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Substantial very late MACE risk after PCI for SIHD
Patients with stable ischemic heart disease remain at substantial risk for major adverse cardiovascular events 1-5 years after percutaneous coronary intervention, even with contemporary second-generation drug-eluting stents, according to a pooled analysis of long-term follow-up data on 10,987 patients in 19 prospective, randomized, head-to-head metallic stent trials.
The analysis showed that, although most major adverse cardiovascular events (MACE) occurred during the first year after stenting, no plateau in MACE was reached between years 1 and 5, Mahesh V. Madhavan, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“Further studies are required to understand the mechanisms of late events and whether improvements in stent technology, revascularization technique, and adjunctive therapies may improve outcomes in patients with SIHD [stable ischemic heart disease],” said Dr. Madhavan, a cardiology fellow at Columbia University Irving Medical Center and New York–Presbyterian Hospital.
This post hoc analysis of pooled individual patient-level data from 19 randomized trials included 10,987 metallic stent recipients with SIHD. Sixty-one percent got second-generation drug-eluting stents (DES), 25% received first-generation DES, and 15% got bare metal stents (BMS). The largest prospective head-to-head RCT was SPIRIT IV, with 2,130 patients. All five TAXUS trials were also included.
The 5-year rate of the primary composite MACE endpoint composed of cardiac death, MI, or ischemia-driven target lesion revascularization was 24.1% in patients with BMS stents, 17.9% with first-gen DES, and 13.4% with second-gen DES, reflecting the advances in stent technology over time. Most of these MACE events occurred during the first year after PCI, with rates of 18%, 8.6%, and 5.3%, respectively, in the three groups. However, the MACE rate beyond the first year out through year 5 remained substantial: 10.2% with first-gen DES, 8.5% with second-gen DES, and 7.4% in the BMS group.
The cardiac death rate from PCI through year 5 was 3.8% with second-gen DES, 3.6% with first-gen DES, and 3.3% with BMS. The MI rate was 7.7% with first-gen DES, 6.1% with BMS, and 5% with second-gen DES.
Stent thrombosis occurred during the first year in 0.9% of first-gen DES and BMS recipients and in 0.7% of patients with second-gen DES. During years 1-5, the rates were 1.6% with first-gen DES, 0.9% with second-gen devices, and 0.2% with BMS.
Second-gen DES provided a big advantage in terms of lessened need for ischemia-driven target lesion revascularization through the first 5 years, with a rate of 7.3%, compared to 18.7% in patients with first-gen DES and 10.5% with BMS.
In a multivariate regression analysis, independent predictors of MACE in the first 5 years post PCI included indicators of greater lesion and/or procedural complexity, such as left main or left anterior descending disease, greater lesion length, and more than one treated lesion, as well as standard cardiovascular risk factors, including recent smoking, hypertension, and diabetes.
In contrast, hyperlipidemia was associated with a significant 15% reduction in MACE risk, which in an interview Dr. Madhavan said may have been due to aggressive lipid-lowering therapy, although he added that this is conjecture because he and his coinvestigators didn’t have access to data on the use of guideline-directed medical therapy or antiplatelet regimens.
Asked about future prospects for reducing the substantial very late risk of MACE highlighted in his study, Dr. Madhavan cited the use of adjunctive imaging during PCI as promising.
“The currently enrolling ILUMEN IV trial, among other studies, will help determine whether imaging-guided intervention can help improve intermediate and long-term rates of MACE,” he observed.
Promising medical therapies that could potentially confer benefit in terms of reducing long-term MACE in patients who’ve undergone PCI for SIHD include novel lipid-lowering drugs, tailored antithrombotic strategies, new anti-inflammatory agents, and the SGLT2 inhibitors, Dr. Madhavan continued.
In terms of advances in stent design, he cited recent evidence that ultrathin-strut stents featuring bioresorbable polymer, such as the Orsiro stent, may reduce late stent-related MACE through 3 years.
“We’ll have to see if these benefits extend to longer-term follow-up up to 5 years,” he said.
