t have any side effects to be used in prophylaxis of health care workers and for people who are exposed by family members being infected. And so far there is no such thing, even on the horizon,” according to the rheumatologist.

Fellow panelist Jinoos Yazdany, MD, concurred.

“As we talk to experts around the country, it seems like there isn’t very much optimism about such a blockbuster drug. Most people are actually putting their hope in a vaccine,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.

Another research priority is identification of biomarkers in blood or bronchoalveolar lavage fluid to identify early on the subgroup of infected patients who are likely to crash and develop severe disease. That would permit a targeted approach to inhibition of the inflammatory pathways contributing to development of acute respiratory distress syndrome before this full-blown cytokine storm-like syndrome can occur. There is great interest in trying to achieve this by repurposing many biologic agents widely used by rheumatologists, including the interleukin-1 blocker anakinra (Kineret) and the IL-6 blocker tocilizumab (Actemra).

Dr. Matloubian reported having no financial conflicts of interest regarding his presentation.

bjancin@mdedge.com

A successful vaccine for prevention of SARS-CoV-2 infection will probably need to incorporate T-cell epitopes to induce a long-term memory T-cell immune response to the virus, Mehrdad Matloubian, MD, PhD, predicted at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

Vaccine-induced neutralizing antibodies may not be sufficient to reliably provide sustained protection against infection. In mouse studies, T-cell immunity has protected against reinfection with the novel coronaviruses. And in some but not all studies of patients infected with the SARS virus, which shares 80% genetic overlap with the SARS-CoV-2 virus responsible for the COVID-19 pandemic, neutralizing antibodies have waned over time.

“In one study, 20 of 26 patients with SARS had lost their antibody response by 6 years post infection. And they had no B-cell immunity against the SARS antigens. The good news is they did have T-cell memory against SARS virus, and people with more severe disease tended to have more T-cell memory against SARS. All of this has really important implications for vaccine development,” observed Dr. Matloubian, a rheumatologist at the University of California, San Francisco.

Dr. Matloubian is among those who are convinced that the ongoing massive global accelerated effort to develop a safe and effective vaccine affords the best opportunity to gain the upper hand in the COVID-19 pandemic. A large array of vaccines are in development.

A key safety concern to watch for in the coming months is whether a vaccine candidate is able to sidestep the issue of antibody-dependent enhancement, whereby prior infection with a non-SARS coronavirus, such as those that cause the common cold, might result in creation of rogue subneutralizing coronavirus antibodies in response to vaccination. There is concern that these nonneutralizing antibodies could facilitate entry of the virus into monocytes and other cells lacking the ACE2 receptor, its usual portal of entry. This in turn could trigger expanded viral replication, a hyperinflammatory response, and viral spread to sites beyond the lung, such as the heart or kidneys.
 

Little optimism about antivirals’ impact

Dr. Matloubian predicted that antiviral medications, including the much-ballyhooed remdesivir, are unlikely to be a game changer in the COVID-19 pandemic. That’s because most patients who become symptomatic don’t do so until at least 2 days post infection. By that point, their viral load has already peaked and is waning and the B- and T-cell immune responses are starting to gear up.

“Timing seems to be everything when it comes to treatment with antivirals,” he observed. “The virus titer is usually declining by the time people present with severe COVID-19, suggesting that at this time antiviral therapy might be of little use to change the course of the disease, especially if it’s mainly immune-mediated by then. Even with influenza virus, there’s a really short window where Tamiflu [oseltamivir] is effective. It’s going to be the same case for antivirals used for treatment of COVID-19.”

He noted that in a placebo-controlled, randomized trial of remdesivir in 236 Chinese patients with severe COVID-19, intravenous remdesivir wasn’t associated with a significantly shorter time to clinical improvement, although there was a trend in that direction in the subgroup with symptom duration of 10 days or less at initiation of treatment.

A National Institutes of Health press release announcing that remdesivir had a positive impact on duration of hospitalization in a separate randomized trial drew enormous attention from a public desperate for good news. However, the full study has yet to be published, and it’s unclear when during the disease course the antiviral agent was started.

“We need a blockbuster antiviral that’s oral, highly effective, and doesn’t have any side effects to be used in prophylaxis of health care workers and for people who are exposed by family members being infected. And so far there is no such thing, even on the horizon,” according to the rheumatologist.

Fellow panelist Jinoos Yazdany, MD, concurred.

“As we talk to experts around the country, it seems like there isn’t very much optimism about such a blockbuster drug. Most people are actually putting their hope in a vaccine,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.

Another research priority is identification of biomarkers in blood or bronchoalveolar lavage fluid to identify early on the subgroup of infected patients who are likely to crash and develop severe disease. That would permit a targeted approach to inhibition of the inflammatory pathways contributing to development of acute respiratory distress syndrome before this full-blown cytokine storm-like syndrome can occur. There is great interest in trying to achieve this by repurposing many biologic agents widely used by rheumatologists, including the interleukin-1 blocker anakinra (Kineret) and the IL-6 blocker tocilizumab (Actemra).

Dr. Matloubian reported having no financial conflicts of interest regarding his presentation.

bjancin@mdedge.com

A successful vaccine for prevention of SARS-CoV-2 infection will probably need to incorporate T-cell epitopes to induce a long-term memory T-cell immune response to the virus, Mehrdad Matloubian, MD, PhD, predicted at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.

Vaccine-induced neutralizing antibodies may not be sufficient to reliably provide sustained protection against infection. In mouse studies, T-cell immunity has protected against reinfection with the novel coronaviruses. And in some but not all studies of patients infected with the SARS virus, which shares 80% genetic overlap with the SARS-CoV-2 virus responsible for the COVID-19 pandemic, neutralizing antibodies have waned over time.

“In one study, 20 of 26 patients with SARS had lost their antibody response by 6 years post infection. And they had no B-cell immunity against the SARS antigens. The good news is they did have T-cell memory against SARS virus, and people with more severe disease tended to have more T-cell memory against SARS. All of this has really important implications for vaccine development,” observed Dr. Matloubian, a rheumatologist at the University of California, San Francisco.

Dr. Matloubian is among those who are convinced that the ongoing massive global accelerated effort to develop a safe and effective vaccine affords the best opportunity to gain the upper hand in the COVID-19 pandemic. A large array of vaccines are in development.

A key safety concern to watch for in the coming months is whether a vaccine candidate is able to sidestep the issue of antibody-dependent enhancement, whereby prior infection with a non-SARS coronavirus, such as those that cause the common cold, might result in creation of rogue subneutralizing coronavirus antibodies in response to vaccination. There is concern that these nonneutralizing antibodies could facilitate entry of the virus into monocytes and other cells lacking the ACE2 receptor, its usual portal of entry. This in turn could trigger expanded viral replication, a hyperinflammatory response, and viral spread to sites beyond the lung, such as the heart or kidneys.
 

Little optimism about antivirals’ impact

Dr. Matloubian predicted that antiviral medications, including the much-ballyhooed remdesivir, are unlikely to be a game changer in the COVID-19 pandemic. That’s because most patients who become symptomatic don’t do so until at least 2 days post infection. By that point, their viral load has already peaked and is waning and the B- and T-cell immune responses are starting to gear up.

“Timing seems to be everything when it comes to treatment with antivirals,” he observed. “The virus titer is usually declining by the time people present with severe COVID-19, suggesting that at this time antiviral therapy might be of little use to change the course of the disease, especially if it’s mainly immune-mediated by then. Even with influenza virus, there’s a really short window where Tamiflu [oseltamivir] is effective. It’s going to be the same case for antivirals used for treatment of COVID-19.”

He noted that in a placebo-controlled, randomized trial of remdesivir in 236 Chinese patients with severe COVID-19, intravenous remdesivir wasn’t associated with a significantly shorter time to clinical improvement, although there was a trend in that direction in the subgroup with symptom duration of 10 days or less at initiation of treatment.

A National Institutes of Health press release announcing that remdesivir had a positive impact on duration of hospitalization in a separate randomized trial drew enormous attention from a public desperate for good news. However, the full study has yet to be published, and it’s unclear when during the disease course the antiviral agent was started.

“We need a blockbuster antiviral that’s oral, highly effective, and doesn’t have any side effects to be used in prophylaxis of health care workers and for people who are exposed by family members being infected. And so far there is no such thing, even on the horizon,” according to the rheumatologist.

Fellow panelist Jinoos Yazdany, MD, concurred.

“As we talk to experts around the country, it seems like there isn’t very much optimism about such a blockbuster drug. Most people are actually putting their hope in a vaccine,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.

Another research priority is identification of biomarkers in blood or bronchoalveolar lavage fluid to identify early on the subgroup of infected patients who are likely to crash and develop severe disease. That would permit a targeted approach to inhibition of the inflammatory pathways contributing to development of acute respiratory distress syndrome before this full-blown cytokine storm-like syndrome can occur. There is great interest in trying to achieve this by repurposing many biologic agents widely used by rheumatologists, including the interleukin-1 blocker anakinra (Kineret) and the IL-6 blocker tocilizumab (Actemra).