He deemed his study results “fairly consistent” with those of the ISCHEMIA trial, where ischemic events in the patients with SIHD assigned to an initial invasive strategy continued to occur in the latter years of follow-up without any clear plateau effect (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Dr. Madhavan reported no financial conflicts regarding his study, funded by an institutional research grant from the National Heart, Lung, and Blood Institute.
Shortly following Dr. Madhavan’s presentation at ACC 2020, the study results were published online (Circ Cardiovasc Interv. 2020 Apr;13[4[:e008565. doi: 10.1161/CIRCINTERVENTIONS.119.008565).
SOURCE: Madhavan MV. ACC 2020, Abstract 909-10.
Patients with stable ischemic heart disease remain at substantial risk for major adverse cardiovascular events 1-5 years after percutaneous coronary intervention, even with contemporary second-generation drug-eluting stents, according to a pooled analysis of long-term follow-up data on 10,987 patients in 19 prospective, randomized, head-to-head metallic stent trials.
The analysis showed that, although most major adverse cardiovascular events (MACE) occurred during the first year after stenting, no plateau in MACE was reached between years 1 and 5, Mahesh V. Madhavan, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“Further studies are required to understand the mechanisms of late events and whether improvements in stent technology, revascularization technique, and adjunctive therapies may improve outcomes in patients with SIHD [stable ischemic heart disease],” said Dr. Madhavan, a cardiology fellow at Columbia University Irving Medical Center and New York–Presbyterian Hospital.
This post hoc analysis of pooled individual patient-level data from 19 randomized trials included 10,987 metallic stent recipients with SIHD. Sixty-one percent got second-generation drug-eluting stents (DES), 25% received first-generation DES, and 15% got bare metal stents (BMS). The largest prospective head-to-head RCT was SPIRIT IV, with 2,130 patients. All five TAXUS trials were also included.
The 5-year rate of the primary composite MACE endpoint composed of cardiac death, MI, or ischemia-driven target lesion revascularization was 24.1% in patients with BMS stents, 17.9% with first-gen DES, and 13.4% with second-gen DES, reflecting the advances in stent technology over time. Most of these MACE events occurred during the first year after PCI, with rates of 18%, 8.6%, and 5.3%, respectively, in the three groups. However, the MACE rate beyond the first year out through year 5 remained substantial: 10.2% with first-gen DES, 8.5% with second-gen DES, and 7.4% in the BMS group.
The cardiac death rate from PCI through year 5 was 3.8% with second-gen DES, 3.6% with first-gen DES, and 3.3% with BMS. The MI rate was 7.7% with first-gen DES, 6.1% with BMS, and 5% with second-gen DES.
Stent thrombosis occurred during the first year in 0.9% of first-gen DES and BMS recipients and in 0.7% of patients with second-gen DES. During years 1-5, the rates were 1.6% with first-gen DES, 0.9% with second-gen devices, and 0.2% with BMS.
Second-gen DES provided a big advantage in terms of lessened need for ischemia-driven target lesion revascularization through the first 5 years, with a rate of 7.3%, compared to 18.7% in patients with first-gen DES and 10.5% with BMS.
In a multivariate regression analysis, independent predictors of MACE in the first 5 years post PCI included indicators of greater lesion and/or procedural complexity, such as left main or left anterior descending disease, greater lesion length, and more than one treated lesion, as well as standard cardiovascular risk factors, including recent smoking, hypertension, and diabetes.
In contrast, hyperlipidemia was associated with a significant 15% reduction in MACE risk, which in an interview Dr. Madhavan said may have been due to aggressive lipid-lowering therapy, although he added that this is conjecture because he and his coinvestigators didn’t have access to data on the use of guideline-directed medical therapy or antiplatelet regimens.
Asked about future prospects for reducing the substantial very late risk of MACE highlighted in his study, Dr. Madhavan cited the use of adjunctive imaging during PCI as promising.
“The currently enrolling ILUMEN IV trial, among other studies, will help determine whether imaging-guided intervention can help improve intermediate and long-term rates of MACE,” he observed.
Promising medical therapies that could potentially confer benefit in terms of reducing long-term MACE in patients who’ve undergone PCI for SIHD include novel lipid-lowering drugs, tailored antithrombotic strategies, new anti-inflammatory agents, and the SGLT2 inhibitors, Dr. Madhavan continued.