Dr. Matloubian reported having no financial conflicts of interest regarding his presentation.

bjancin@mdedge.com

No restriction of oral food intake prior to nonemergent cardiac catheterization is as safe as the current traditional NPO [nothing by mouth] strategy, results from a large, single-center, randomized controlled trial showed.

According to lead investigator Abhishek Mishra, MD, NPO after midnight has been a standard practice before major surgery requiring general anesthesia since Mendelson Syndrome was first described in 1946. “The rational for keeping NPO after midnight has been to keep the stomach empty, to reduce gastric contents and acidity – which would reduce emesis – and eventually reduce the risk of aspiration,” Dr. Mishra, a cardiologist at the Heart and Vascular Institute at Vidant Health in Greenville, N.C., said at the at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions. “The rationale of NPO in the setting of cardiac catheterization is to reduce the risk of aspiration, and more so, of a patient needing emergent cardiac surgery.” The clinical question was, do we really need to keep our patients NPO prior to elective cardiac catheterization? So far, no large randomized study has been done to answer this question.”

To find out, Dr. Mishra and colleagues carried out CHOW NOW (Can We Safely Have Our Patients Eat With Cardiac Catheterization – Nix or Allow), a single-center, prospective, randomized, single-blinded study that compared the safety of a nonfasting strategy with the current fasting protocol strategies in 599 patients who underwent nonemergent cardiac catheterization at The Guthrie Clinic/Robert Packer Hospital in Sayre, Pa.

Patients in the fasting group were instructed to be NPO after midnight, but could have clear liquids up to 2 hours prior to the procedure, while those in the nonfasting group had no restriction of oral intake, irrespective of time of cardiac catheterization. The primary outcome was a composite of aspiration pneumonia, preprocedural hypertension, preprocedural hypoglycemia or hyperglycemia, incidence of nausea/vomiting, and contrast-induced neuropathy. Secondary outcomes included total cost of the index hospitalization, patient satisfaction via a questionnaire containing seven questions, and in-hospital mortality.

Of the 599 patients, 306 were assigned to the standard fasting group and the remaining 293 to the nonfasting group. Their mean age was 67 years, 45% were on a proton pump inhibitor or H2 blockers, and 33% had diabetes. In addition, 40% had acute coronary syndrome, and 23% underwent percutaneous intervention.

The researchers observed no statistically significant difference in the primary or secondary outcomes between the study groups. In the nonfasting group, 11.3% of patients met the primary endpoint, compared with 9.8% of the patients in the standard fasting group (P = .65). In addition, the nonfasting strategy was found to be noninferior to the standard fasting strategy for the primary outcome at a noninferiority margin threshold of 0.059.

Dr. Mishra and colleagues observed no differences between the standard fasting and nonfasting groups with respect to in-hospital mortality (0.3% vs. 0.7%, respectively; P = .616), patient satisfaction score (a mean of 4.4 vs. a mean of 4.5; P = .257), and mean total cost of hospitalization ($8,446 vs. $6,960; P = .654).

“In this randomized, controlled trial, we found that there was no significant difference in the rate of overall adverse events with an approach of unrestricted oral intake prior to cardiac catheterization compared to strict fasting, and it was associated with better patient satisfaction and lower cost of care, especially for hospitalized patients,” concluded Dr. Mishra, who conducted the research during his fellowship at The Guthrie Clinic.

He acknowledged certain limitations of the trial, including the fact that results are applicable only to cardiac catheterization procedures, including coronary angiographies, percutaneous coronary interventions, and left heart catheterizations. “These results are not applicable to certain high-risk coronary procedures that required the use of a large-bore access or any valve procedures,” he said.

One of the session’s invited panelists, Cindy L. Grines, MD,, said that she and other interventional cardiologists have “gone around and around” on the issue of NPO prior to nonemergent cardiac catheterization. “I actually let my patients get fluids up until the time they’re put on the cath lab table,” said Dr. Grines, chief scientific officer of the Northside Cardiovascular Institute in Atlanta. “I haven’t been giving them solid food like this, though.”

Another panelist, Timothy D. Henry, MD, said that in his clinical experience, “patients don’t like being NPO, and I think we’ve all seen cases where patients are actually volume-depleted in the morning.” Dr. Henry, medical director of The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital in Cincinnati, pointed out that most NPO policy “is not dictated by us as interventional cardiologists; it’s dictated by hospital policies or by anesthesiologists. Will [the results of this study] change what we do?”

The Donald Guthrie Research Foundation funded the study. Daniel P. Sporn, MD, FACC, was the study’s principal investigator. Dr. Mishra reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Mishra A et al., SCAI 2020, abstract 11758.

No restriction of oral food intake prior to nonemergent cardiac catheterization is as safe as the current traditional NPO [nothing by mouth] strategy, results from a large, single-center, randomized controlled trial showed.

According to lead investigator Abhishek Mishra, MD, NPO after midnight has been a standard practice before major surgery requiring general anesthesia since Mendelson Syndrome was first described in 1946. “The rational for keeping NPO after midnight has been to keep the stomach empty, to reduce gastric contents and acidity – which would reduce emesis – and eventually reduce the risk of aspiration,” Dr. Mishra, a cardiologist at the Heart and Vascular Institute at Vidant Health in Greenville, N.C., said at the at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions. “The rationale of NPO in the setting of cardiac catheterization is to reduce the risk of aspiration, and more so, of a patient needing emergent cardiac surgery.” The clinical question was, do we really need to keep our patients NPO prior to elective cardiac catheterization? So far, no large randomized study has been done to answer this question.”

To find out, Dr. Mishra and colleagues carried out CHOW NOW (Can We Safely Have Our Patients Eat With Cardiac Catheterization – Nix or Allow), a single-center, prospective, randomized, single-blinded study that compared the safety of a nonfasting strategy with the current fasting protocol strategies in 599 patients who underwent nonemergent cardiac catheterization at The Guthrie Clinic/Robert Packer Hospital in Sayre, Pa.

Patients in the fasting group were instructed to be NPO after midnight, but could have clear liquids up to 2 hours prior to the procedure, while those in the nonfasting group had no restriction of oral intake, irrespective of time of cardiac catheterization. The primary outcome was a composite of aspiration pneumonia, preprocedural hypertension, preprocedural hypoglycemia or hyperglycemia, incidence of nausea/vomiting, and contrast-induced neuropathy. Secondary outcomes included total cost of the index hospitalization, patient satisfaction via a questionnaire containing seven questions, and in-hospital mortality.

Of the 599 patients, 306 were assigned to the standard fasting group and the remaining 293 to the nonfasting group. Their mean age was 67 years, 45% were on a proton pump inhibitor or H2 blockers, and 33% had diabetes. In addition, 40% had acute coronary syndrome, and 23% underwent percutaneous intervention.

The researchers observed no statistically significant difference in the primary or secondary outcomes between the study groups. In the nonfasting group, 11.3% of patients met the primary endpoint, compared with 9.8% of the patients in the standard fasting group (P = .65). In addition, the nonfasting strategy was found to be noninferior to the standard fasting strategy for the primary outcome at a noninferiority margin threshold of 0.059.

Dr. Mishra and colleagues observed no differences between the standard fasting and nonfasting groups with respect to in-hospital mortality (0.3% vs. 0.7%, respectively; P = .616), patient satisfaction score (a mean of 4.4 vs. a mean of 4.5; P = .257), and mean total cost of hospitalization ($8,446 vs. $6,960; P = .654).

“In this randomized, controlled trial, we found that there was no significant difference in the rate of overall adverse events with an approach of unrestricted oral intake prior to cardiac catheterization compared to strict fasting, and it was associated with better patient satisfaction and lower cost of care, especially for hospitalized patients,” concluded Dr. Mishra, who conducted the research during his fellowship at The Guthrie Clinic.

He acknowledged certain limitations of the trial, including the fact that results are applicable only to cardiac catheterization procedures, including coronary angiographies, percutaneous coronary interventions, and left heart catheterizations. “These results are not applicable to certain high-risk coronary procedures that required the use of a large-bore access or any valve procedures,” he said.

One of the session’s invited panelists, Cindy L. Grines, MD,, said that she and other interventional cardiologists have “gone around and around” on the issue of NPO prior to nonemergent cardiac catheterization. “I actually let my patients get fluids up until the time they’re put on the cath lab table,” said Dr. Grines, chief scientific officer of the Northside Cardiovascular Institute in Atlanta. “I haven’t been giving them solid food like this, though.”

Another panelist, Timothy D. Henry, MD, said that in his clinical experience, “patients don’t like being NPO, and I think we’ve all seen cases where patients are actually volume-depleted in the morning.” Dr. Henry, medical director of The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital in Cincinnati, pointed out that most NPO policy “is not dictated by us as interventional cardiologists; it’s dictated by hospital policies or by anesthesiologists. Will [the results of this study] change what we do?”