In terms of advances in stent design, he cited recent evidence that ultrathin-strut stents featuring bioresorbable polymer, such as the Orsiro stent, may reduce late stent-related MACE through 3 years.
“We’ll have to see if these benefits extend to longer-term follow-up up to 5 years,” he said.
He deemed his study results “fairly consistent” with those of the ISCHEMIA trial, where ischemic events in the patients with SIHD assigned to an initial invasive strategy continued to occur in the latter years of follow-up without any clear plateau effect (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Dr. Madhavan reported no financial conflicts regarding his study, funded by an institutional research grant from the National Heart, Lung, and Blood Institute.
Shortly following Dr. Madhavan’s presentation at ACC 2020, the study results were published online (Circ Cardiovasc Interv. 2020 Apr;13[4[:e008565. doi: 10.1161/CIRCINTERVENTIONS.119.008565).
SOURCE: Madhavan MV. ACC 2020, Abstract 909-10.
Patients with stable ischemic heart disease remain at substantial risk for major adverse cardiovascular events 1-5 years after percutaneous coronary intervention, even with contemporary second-generation drug-eluting stents, according to a pooled analysis of long-term follow-up data on 10,987 patients in 19 prospective, randomized, head-to-head metallic stent trials.
The analysis showed that, although most major adverse cardiovascular events (MACE) occurred during the first year after stenting, no plateau in MACE was reached between years 1 and 5, Mahesh V. Madhavan, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“Further studies are required to understand the mechanisms of late events and whether improvements in stent technology, revascularization technique, and adjunctive therapies may improve outcomes in patients with SIHD [stable ischemic heart disease],” said Dr. Madhavan, a cardiology fellow at Columbia University Irving Medical Center and New York–Presbyterian Hospital.
This post hoc analysis of pooled individual patient-level data from 19 randomized trials included 10,987 metallic stent recipients with SIHD. Sixty-one percent got second-generation drug-eluting stents (DES), 25% received first-generation DES, and 15% got bare metal stents (BMS). The largest prospective head-to-head RCT was SPIRIT IV, with 2,130 patients. All five TAXUS trials were also included.
The 5-year rate of the primary composite MACE endpoint composed of cardiac death, MI, or ischemia-driven target lesion revascularization was 24.1% in patients with BMS stents, 17.9% with first-gen DES, and 13.4% with second-gen DES, reflecting the advances in stent technology over time. Most of these MACE events occurred during the first year after PCI, with rates of 18%, 8.6%, and 5.3%, respectively, in the three groups. However, the MACE rate beyond the first year out through year 5 remained substantial: 10.2% with first-gen DES, 8.5% with second-gen DES, and 7.4% in the BMS group.
The cardiac death rate from PCI through year 5 was 3.8% with second-gen DES, 3.6% with first-gen DES, and 3.3% with BMS. The MI rate was 7.7% with first-gen DES, 6.1% with BMS, and 5% with second-gen DES.
Stent thrombosis occurred during the first year in 0.9% of first-gen DES and BMS recipients and in 0.7% of patients with second-gen DES. During years 1-5, the rates were 1.6% with first-gen DES, 0.9% with second-gen devices, and 0.2% with BMS.
Second-gen DES provided a big advantage in terms of lessened need for ischemia-driven target lesion revascularization through the first 5 years, with a rate of 7.3%, compared to 18.7% in patients with first-gen DES and 10.5% with BMS.
In a multivariate regression analysis, independent predictors of MACE in the first 5 years post PCI included indicators of greater lesion and/or procedural complexity, such as left main or left anterior descending disease, greater lesion length, and more than one treated lesion, as well as standard cardiovascular risk factors, including recent smoking, hypertension, and diabetes.
In contrast, hyperlipidemia was associated with a significant 15% reduction in MACE risk, which in an interview Dr. Madhavan said may have been due to aggressive lipid-lowering therapy, although he added that this is conjecture because he and his coinvestigators didn’t have access to data on the use of guideline-directed medical therapy or antiplatelet regimens.
Asked about future prospects for reducing the substantial very late risk of MACE highlighted in his study, Dr. Madhavan cited the use of adjunctive imaging during PCI as promising.
“The currently enrolling ILUMEN IV trial, among other studies, will help determine whether imaging-guided intervention can help improve intermediate and long-term rates of MACE,” he observed.
Promising medical therapies that could potentially confer benefit in terms of reducing long-term MACE in patients who’ve undergone PCI for SIHD include novel lipid-lowering drugs, tailored antithrombotic strategies, new anti-inflammatory agents, and the SGLT2 inhibitors, Dr. Madhavan continued.
In terms of advances in stent design, he cited recent evidence that ultrathin-strut stents featuring bioresorbable polymer, such as the Orsiro stent, may reduce late stent-related MACE through 3 years.
“We’ll have to see if these benefits extend to longer-term follow-up up to 5 years,” he said.
He deemed his study results “fairly consistent” with those of the ISCHEMIA trial, where ischemic events in the patients with SIHD assigned to an initial invasive strategy continued to occur in the latter years of follow-up without any clear plateau effect (N Engl J Med. 2020 Apr 9;382[15]:1395-407).
Dr. Madhavan reported no financial conflicts regarding his study, funded by an institutional research grant from the National Heart, Lung, and Blood Institute.
Shortly following Dr. Madhavan’s presentation at ACC 2020, the study results were published online (Circ Cardiovasc Interv. 2020 Apr;13[4[:e008565. doi: 10.1161/CIRCINTERVENTIONS.119.008565).
SOURCE: Madhavan MV. ACC 2020, Abstract 909-10.
FROM ACC 20
COVID-19: An opportunity, challenge for addiction treatment, NIDA boss says
The COVID-19 pandemic is posing significant challenges while also providing unique opportunities for patients with substance use disorders (SUD), a leading expert says.
Nora Volkow, MD, director of the National Institute on Drug Abuse, said that the pandemic has accelerated the use of telemedicine, making it easier for patients with SUD to access treatment. It has also led to the proliferation of more mental health hotlines, which is critical since the vast majority of these patients have comorbid mental illness.
In addition, COVID-19 has resulted in increased availability of “alternative” peer support mechanisms via cellphones or computers to aid individuals’ sobriety.
Dr. Volkow spoke at the virtual American Psychiatric Association Spring Highlights Meeting 2020, which is replacing the organization’s canceled annual meeting.
While methadone clinics have had to close during the pandemic, making it challenging for those on medically assisted treatment to receive methadone or buprenorphine, some of the rules and regulations have been relaxed in order to make these medications accessible without the need for in-person attendance at a clinic. In addition, the Substance Abuse and Mental Health Services Administration has relaxed some of its own regulations regarding telehealth and opioid treatment programs.
Social isolation, stigma intensified
A pandemic increases anxiety in the general population, but for patients with SUD who may be also be struggling with homelessness and comorbid mental illness, the situation can further exacerbate social stigma and isolation – leading to relapse, more overdoses, and overdose deaths, Dr. Volkow said. Social interaction is “extraordinarily important” for patients and “one of the most powerful tools we have” to build resilience.
Right now, said Dr. Volkow, “we are in the dark as to how COVID infections have affected the number of overdose deaths.”
However, she noted that
“So even through this devastation, we can actually extract something that may help others in future,” she said.
Dr. Volkow noted that during the pandemic it is critical to reinforce the importance of engaging in – and remaining in – treatment to SUD patients. It’s also crucial to make patients aware of social support systems and behavioral interventions to help them cope with stress and to mitigate relapse risk.
COVID-19 and relapse
Elie G. Aoun, MD, assistant professor of psychiatry at New York University and vice chair of the APA’s Council on Addiction Psychiatry, said in an interview that Dr. Volkow’s presentation provided “exactly the kind of accessible information” clinicians need.
Dr. Aoun said he sees the impact of the COVID-19 crisis in his practice every day. Patients with SUD “are getting the short end of the stick.”
Social distancing measures prompted by the pandemic can be “very triggering” for SUD patients, he said. One of his patients told him the current isolation, loneliness, movement restrictions, and boredom remind her of the way she felt when she used drugs.