The Donald Guthrie Research Foundation funded the study. Daniel P. Sporn, MD, FACC, was the study’s principal investigator. Dr. Mishra reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Mishra A et al., SCAI 2020, abstract 11758.

No restriction of oral food intake prior to nonemergent cardiac catheterization is as safe as the current traditional NPO [nothing by mouth] strategy, results from a large, single-center, randomized controlled trial showed.

According to lead investigator Abhishek Mishra, MD, NPO after midnight has been a standard practice before major surgery requiring general anesthesia since Mendelson Syndrome was first described in 1946. “The rational for keeping NPO after midnight has been to keep the stomach empty, to reduce gastric contents and acidity – which would reduce emesis – and eventually reduce the risk of aspiration,” Dr. Mishra, a cardiologist at the Heart and Vascular Institute at Vidant Health in Greenville, N.C., said at the at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions. “The rationale of NPO in the setting of cardiac catheterization is to reduce the risk of aspiration, and more so, of a patient needing emergent cardiac surgery.” The clinical question was, do we really need to keep our patients NPO prior to elective cardiac catheterization? So far, no large randomized study has been done to answer this question.”

To find out, Dr. Mishra and colleagues carried out CHOW NOW (Can We Safely Have Our Patients Eat With Cardiac Catheterization – Nix or Allow), a single-center, prospective, randomized, single-blinded study that compared the safety of a nonfasting strategy with the current fasting protocol strategies in 599 patients who underwent nonemergent cardiac catheterization at The Guthrie Clinic/Robert Packer Hospital in Sayre, Pa.

Patients in the fasting group were instructed to be NPO after midnight, but could have clear liquids up to 2 hours prior to the procedure, while those in the nonfasting group had no restriction of oral intake, irrespective of time of cardiac catheterization. The primary outcome was a composite of aspiration pneumonia, preprocedural hypertension, preprocedural hypoglycemia or hyperglycemia, incidence of nausea/vomiting, and contrast-induced neuropathy. Secondary outcomes included total cost of the index hospitalization, patient satisfaction via a questionnaire containing seven questions, and in-hospital mortality.

Of the 599 patients, 306 were assigned to the standard fasting group and the remaining 293 to the nonfasting group. Their mean age was 67 years, 45% were on a proton pump inhibitor or H2 blockers, and 33% had diabetes. In addition, 40% had acute coronary syndrome, and 23% underwent percutaneous intervention.

The researchers observed no statistically significant difference in the primary or secondary outcomes between the study groups. In the nonfasting group, 11.3% of patients met the primary endpoint, compared with 9.8% of the patients in the standard fasting group (P = .65). In addition, the nonfasting strategy was found to be noninferior to the standard fasting strategy for the primary outcome at a noninferiority margin threshold of 0.059.

Dr. Mishra and colleagues observed no differences between the standard fasting and nonfasting groups with respect to in-hospital mortality (0.3% vs. 0.7%, respectively; P = .616), patient satisfaction score (a mean of 4.4 vs. a mean of 4.5; P = .257), and mean total cost of hospitalization ($8,446 vs. $6,960; P = .654).

“In this randomized, controlled trial, we found that there was no significant difference in the rate of overall adverse events with an approach of unrestricted oral intake prior to cardiac catheterization compared to strict fasting, and it was associated with better patient satisfaction and lower cost of care, especially for hospitalized patients,” concluded Dr. Mishra, who conducted the research during his fellowship at The Guthrie Clinic.

He acknowledged certain limitations of the trial, including the fact that results are applicable only to cardiac catheterization procedures, including coronary angiographies, percutaneous coronary interventions, and left heart catheterizations. “These results are not applicable to certain high-risk coronary procedures that required the use of a large-bore access or any valve procedures,” he said.

One of the session’s invited panelists, Cindy L. Grines, MD,, said that she and other interventional cardiologists have “gone around and around” on the issue of NPO prior to nonemergent cardiac catheterization. “I actually let my patients get fluids up until the time they’re put on the cath lab table,” said Dr. Grines, chief scientific officer of the Northside Cardiovascular Institute in Atlanta. “I haven’t been giving them solid food like this, though.”

Another panelist, Timothy D. Henry, MD, said that in his clinical experience, “patients don’t like being NPO, and I think we’ve all seen cases where patients are actually volume-depleted in the morning.” Dr. Henry, medical director of The Carl and Edyth Lindner Center for Research and Education at The Christ Hospital in Cincinnati, pointed out that most NPO policy “is not dictated by us as interventional cardiologists; it’s dictated by hospital policies or by anesthesiologists. Will [the results of this study] change what we do?”

The Donald Guthrie Research Foundation funded the study. Daniel P. Sporn, MD, FACC, was the study’s principal investigator. Dr. Mishra reported having no financial disclosures.

dbrunk@mdedge.com

SOURCE: Mishra A et al., SCAI 2020, abstract 11758.

Combination therapy with relugolix, an investigational oral gonadotropin-releasing hormone antagonist, estradiol, and norethindrone acetate effectively preserved bone mineral density (BMD) in two replicate phase 3 studies enrolling women with heavy menstrual bleeding associated with uterine fibroids.

The BMD findings, released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists, build upon previously reported positive primary endpoint data from the LIBERTY 1 and LIBERTY 2 studies. ACOG canceled the meeting and released abstracts for press coverage.

The developer of the drug, Myovant Sciences, plans to submit a new drug application to the Food and Drug Administration for approval of the single-tablet combination therapy for women with uterine fibroids, according to Albert Liao, the company’s director of corporate communications.

The two multinational LIBERTY studies randomized women who had a monthly menstrual blood loss volume of at least 80 mL in two consecutive cycles (or 160 mL in one cycle) in a 1:1:1 ratio to one of three groups: relugolix combination therapy for 24 weeks (once-daily relugolix 40 mg plus estradiol 1.0 mg plus norethindrone acetate 0.5 mg); relugolix alone (40 mg once daily) for 12 weeks followed by relugolix combination therapy for 12 weeks; or placebo for 24 weeks.

In October 2019 at the American Society for Reproductive Medicine Scientific Congress, investigators reported that 73% of women receiving combination therapy in the LIBERTY 1 trial achieved a menstrual blood loss of less than 80 mL and a 50% or greater reduction from baseline over the last 35 days of treatment, compared with 19% in the placebo group. The mean percent reduction in menstrual blood loss from baseline at week 24 was 84% for combination therapy and 23% for placebo.

Earlier in 2019, Myovant Sciences announced that, in the LIBERTY 2 study, 71% of women receiving combination therapy met the primary endpoints, compared with 15% in the placebo group. The reduction in menstrual blood loss in this study’s combination therapy arm was also 84%, according to a company press release from June 2019.

Each of the two clinical trials enrolled upwards of 380 women.

The new abstract released for press coverage by ACOG and published in Obstetrics & Gynecology reports that women receiving relugolix combination therapy in the LIBERTY 1 and LIBERTY 2 studies had a mean change in lumbar spine BMD of –0.36% and –0.13%, respectively, from baseline to 24 weeks. Percent change in lumbar spine BMD in the delayed combination therapy groups (12 initial weeks of relugolix monotherapy) was –1.82% and –2.12%. In the placebo groups, the change was 0.05% and 0.32%.

Michael R. McClung, MD, who is the lead author of the abstract and was scheduled to present the findings at the ACOG meeting, said in an interview that the slight decreases in lumbar spine BMD with combination therapy were noted largely at week 12 and are “clinically insignificant in my opinion.” BMD by dual-energy x-ray absorptiometry was assessed at weeks 12 and 24.

“There was no further increase [after week 12] and [in some patients] there was even a return to baseline,” said Dr. McClung, of the Oregon Osteoporosis Center in Portland.

The safety and efficacy of longer-term treatment with relugolix combination therapy has been investigated thus far through an open-label extension study that brought the treatment period to 52 weeks. The 1-year data has been positive and will be presented or published soon, said Mr. Liao. In addition, a “second, 52-week randomized withdrawal study has been designed to provide 2-year safety and efficacy data … and to evaluate the need for maintenance therapy.”

It’s important, Dr. McClung said, “for clinicians to be confident that BMD loss is prevented or minimized with longer-term relugolix combination therapy since treatment for uterine fibroids is not a short-term proposition. Given the stability of BMD values between weeks 12 and 24 in the LIBERTY studies, I’d anticipate that we will see stable values with longer-term treatment.”

Dr. McClung disclosed that he has served as a consultant/advisory board member and speaker for Amgen and a consultant/advisory board member for Myovant. Several of his coauthors disclosed employment and ownerships interests in Myovant.

SOURCE: McClung MR et al. Obstet Gynecol. 2020 May. doi: 10.1097/01.AOG.0000662944.34860.b4.

Combination therapy with relugolix, an investigational oral gonadotropin-releasing hormone antagonist, estradiol, and norethindrone acetate effectively preserved bone mineral density (BMD) in two replicate phase 3 studies enrolling women with heavy menstrual bleeding associated with uterine fibroids.

The BMD findings, released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists, build upon previously reported positive primary endpoint data from the LIBERTY 1 and LIBERTY 2 studies. ACOG canceled the meeting and released abstracts for press coverage.

The developer of the drug, Myovant Sciences, plans to submit a new drug application to the Food and Drug Administration for approval of the single-tablet combination therapy for women with uterine fibroids, according to Albert Liao, the company’s director of corporate communications.

The two multinational LIBERTY studies randomized women who had a monthly menstrual blood loss volume of at least 80 mL in two consecutive cycles (or 160 mL in one cycle) in a 1:1:1 ratio to one of three groups: relugolix combination therapy for 24 weeks (once-daily relugolix 40 mg plus estradiol 1.0 mg plus norethindrone acetate 0.5 mg); relugolix alone (40 mg once daily) for 12 weeks followed by relugolix combination therapy for 12 weeks; or placebo for 24 weeks.

In October 2019 at the American Society for Reproductive Medicine Scientific Congress, investigators reported that 73% of women receiving combination therapy in the LIBERTY 1 trial achieved a menstrual blood loss of less than 80 mL and a 50% or greater reduction from baseline over the last 35 days of treatment, compared with 19% in the placebo group. The mean percent reduction in menstrual blood loss from baseline at week 24 was 84% for combination therapy and 23% for placebo.

Earlier in 2019, Myovant Sciences announced that, in the LIBERTY 2 study, 71% of women receiving combination therapy met the primary endpoints, compared with 15% in the placebo group. The reduction in menstrual blood loss in this study’s combination therapy arm was also 84%, according to a company press release from June 2019.

Each of the two clinical trials enrolled upwards of 380 women.

The new abstract released for press coverage by ACOG and published in Obstetrics & Gynecology reports that women receiving relugolix combination therapy in the LIBERTY 1 and LIBERTY 2 studies had a mean change in lumbar spine BMD of –0.36% and –0.13%, respectively, from baseline to 24 weeks. Percent change in lumbar spine BMD in the delayed combination therapy groups (12 initial weeks of relugolix monotherapy) was –1.82% and –2.12%. In the placebo groups, the change was 0.05% and 0.32%.

Michael R. McClung, MD, who is the lead author of the abstract and was scheduled to present the findings at the ACOG meeting, said in an interview that the slight decreases in lumbar spine BMD with combination therapy were noted largely at week 12 and are “clinically insignificant in my opinion.” BMD by dual-energy x-ray absorptiometry was assessed at weeks 12 and 24.

“There was no further increase [after week 12] and [in some patients] there was even a return to baseline,” said Dr. McClung, of the Oregon Osteoporosis Center in Portland.

The safety and efficacy of longer-term treatment with relugolix combination therapy has been investigated thus far through an open-label extension study that brought the treatment period to 52 weeks. The 1-year data has been positive and will be presented or published soon, said Mr. Liao. In addition, a “second, 52-week randomized withdrawal study has been designed to provide 2-year safety and efficacy data … and to evaluate the need for maintenance therapy.”

It’s important, Dr. McClung said, “for clinicians to be confident that BMD loss is prevented or minimized with longer-term relugolix combination therapy since treatment for uterine fibroids is not a short-term proposition. Given the stability of BMD values between weeks 12 and 24 in the LIBERTY studies, I’d anticipate that we will see stable values with longer-term treatment.”

Dr. McClung disclosed that he has served as a consultant/advisory board member and speaker for Amgen and a consultant/advisory board member for Myovant. Several of his coauthors disclosed employment and ownerships interests in Myovant.

SOURCE: McClung MR et al. Obstet Gynecol. 2020 May. doi: 10.1097/01.AOG.0000662944.34860.b4.

Combination therapy with relugolix, an investigational oral gonadotropin-releasing hormone antagonist, estradiol, and norethindrone acetate effectively preserved bone mineral density (BMD) in two replicate phase 3 studies enrolling women with heavy menstrual bleeding associated with uterine fibroids.

The BMD findings, released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists, build upon previously reported positive primary endpoint data from the LIBERTY 1 and LIBERTY 2 studies. ACOG canceled the meeting and released abstracts for press coverage.

The developer of the drug, Myovant Sciences, plans to submit a new drug application to the Food and Drug Administration for approval of the single-tablet combination therapy for women with uterine fibroids, according to Albert Liao, the company’s director of corporate communications.

The two multinational LIBERTY studies randomized women who had a monthly menstrual blood loss volume of at least 80 mL in two consecutive cycles (or 160 mL in one cycle) in a 1:1:1 ratio to one of three groups: relugolix combination therapy for 24 weeks (once-daily relugolix 40 mg plus estradiol 1.0 mg plus norethindrone acetate 0.5 mg); relugolix alone (40 mg once daily) for 12 weeks followed by relugolix combination therapy for 12 weeks; or placebo for 24 weeks.

In October 2019 at the American Society for Reproductive Medicine Scientific Congress, investigators reported that 73% of women receiving combination therapy in the LIBERTY 1 trial achieved a menstrual blood loss of less than 80 mL and a 50% or greater reduction from baseline over the last 35 days of treatment, compared with 19% in the placebo group. The mean percent reduction in menstrual blood loss from baseline at week 24 was 84% for combination therapy and 23% for placebo.

Earlier in 2019, Myovant Sciences announced that, in the LIBERTY 2 study, 71% of women receiving combination therapy met the primary endpoints, compared with 15% in the placebo group. The reduction in menstrual blood loss in this study’s combination therapy arm was also 84%, according to a company press release from June 2019.

Each of the two clinical trials enrolled upwards of 380 women.

The new abstract released for press coverage by ACOG and published in Obstetrics & Gynecology reports that women receiving relugolix combination therapy in the LIBERTY 1 and LIBERTY 2 studies had a mean change in lumbar spine BMD of –0.36% and –0.13%, respectively, from baseline to 24 weeks. Percent change in lumbar spine BMD in the delayed combination therapy groups (12 initial weeks of relugolix monotherapy) was –1.82% and –2.12%. In the placebo groups, the change was 0.05% and 0.32%.

Michael R. McClung, MD, who is the lead author of the abstract and was scheduled to present the findings at the ACOG meeting, said in an interview that the slight decreases in lumbar spine BMD with combination therapy were noted largely at week 12 and are “clinically insignificant in my opinion.” BMD by dual-energy x-ray absorptiometry was assessed at weeks 12 and 24.

“There was no further increase [after week 12] and [in some patients] there was even a return to baseline,” said Dr. McClung, of the Oregon Osteoporosis Center in Portland.

The safety and efficacy of longer-term treatment with relugolix combination therapy has been investigated thus far through an open-label extension study that brought the treatment period to 52 weeks. The 1-year data has been positive and will be presented or published soon, said Mr. Liao. In addition, a “second, 52-week randomized withdrawal study has been designed to provide 2-year safety and efficacy data … and to evaluate the need for maintenance therapy.”

It’s important, Dr. McClung said, “for clinicians to be confident that BMD loss is prevented or minimized with longer-term relugolix combination therapy since treatment for uterine fibroids is not a short-term proposition. Given the stability of BMD values between weeks 12 and 24 in the LIBERTY studies, I’d anticipate that we will see stable values with longer-term treatment.”

Dr. McClung disclosed that he has served as a consultant/advisory board member and speaker for Amgen and a consultant/advisory board member for Myovant. Several of his coauthors disclosed employment and ownerships interests in Myovant.

SOURCE: McClung MR et al. Obstet Gynecol. 2020 May. doi: 10.1097/01.AOG.0000662944.34860.b4.

Use of testicular sperm in nonazoospermic couples who had prior in vitro fertilization failure using ejaculated sperm appears to improve embryo development and rates of clinical pregnancy and live birth, a retrospective observational study has found.

©ktsimage/iStockphoto.com

The findings were released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. ACOG canceled the meeting and released abstracts for press coverage.

The study, which won the college’s Donald F. Richardson Memorial Prize Research Paper award, evaluated 112 nonazoospermic couples with an average of 2.3 failed in vitro fertilization (IVF) cycles (range of 1-8). The couples, patients at Shade Grove Fertility in Washington, underwent 157 total intracytoplasmic sperm injection (ICSI) cycles (133 using fresh testicular sperm and 24 using frozen/thawed sperm) and had a total of 101 embryo transfers.

Use of ICSI with testicular sperm compared with prior cycles using ejaculated sperm significantly improved blastocyst development (65% vs. 33%, P < .001), blastocyst conversion rates (67% vs. 35%, P < .001) and the number of embryos available for vitrification (1.6 vs. 0.7, P < .001). Fertilization rates were similar (70% vs. 58%). The clinical pregnancy and live birth rates in couples who used testicular sperm were 44% and 32%, respectively.