Dr. Aoun said four of his patients have relapsed since the pandemic began. Two of them had just started treatment after years of using drugs, so this was a “major setback” for them.
He and his colleagues were “not really prepared” to provide care via video link, which he believes is not as effective as in-person sessions.
In addition to disrupting patient care, said Dr. Aoun, the pandemic is forcing the medical community to face social determinants of health, such as poverty and homelessness, as they relate to addiction disorders and whether or not someone receives care.
This article originally appeared on Medscape.com.
The COVID-19 pandemic is posing significant challenges while also providing unique opportunities for patients with substance use disorders (SUD), a leading expert says.
Nora Volkow, MD, director of the National Institute on Drug Abuse, said that the pandemic has accelerated the use of telemedicine, making it easier for patients with SUD to access treatment. It has also led to the proliferation of more mental health hotlines, which is critical since the vast majority of these patients have comorbid mental illness.
In addition, COVID-19 has resulted in increased availability of “alternative” peer support mechanisms via cellphones or computers to aid individuals’ sobriety.
Dr. Volkow spoke at the virtual American Psychiatric Association Spring Highlights Meeting 2020, which is replacing the organization’s canceled annual meeting.
While methadone clinics have had to close during the pandemic, making it challenging for those on medically assisted treatment to receive methadone or buprenorphine, some of the rules and regulations have been relaxed in order to make these medications accessible without the need for in-person attendance at a clinic. In addition, the Substance Abuse and Mental Health Services Administration has relaxed some of its own regulations regarding telehealth and opioid treatment programs.
Social isolation, stigma intensified
A pandemic increases anxiety in the general population, but for patients with SUD who may be also be struggling with homelessness and comorbid mental illness, the situation can further exacerbate social stigma and isolation – leading to relapse, more overdoses, and overdose deaths, Dr. Volkow said. Social interaction is “extraordinarily important” for patients and “one of the most powerful tools we have” to build resilience.
Right now, said Dr. Volkow, “we are in the dark as to how COVID infections have affected the number of overdose deaths.”
However, she noted that
“So even through this devastation, we can actually extract something that may help others in future,” she said.
Dr. Volkow noted that during the pandemic it is critical to reinforce the importance of engaging in – and remaining in – treatment to SUD patients. It’s also crucial to make patients aware of social support systems and behavioral interventions to help them cope with stress and to mitigate relapse risk.
COVID-19 and relapse
Elie G. Aoun, MD, assistant professor of psychiatry at New York University and vice chair of the APA’s Council on Addiction Psychiatry, said in an interview that Dr. Volkow’s presentation provided “exactly the kind of accessible information” clinicians need.
Dr. Aoun said he sees the impact of the COVID-19 crisis in his practice every day. Patients with SUD “are getting the short end of the stick.”
Social distancing measures prompted by the pandemic can be “very triggering” for SUD patients, he said. One of his patients told him the current isolation, loneliness, movement restrictions, and boredom remind her of the way she felt when she used drugs.
Dr. Aoun said four of his patients have relapsed since the pandemic began. Two of them had just started treatment after years of using drugs, so this was a “major setback” for them.
He and his colleagues were “not really prepared” to provide care via video link, which he believes is not as effective as in-person sessions.
In addition to disrupting patient care, said Dr. Aoun, the pandemic is forcing the medical community to face social determinants of health, such as poverty and homelessness, as they relate to addiction disorders and whether or not someone receives care.
This article originally appeared on Medscape.com.
The COVID-19 pandemic is posing significant challenges while also providing unique opportunities for patients with substance use disorders (SUD), a leading expert says.
Nora Volkow, MD, director of the National Institute on Drug Abuse, said that the pandemic has accelerated the use of telemedicine, making it easier for patients with SUD to access treatment. It has also led to the proliferation of more mental health hotlines, which is critical since the vast majority of these patients have comorbid mental illness.
In addition, COVID-19 has resulted in increased availability of “alternative” peer support mechanisms via cellphones or computers to aid individuals’ sobriety.
Dr. Volkow spoke at the virtual American Psychiatric Association Spring Highlights Meeting 2020, which is replacing the organization’s canceled annual meeting.