The findings suggest improved embryo development and pregnancy rates, and offer more evidence “that this might be something we can offer patients who’ve had multiple failures and no other reason as to why,” M. Blake Evans, DO, clinical fellow in reproductive endocrinology and infertility at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Md., said in a interview. “It looks like there is promise, and we need more research to be conducted.”

The integration of the use of testicular sperm at Shady Grove, a private practice fertility center, and the newly completed analysis of outcomes, were driven by studies “showing that testicular sperm has a low DNA fragmentation index and suggesting that it [offers a] better chance of successful IVF outcomes in patients who have had prior failures,” he said.

Almost all of the men who had ICSC using testicular sperm – 105 of the 112 – had a sperm DNA fragmentation (SDF) assessment of their ejaculate sperm. The mean SDF was 32% and of these 105 men, 66 had an SDF greater than 25% (mean of 49%), a value considered abnormal. The outcomes for patients with elevated SDF did not differ significantly from the overall cohort, Dr. Evans and coinvestigators reported in their abstract.

Dr. Evans said that it’s too early to draw any conclusions about the utility of SDF testing, and that the investigators plan to start prospectively evaluating whether levels of sperm DNA damage as reflected in SDF testing correlate with IVF outcomes.

“Right now the evidence is so conflicting as to whether [SDF testing offers] information that all IVF patients or infertility patients should be receiving,” he said. “Is the reason that testicular sperm works better because there’s lower DNA fragmentation? We think so. … But now that we see [that it] appears the outcomes are better [using testicular sperm], we need to take it a step further and look prospectively at the impact of DNA fragmentation, comparing all the outcomes with normal and abnormal DNA [levels].”

Mark P. Trolice, MD, director of Fertility CARE: The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando, said in an interview that while “there is increasing evidence – and rather clear evidence – that testicular sperm has less DNA damage,” there has been controversy over available outcomes data, most of which have come from small, retrospective studies. Dr. Trolice was not involved in this study presented at ACOG.

In the case of “very poor outcomes with use of ejaculated sperm and a high SDF index, there seems to be support for the use of testicular sperm on the next IVF cycle,” he said. “But there’s also evidence to support that there’s no significant difference in the outcomes of IUI [intrauterine insemination] or IVF based on the SDF index. So this [study] really took a tremendous leap of faith.”

Dr. Trolice said he looks forward to more research – ideally prospective, randomized studies of men with high SDF levels who proceed with assisted reproductive technologies using ejaculated or testicular sperm.

The research was supported by the division of intramural research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Evans did not report any relevant financial disclosures. One of his coinvestigators. Micah J. Hill, DO, disclosed having served on the advisory board of Ohana Biosciences. Dr. Trolice reported that he has no relevant financial disclosures. He is a member of the Ob.Gyn. News editorial advisory board.

The abstract was first presented by coauthor Lt. Allison A. Eubanks, MD, of Walter Reed National Military Medical Center, at the ACOG Armed Forces District Annual District Meeting in September 2019.

pdnews@mdedge.com

Use of testicular sperm in nonazoospermic couples who had prior in vitro fertilization failure using ejaculated sperm appears to improve embryo development and rates of clinical pregnancy and live birth, a retrospective observational study has found.

©ktsimage/iStockphoto.com

The findings were released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. ACOG canceled the meeting and released abstracts for press coverage.

The study, which won the college’s Donald F. Richardson Memorial Prize Research Paper award, evaluated 112 nonazoospermic couples with an average of 2.3 failed in vitro fertilization (IVF) cycles (range of 1-8). The couples, patients at Shade Grove Fertility in Washington, underwent 157 total intracytoplasmic sperm injection (ICSI) cycles (133 using fresh testicular sperm and 24 using frozen/thawed sperm) and had a total of 101 embryo transfers.

Use of ICSI with testicular sperm compared with prior cycles using ejaculated sperm significantly improved blastocyst development (65% vs. 33%, P < .001), blastocyst conversion rates (67% vs. 35%, P < .001) and the number of embryos available for vitrification (1.6 vs. 0.7, P < .001). Fertilization rates were similar (70% vs. 58%). The clinical pregnancy and live birth rates in couples who used testicular sperm were 44% and 32%, respectively.

The findings suggest improved embryo development and pregnancy rates, and offer more evidence “that this might be something we can offer patients who’ve had multiple failures and no other reason as to why,” M. Blake Evans, DO, clinical fellow in reproductive endocrinology and infertility at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Md., said in a interview. “It looks like there is promise, and we need more research to be conducted.”

The integration of the use of testicular sperm at Shady Grove, a private practice fertility center, and the newly completed analysis of outcomes, were driven by studies “showing that testicular sperm has a low DNA fragmentation index and suggesting that it [offers a] better chance of successful IVF outcomes in patients who have had prior failures,” he said.

Almost all of the men who had ICSC using testicular sperm – 105 of the 112 – had a sperm DNA fragmentation (SDF) assessment of their ejaculate sperm. The mean SDF was 32% and of these 105 men, 66 had an SDF greater than 25% (mean of 49%), a value considered abnormal. The outcomes for patients with elevated SDF did not differ significantly from the overall cohort, Dr. Evans and coinvestigators reported in their abstract.

Dr. Evans said that it’s too early to draw any conclusions about the utility of SDF testing, and that the investigators plan to start prospectively evaluating whether levels of sperm DNA damage as reflected in SDF testing correlate with IVF outcomes.

“Right now the evidence is so conflicting as to whether [SDF testing offers] information that all IVF patients or infertility patients should be receiving,” he said. “Is the reason that testicular sperm works better because there’s lower DNA fragmentation? We think so. … But now that we see [that it] appears the outcomes are better [using testicular sperm], we need to take it a step further and look prospectively at the impact of DNA fragmentation, comparing all the outcomes with normal and abnormal DNA [levels].”

Mark P. Trolice, MD, director of Fertility CARE: The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando, said in an interview that while “there is increasing evidence – and rather clear evidence – that testicular sperm has less DNA damage,” there has been controversy over available outcomes data, most of which have come from small, retrospective studies. Dr. Trolice was not involved in this study presented at ACOG.

In the case of “very poor outcomes with use of ejaculated sperm and a high SDF index, there seems to be support for the use of testicular sperm on the next IVF cycle,” he said. “But there’s also evidence to support that there’s no significant difference in the outcomes of IUI [intrauterine insemination] or IVF based on the SDF index. So this [study] really took a tremendous leap of faith.”

Dr. Trolice said he looks forward to more research – ideally prospective, randomized studies of men with high SDF levels who proceed with assisted reproductive technologies using ejaculated or testicular sperm.

The research was supported by the division of intramural research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Evans did not report any relevant financial disclosures. One of his coinvestigators. Micah J. Hill, DO, disclosed having served on the advisory board of Ohana Biosciences. Dr. Trolice reported that he has no relevant financial disclosures. He is a member of the Ob.Gyn. News editorial advisory board.

The abstract was first presented by coauthor Lt. Allison A. Eubanks, MD, of Walter Reed National Military Medical Center, at the ACOG Armed Forces District Annual District Meeting in September 2019.

pdnews@mdedge.com

Use of testicular sperm in nonazoospermic couples who had prior in vitro fertilization failure using ejaculated sperm appears to improve embryo development and rates of clinical pregnancy and live birth, a retrospective observational study has found.

©ktsimage/iStockphoto.com

The findings were released ahead of the study’s scheduled presentation at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists. ACOG canceled the meeting and released abstracts for press coverage.

The study, which won the college’s Donald F. Richardson Memorial Prize Research Paper award, evaluated 112 nonazoospermic couples with an average of 2.3 failed in vitro fertilization (IVF) cycles (range of 1-8). The couples, patients at Shade Grove Fertility in Washington, underwent 157 total intracytoplasmic sperm injection (ICSI) cycles (133 using fresh testicular sperm and 24 using frozen/thawed sperm) and had a total of 101 embryo transfers.

Use of ICSI with testicular sperm compared with prior cycles using ejaculated sperm significantly improved blastocyst development (65% vs. 33%, P < .001), blastocyst conversion rates (67% vs. 35%, P < .001) and the number of embryos available for vitrification (1.6 vs. 0.7, P < .001). Fertilization rates were similar (70% vs. 58%). The clinical pregnancy and live birth rates in couples who used testicular sperm were 44% and 32%, respectively.

The findings suggest improved embryo development and pregnancy rates, and offer more evidence “that this might be something we can offer patients who’ve had multiple failures and no other reason as to why,” M. Blake Evans, DO, clinical fellow in reproductive endocrinology and infertility at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Md., said in a interview. “It looks like there is promise, and we need more research to be conducted.”

The integration of the use of testicular sperm at Shady Grove, a private practice fertility center, and the newly completed analysis of outcomes, were driven by studies “showing that testicular sperm has a low DNA fragmentation index and suggesting that it [offers a] better chance of successful IVF outcomes in patients who have had prior failures,” he said.

Almost all of the men who had ICSC using testicular sperm – 105 of the 112 – had a sperm DNA fragmentation (SDF) assessment of their ejaculate sperm. The mean SDF was 32% and of these 105 men, 66 had an SDF greater than 25% (mean of 49%), a value considered abnormal. The outcomes for patients with elevated SDF did not differ significantly from the overall cohort, Dr. Evans and coinvestigators reported in their abstract.

Dr. Evans said that it’s too early to draw any conclusions about the utility of SDF testing, and that the investigators plan to start prospectively evaluating whether levels of sperm DNA damage as reflected in SDF testing correlate with IVF outcomes.

“Right now the evidence is so conflicting as to whether [SDF testing offers] information that all IVF patients or infertility patients should be receiving,” he said. “Is the reason that testicular sperm works better because there’s lower DNA fragmentation? We think so. … But now that we see [that it] appears the outcomes are better [using testicular sperm], we need to take it a step further and look prospectively at the impact of DNA fragmentation, comparing all the outcomes with normal and abnormal DNA [levels].”

Mark P. Trolice, MD, director of Fertility CARE: The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando, said in an interview that while “there is increasing evidence – and rather clear evidence – that testicular sperm has less DNA damage,” there has been controversy over available outcomes data, most of which have come from small, retrospective studies. Dr. Trolice was not involved in this study presented at ACOG.

In the case of “very poor outcomes with use of ejaculated sperm and a high SDF index, there seems to be support for the use of testicular sperm on the next IVF cycle,” he said. “But there’s also evidence to support that there’s no significant difference in the outcomes of IUI [intrauterine insemination] or IVF based on the SDF index. So this [study] really took a tremendous leap of faith.”

Dr. Trolice said he looks forward to more research – ideally prospective, randomized studies of men with high SDF levels who proceed with assisted reproductive technologies using ejaculated or testicular sperm.

The research was supported by the division of intramural research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr. Evans did not report any relevant financial disclosures. One of his coinvestigators. Micah J. Hill, DO, disclosed having served on the advisory board of Ohana Biosciences. Dr. Trolice reported that he has no relevant financial disclosures. He is a member of the Ob.Gyn. News editorial advisory board.

The abstract was first presented by coauthor Lt. Allison A. Eubanks, MD, of Walter Reed National Military Medical Center, at the ACOG Armed Forces District Annual District Meeting in September 2019.

pdnews@mdedge.com

Almost half of people presenting for low back pain to the Tufts University primary care clinic in Boston were not asked about inflammatory signs and symptoms, according to a review of 239 charts there by rheumatologists and rheumatology fellows.

©Wavebreakmedia Ltd/Thinkstock

In more than two-thirds of cases, the reviewers were unable to determine if patients had inflammatory back pain or not based on what was documented. When symptoms relevant to inflammation – such as improvement with movement – were documented, it wasn’t clear if providers were actually trying to solicit a history of inflammation or if they simply recorded what patients volunteered.

Spondyloarthritis was listed in the differential of just five charts (2%), and only eight (3.3%) documented considering a rheumatology referral.

It raises the possibility that, in at least some cases, an opportunity to diagnose and treat spondyloarthritis early was missed. It’s a known problem in the literature; previous studies report a delay of 2-10 years before ankylosing spondylitis diagnosis.

“In our primary care practice, there appears to be poor awareness of inflammatory back pain [that] could lead to diagnostic delay,” said senior investigator and rheumatologist Steven Vlad, MD, PhD, an assistant professor at Tufts. Primary care providers are usually the first to see back pain patients, but they “did not seem to be screening for” inflammation, he said.

Dr. Vlad presented the study results at the virtual annual meeting of the Spondyloarthritis Research and Treatment Network. The meeting was held online this year because of the COVID-19 pandemic.

The findings suggest that a reminder to check for inflammation might be in order. Dr. Vlad and his colleagues have since held educational sessions, and plan to do more, with the idea of repeating the study in a year or 2 to see if the sessions made a difference.

“People take away what they learn as residents. We probably need to focus on resident education if we really want to make a dent in this,” he said.

The generalizability of the single-center results is unclear, and it’s possible at least in some cases that providers asked the right questions but did not document them in the chart. Even so, the issue “deserves future study in other populations,” Dr. Vlad said.

The subjects all had a diagnostic code for low back pain and were seen by Tuft’s primary care at least twice 3 or more months apart, which indicated chronic pain. Chart reviews included clinical notes, labs, imaging studies, and consultation reports. “We looked for specific documentation that primary care physicians had been asking questions related to inflammatory back pain,” Dr. Vlad explained.

Overall, 128 charts (53.6%) documented some feature of inflammatory low back pain. Insidious onset was the most common, but morning stiffness, a cardinal sign, was the least common, noted in only five charts (2%). About 30% of the subjects had a lumbar spine x-ray, which was the most common imaging study, followed by lumbar spine MRI. Only a handful had imaging of the sacroiliac joints.

In 111 charts (46.4%), there was no documentation that primary care providers had looked for inflammatory features or asked questions about them.

Patients were seen from Jan. 2016 to May 2018. The average age in the study was 37.6 years, and two-thirds of the subjects were women.

Funding source and disclosures weren’t reported.

aotto@mdedge.com

Almost half of people presenting for low back pain to the Tufts University primary care clinic in Boston were not asked about inflammatory signs and symptoms, according to a review of 239 charts there by rheumatologists and rheumatology fellows.

©Wavebreakmedia Ltd/Thinkstock

In more than two-thirds of cases, the reviewers were unable to determine if patients had inflammatory back pain or not based on what was documented. When symptoms relevant to inflammation – such as improvement with movement – were documented, it wasn’t clear if providers were actually trying to solicit a history of inflammation or if they simply recorded what patients volunteered.

Spondyloarthritis was listed in the differential of just five charts (2%), and only eight (3.3%) documented considering a rheumatology referral.

It raises the possibility that, in at least some cases, an opportunity to diagnose and treat spondyloarthritis early was missed. It’s a known problem in the literature; previous studies report a delay of 2-10 years before ankylosing spondylitis diagnosis.

“In our primary care practice, there appears to be poor awareness of inflammatory back pain [that] could lead to diagnostic delay,” said senior investigator and rheumatologist Steven Vlad, MD, PhD, an assistant professor at Tufts. Primary care providers are usually the first to see back pain patients, but they “did not seem to be screening for” inflammation, he said.

Dr. Vlad presented the study results at the virtual annual meeting of the Spondyloarthritis Research and Treatment Network. The meeting was held online this year because of the COVID-19 pandemic.

The findings suggest that a reminder to check for inflammation might be in order. Dr. Vlad and his colleagues have since held educational sessions, and plan to do more, with the idea of repeating the study in a year or 2 to see if the sessions made a difference.

“People take away what they learn as residents. We probably need to focus on resident education if we really want to make a dent in this,” he said.

The generalizability of the single-center results is unclear, and it’s possible at least in some cases that providers asked the right questions but did not document them in the chart. Even so, the issue “deserves future study in other populations,” Dr. Vlad said.

The subjects all had a diagnostic code for low back pain and were seen by Tuft’s primary care at least twice 3 or more months apart, which indicated chronic pain. Chart reviews included clinical notes, labs, imaging studies, and consultation reports. “We looked for specific documentation that primary care physicians had been asking questions related to inflammatory back pain,” Dr. Vlad explained.

Overall, 128 charts (53.6%) documented some feature of inflammatory low back pain. Insidious onset was the most common, but morning stiffness, a cardinal sign, was the least common, noted in only five charts (2%). About 30% of the subjects had a lumbar spine x-ray, which was the most common imaging study, followed by lumbar spine MRI. Only a handful had imaging of the sacroiliac joints.

In 111 charts (46.4%), there was no documentation that primary care providers had looked for inflammatory features or asked questions about them.

Patients were seen from Jan. 2016 to May 2018. The average age in the study was 37.6 years, and two-thirds of the subjects were women.

Funding source and disclosures weren’t reported.

aotto@mdedge.com

Almost half of people presenting for low back pain to the Tufts University primary care clinic in Boston were not asked about inflammatory signs and symptoms, according to a review of 239 charts there by rheumatologists and rheumatology fellows.

©Wavebreakmedia Ltd/Thinkstock

In more than two-thirds of cases, the reviewers were unable to determine if patients had inflammatory back pain or not based on what was documented. When symptoms relevant to inflammation – such as improvement with movement – were documented, it wasn’t clear if providers were actually trying to solicit a history of inflammation or if they simply recorded what patients volunteered.

Spondyloarthritis was listed in the differential of just five charts (2%), and only eight (3.3%) documented considering a rheumatology referral.

It raises the possibility that, in at least some cases, an opportunity to diagnose and treat spondyloarthritis early was missed. It’s a known problem in the literature; previous studies report a delay of 2-10 years before ankylosing spondylitis diagnosis.

“In our primary care practice, there appears to be poor awareness of inflammatory back pain [that] could lead to diagnostic delay,” said senior investigator and rheumatologist Steven Vlad, MD, PhD, an assistant professor at Tufts. Primary care providers are usually the first to see back pain patients, but they “did not seem to be screening for” inflammation, he said.

Dr. Vlad presented the study results at the virtual annual meeting of the Spondyloarthritis Research and Treatment Network. The meeting was held online this year because of the COVID-19 pandemic.

The findings suggest that a reminder to check for inflammation might be in order. Dr. Vlad and his colleagues have since held educational sessions, and plan to do more, with the idea of repeating the study in a year or 2 to see if the sessions made a difference.

“People take away what they learn as residents. We probably need to focus on resident education if we really want to make a dent in this,” he said.

The generalizability of the single-center results is unclear, and it’s possible at least in some cases that providers asked the right questions but did not document them in the chart. Even so, the issue “deserves future study in other populations,” Dr. Vlad said.

The subjects all had a diagnostic code for low back pain and were seen by Tuft’s primary care at least twice 3 or more months apart, which indicated chronic pain. Chart reviews included clinical notes, labs, imaging studies, and consultation reports. “We looked for specific documentation that primary care physicians had been asking questions related to inflammatory back pain,” Dr. Vlad explained.

Overall, 128 charts (53.6%) documented some feature of inflammatory low back pain. Insidious onset was the most common, but morning stiffness, a cardinal sign, was the least common, noted in only five charts (2%). About 30% of the subjects had a lumbar spine x-ray, which was the most common imaging study, followed by lumbar spine MRI. Only a handful had imaging of the sacroiliac joints.

In 111 charts (46.4%), there was no documentation that primary care providers had looked for inflammatory features or asked questions about them.

Patients were seen from Jan. 2016 to May 2018. The average age in the study was 37.6 years, and two-thirds of the subjects were women.

Funding source and disclosures weren’t reported.

aotto@mdedge.com

A universal chimeric antigen receptor (CAR) T-cell therapy produced responses in adults with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL), according to initial findings from an ongoing study.

The first five patients enrolled in this first-in-human study received conditioning and an infusion of the premanufactured CD7-targeted CAR T-cell therapy, TruUCAR GC027.

All five patients achieved a complete remission (CR) or CR with incomplete count recovery (CRi), although one patient had a morphological relapse at 1 month.

Xinxin Wang, PhD, reported these results at the AACR Virtual Meeting I. Dr. Wang is employed by Gracell Biotechnologies in Shanghai, China, which is the company developing TruUCAR GC027.

The CAR T-cell therapy is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors, according to Dr. Wang. TruUCAR GC027 contains second-generation CAR T cells with genomic disruption of TCR-alpha and CD7 to help prevent graft-versus-host disease and fratricide.

TruUCAR GC027 was previously shown to expand and have antileukemic activity in a murine model, Dr. Wang noted.
 

Patients and treatment

The five patients in the phase 1 study had a median age of 24 years (range, 19 to 38 years). They had heavily pretreated T-ALL, with a median of 5 prior lines of therapy (range, 1-9). Baseline bone marrow tumor burden ranged from 4% to 80.2% (median, 38.2%).

None of the patients received prior allogeneic hematopoietic stem cell transplant.

All patients received a preconditioning chemotherapy regimen. One patient received TruUCAR GC027 at dose level 1 (6 x 10⁶ cells/kg), three patients received dose level 2 (1 x 10⁷ cells/kg), and one patient received dose level 3 (1.5 x 10⁷ cells/kg) – each as a single infusion.
 

Expansion, response, and safety

“GC027 expansion, analyzed by flow [cytometry] was observed in most of the patients treated,” Dr. Wang said. “We started to see GC027 in the peripheral blood as early as day 5, with peaks around day 7-14.”

All five patients had a CR or CRi at the first postinfusion evaluation, which occurred at day 14 in four of the five patients. Four patients also achieved minimum residual disease (MRD) negativity by 1 month of follow-up and remained in MRD-negative CR at the February 6, 2020, data cutoff.

One patient achieved MRD-positive CR at day 14 but experienced morphological relapse at 1 month.

In the four patients with MRD-negative CR at 1 month, cellular expansion was observed as early as day 5 and continued for 2 weeks, but the patient who relapsed at day 29 showed no cellular expansion on flow cytometry, Dr. Wang said.

However, by a more sensitive quantitative polymerase chain reaction analysis, cellular expansion was observed in all five patients starting as early as day 1 after infusion, although the patient who relapsed had the shortest duration of expansion.

All patients developed cytokine release syndrome (CRS). Four patients experienced grade 3 CRS, and one experienced grade 4 CRS.

“The CRS was manageable and reversible,” Dr. Wang said, adding that none of the patients experienced neurotoxicity or graft-versus-host disease.

Prolonged cytopenia occurred in four patients, including one grade 1 case, two grade 3 cases, and one grade 4 case. Grade 3 pulmonary infections occurred in three patients, and grade 3 neutropenia occurred in all five patients.
 

‘Very impressive’ early results

Dr. Wang said the responses observed in this trial are notable because T-ALL constitutes 20%-25% of all adult ALL and 12%-15% of all pediatric ALL. T-ALL is highly aggressive, with event-free and overall survival of less than 25% in the relapsed setting. Dr. Wang noted that, despite the high unmet medical need and lack of treatment options for T-ALL, the development of novel immunotherapies has lagged.

One challenge is that T-ALL and normal T cells share common surface antigens, so targeted therapies for T-ALL will also target normal T cells. Another challenge is the potential contamination by malignant cells in autologous T-cell products, Dr. Wang said, noting that this can be avoided with universal CAR T cells.

Further, CD7 is a good target for T-ALL because it is expressed in more than 95% of T-ALL patients, she added.

“[TruUCAR GC027] demonstrated a very promising early response rate ... and showed a manageable toxicity profile at all three dose levels,” Dr. Wang said in closing, noting that further evaluation is warranted.

Indeed, the results of this next-generation CAR T-cell trial are “very impressive,” said invited discussant Yvonne Y. Chen, PhD, of the University of California, Los Angeles.

There have been concerns that “off-the-shelf” CAR T-cell products like TruUCAR GC027 might be limited by factors such as a reduced level of CAR T-cell persistence and therefore reduced efficacy leading to a need for repeat dosing, Dr. Chen noted. However, Dr. Wang and her colleagues showed a 100% CR/CRi rate with a single dose of CAR T cells and without graft-versus-host disease or neurotoxicity, Dr. Chen emphasized.

“I think it’s also important to note, however, that there’s quite a high incidence rate of grade 3 or higher toxicities, including CRS,” Dr. Chen said. “I suspect this may have something to do with the fairly high dosing levels used in this trial.”

The “big question,” however, is durability of the response, Dr. Chen said. “And this is something that the field will really watch as this trial progresses beyond the 7-month monitoring period ... reported today.”

Dr. Wang is an employee of Gracell Biotechnologies. Dr. Chen is cofounder of Kalthera Therapeutics and a scientific adviser for Gritstone Oncology and Notch Therapeutics.

sworcester@mdedge.com

SOURCE: Wang X et al. AACR 2020, Abstract CT052.

A universal chimeric antigen receptor (CAR) T-cell therapy produced responses in adults with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL), according to initial findings from an ongoing study.

The first five patients enrolled in this first-in-human study received conditioning and an infusion of the premanufactured CD7-targeted CAR T-cell therapy, TruUCAR GC027.

All five patients achieved a complete remission (CR) or CR with incomplete count recovery (CRi), although one patient had a morphological relapse at 1 month.

Xinxin Wang, PhD, reported these results at the AACR Virtual Meeting I. Dr. Wang is employed by Gracell Biotechnologies in Shanghai, China, which is the company developing TruUCAR GC027.

The CAR T-cell therapy is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors, according to Dr. Wang. TruUCAR GC027 contains second-generation CAR T cells with genomic disruption of TCR-alpha and CD7 to help prevent graft-versus-host disease and fratricide.

TruUCAR GC027 was previously shown to expand and have antileukemic activity in a murine model, Dr. Wang noted.
 

Patients and treatment

The five patients in the phase 1 study had a median age of 24 years (range, 19 to 38 years). They had heavily pretreated T-ALL, with a median of 5 prior lines of therapy (range, 1-9). Baseline bone marrow tumor burden ranged from 4% to 80.2% (median, 38.2%).

None of the patients received prior allogeneic hematopoietic stem cell transplant.

All patients received a preconditioning chemotherapy regimen. One patient received TruUCAR GC027 at dose level 1 (6 x 10⁶ cells/kg), three patients received dose level 2 (1 x 10⁷ cells/kg), and one patient received dose level 3 (1.5 x 10⁷ cells/kg) – each as a single infusion.
 

Expansion, response, and safety

“GC027 expansion, analyzed by flow [cytometry] was observed in most of the patients treated,” Dr. Wang said. “We started to see GC027 in the peripheral blood as early as day 5, with peaks around day 7-14.”

All five patients had a CR or CRi at the first postinfusion evaluation, which occurred at day 14 in four of the five patients. Four patients also achieved minimum residual disease (MRD) negativity by 1 month of follow-up and remained in MRD-negative CR at the February 6, 2020, data cutoff.

One patient achieved MRD-positive CR at day 14 but experienced morphological relapse at 1 month.

In the four patients with MRD-negative CR at 1 month, cellular expansion was observed as early as day 5 and continued for 2 weeks, but the patient who relapsed at day 29 showed no cellular expansion on flow cytometry, Dr. Wang said.

However, by a more sensitive quantitative polymerase chain reaction analysis, cellular expansion was observed in all five patients starting as early as day 1 after infusion, although the patient who relapsed had the shortest duration of expansion.

All patients developed cytokine release syndrome (CRS). Four patients experienced grade 3 CRS, and one experienced grade 4 CRS.

“The CRS was manageable and reversible,” Dr. Wang said, adding that none of the patients experienced neurotoxicity or graft-versus-host disease.

Prolonged cytopenia occurred in four patients, including one grade 1 case, two grade 3 cases, and one grade 4 case. Grade 3 pulmonary infections occurred in three patients, and grade 3 neutropenia occurred in all five patients.
 

‘Very impressive’ early results

Dr. Wang said the responses observed in this trial are notable because T-ALL constitutes 20%-25% of all adult ALL and 12%-15% of all pediatric ALL. T-ALL is highly aggressive, with event-free and overall survival of less than 25% in the relapsed setting. Dr. Wang noted that, despite the high unmet medical need and lack of treatment options for T-ALL, the development of novel immunotherapies has lagged.

One challenge is that T-ALL and normal T cells share common surface antigens, so targeted therapies for T-ALL will also target normal T cells. Another challenge is the potential contamination by malignant cells in autologous T-cell products, Dr. Wang said, noting that this can be avoided with universal CAR T cells.

Further, CD7 is a good target for T-ALL because it is expressed in more than 95% of T-ALL patients, she added.

“[TruUCAR GC027] demonstrated a very promising early response rate ... and showed a manageable toxicity profile at all three dose levels,” Dr. Wang said in closing, noting that further evaluation is warranted.

Indeed, the results of this next-generation CAR T-cell trial are “very impressive,” said invited discussant Yvonne Y. Chen, PhD, of the University of California, Los Angeles.

There have been concerns that “off-the-shelf” CAR T-cell products like TruUCAR GC027 might be limited by factors such as a reduced level of CAR T-cell persistence and therefore reduced efficacy leading to a need for repeat dosing, Dr. Chen noted. However, Dr. Wang and her colleagues showed a 100% CR/CRi rate with a single dose of CAR T cells and without graft-versus-host disease or neurotoxicity, Dr. Chen emphasized.

“I think it’s also important to note, however, that there’s quite a high incidence rate of grade 3 or higher toxicities, including CRS,” Dr. Chen said. “I suspect this may have something to do with the fairly high dosing levels used in this trial.”

The “big question,” however, is durability of the response, Dr. Chen said. “And this is something that the field will really watch as this trial progresses beyond the 7-month monitoring period ... reported today.”

Dr. Wang is an employee of Gracell Biotechnologies. Dr. Chen is cofounder of Kalthera Therapeutics and a scientific adviser for Gritstone Oncology and Notch Therapeutics.

sworcester@mdedge.com

SOURCE: Wang X et al. AACR 2020, Abstract CT052.

A universal chimeric antigen receptor (CAR) T-cell therapy produced responses in adults with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL), according to initial findings from an ongoing study.

The first five patients enrolled in this first-in-human study received conditioning and an infusion of the premanufactured CD7-targeted CAR T-cell therapy, TruUCAR GC027.

All five patients achieved a complete remission (CR) or CR with incomplete count recovery (CRi), although one patient had a morphological relapse at 1 month.

Xinxin Wang, PhD, reported these results at the AACR Virtual Meeting I. Dr. Wang is employed by Gracell Biotechnologies in Shanghai, China, which is the company developing TruUCAR GC027.

The CAR T-cell therapy is manufactured using lentivirus and leukopaks from HLA-mismatched healthy donors, according to Dr. Wang. TruUCAR GC027 contains second-generation CAR T cells with genomic disruption of TCR-alpha and CD7 to help prevent graft-versus-host disease and fratricide.

TruUCAR GC027 was previously shown to expand and have antileukemic activity in a murine model, Dr. Wang noted.
 

Patients and treatment

The five patients in the phase 1 study had a median age of 24 years (range, 19 to 38 years). They had heavily pretreated T-ALL, with a median of 5 prior lines of therapy (range, 1-9). Baseline bone marrow tumor burden ranged from 4% to 80.2% (median, 38.2%).

None of the patients received prior allogeneic hematopoietic stem cell transplant.

All patients received a preconditioning chemotherapy regimen. One patient received TruUCAR GC027 at dose level 1 (6 x 10⁶ cells/kg), three patients received dose level 2 (1 x 10⁷ cells/kg), and one patient received dose level 3 (1.5 x 10⁷ cells/kg) – each as a single infusion.
 

Expansion, response, and safety

“GC027 expansion, analyzed by flow [cytometry] was observed in most of the patients treated,” Dr. Wang said. “We started to see GC027 in the peripheral blood as early as day 5, with peaks around day 7-14.”

All five patients had a CR or CRi at the first postinfusion evaluation, which occurred at day 14 in four of the five patients. Four patients also achieved minimum residual disease (MRD) negativity by 1 month of follow-up and remained in MRD-negative CR at the February 6, 2020, data cutoff.

One patient achieved MRD-positive CR at day 14 but experienced morphological relapse at 1 month.

In the four patients with MRD-negative CR at 1 month, cellular expansion was observed as early as day 5 and continued for 2 weeks, but the patient who relapsed at day 29 showed no cellular expansion on flow cytometry, Dr. Wang said.

However, by a more sensitive quantitative polymerase chain reaction analysis, cellular expansion was observed in all five patients starting as early as day 1 after infusion, although the patient who relapsed had the shortest duration of expansion.

All patients developed cytokine release syndrome (CRS). Four patients experienced grade 3 CRS, and one experienced grade 4 CRS.

“The CRS was manageable and reversible,” Dr. Wang said, adding that none of the patients experienced neurotoxicity or graft-versus-host disease.

Prolonged cytopenia occurred in four patients, including one grade 1 case, two grade 3 cases, and one grade 4 case. Grade 3 pulmonary infections occurred in three patients, and grade 3 neutropenia occurred in all five patients.
 

‘Very impressive’ early results

Dr. Wang said the responses observed in this trial are notable because T-ALL constitutes 20%-25% of all adult ALL and 12%-15% of all pediatric ALL. T-ALL is highly aggressive, with event-free and overall survival of less than 25% in the relapsed setting. Dr. Wang noted that, despite the high unmet medical need and lack of treatment options for T-ALL, the development of novel immunotherapies has lagged.

One challenge is that T-ALL and normal T cells share common surface antigens, so targeted therapies for T-ALL will also target normal T cells. Another challenge is the potential contamination by malignant cells in autologous T-cell products, Dr. Wang said, noting that this can be avoided with universal CAR T cells.

Further, CD7 is a good target for T-ALL because it is expressed in more than 95% of T-ALL patients, she added.

“[TruUCAR GC027] demonstrated a very promising early response rate ... and showed a manageable toxicity profile at all three dose levels,” Dr. Wang said in closing, noting that further evaluation is warranted.

Indeed, the results of this next-generation CAR T-cell trial are “very impressive,” said invited discussant Yvonne Y. Chen, PhD, of the University of California, Los Angeles.

There have been concerns that “off-the-shelf” CAR T-cell products like TruUCAR GC027 might be limited by factors such as a reduced level of CAR T-cell persistence and therefore reduced efficacy leading to a need for repeat dosing, Dr. Chen noted. However, Dr. Wang and her colleagues showed a 100% CR/CRi rate with a single dose of CAR T cells and without graft-versus-host disease or neurotoxicity, Dr. Chen emphasized.

“I think it’s also important to note, however, that there’s quite a high incidence rate of grade 3 or higher toxicities, including CRS,” Dr. Chen said. “I suspect this may have something to do with the fairly high dosing levels used in this trial.”

The “big question,” however, is durability of the response, Dr. Chen said. “And this is something that the field will really watch as this trial progresses beyond the 7-month monitoring period ... reported today.”

Dr. Wang is an employee of Gracell Biotechnologies. Dr. Chen is cofounder of Kalthera Therapeutics and a scientific adviser for Gritstone Oncology and Notch Therapeutics.

sworcester@mdedge.com

SOURCE: Wang X et al. AACR 2020, Abstract CT052.