While methadone clinics have had to close during the pandemic, making it challenging for those on medically assisted treatment to receive methadone or buprenorphine, some of the rules and regulations have been relaxed in order to make these medications accessible without the need for in-person attendance at a clinic. In addition, the Substance Abuse and Mental Health Services Administration has relaxed some of its own regulations regarding telehealth and opioid treatment programs.
Social isolation, stigma intensified
A pandemic increases anxiety in the general population, but for patients with SUD who may be also be struggling with homelessness and comorbid mental illness, the situation can further exacerbate social stigma and isolation – leading to relapse, more overdoses, and overdose deaths, Dr. Volkow said. Social interaction is “extraordinarily important” for patients and “one of the most powerful tools we have” to build resilience.
Right now, said Dr. Volkow, “we are in the dark as to how COVID infections have affected the number of overdose deaths.”
However, she noted that
“So even through this devastation, we can actually extract something that may help others in future,” she said.
Dr. Volkow noted that during the pandemic it is critical to reinforce the importance of engaging in – and remaining in – treatment to SUD patients. It’s also crucial to make patients aware of social support systems and behavioral interventions to help them cope with stress and to mitigate relapse risk.
COVID-19 and relapse
Elie G. Aoun, MD, assistant professor of psychiatry at New York University and vice chair of the APA’s Council on Addiction Psychiatry, said in an interview that Dr. Volkow’s presentation provided “exactly the kind of accessible information” clinicians need.
Dr. Aoun said he sees the impact of the COVID-19 crisis in his practice every day. Patients with SUD “are getting the short end of the stick.”
Social distancing measures prompted by the pandemic can be “very triggering” for SUD patients, he said. One of his patients told him the current isolation, loneliness, movement restrictions, and boredom remind her of the way she felt when she used drugs.
Dr. Aoun said four of his patients have relapsed since the pandemic began. Two of them had just started treatment after years of using drugs, so this was a “major setback” for them.
He and his colleagues were “not really prepared” to provide care via video link, which he believes is not as effective as in-person sessions.
In addition to disrupting patient care, said Dr. Aoun, the pandemic is forcing the medical community to face social determinants of health, such as poverty and homelessness, as they relate to addiction disorders and whether or not someone receives care.
This article originally appeared on Medscape.com.
Trials and tribulations: Neurology research during COVID-19
However, researchers remain determined to forge ahead – with many redesigning their studies, at least in part to optimize the safety of their participants and research staff.
Keeping people engaged while protocols are on hold; expanding normal safety considerations; and re-enlisting statisticians to keep their findings as significant as possible are just some of study survival strategies underway.
Alzheimer’s disease research on hold
The pandemic is having a significant impact on Alzheimer’s disease research, and medical research in general, says Heather Snyder, PhD, vice president, Medical & Scientific Relations at the Alzheimer’s Association.
“Many clinical trials worldwide are pausing, changing, or halting the testing of the drug or the intervention,” she told Medscape Medical News. “How the teams have adapted depends on the study,” she added. “As you can imagine, things are changing on a daily basis.”
The US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) trial, for example, is on hold until at least May 31. The Alzheimer’s Association is helping to implement and fund the study along with Wake Forest University Medical Center.
“We’re not randomizing participants at this point in time and the intervention — which is based on a team meeting, and there is a social aspect to that — has been paused,” Dr. Snyder said.
Another pivotal study underway is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (the A4 Study). Investigators are evaluating if an anti-amyloid antibody, solanezumab (Eli Lilly), can slow memory loss among people with amyloid on imaging but no symptoms of cognitive decline at baseline.
“The A4 Study is definitely continuing. However, in an effort to minimize risk to participants, site staff and study integrity, we have implemented an optional study hiatus for both the double-blind and open-label extension phases,” lead investigator Reisa Anne Sperling, MD, told Medscape Medical News.
“We wanted to prioritize the safety of our participants as well as the ability of participants to remain in the study … despite disruptions from the COVID-19 pandemic,” said Dr. Sperling, who is professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.
The ultimate goal is for A4 participants to receive the full number of planned infusions and assessments, even if it takes longer, she added.
Many Alzheimer’s disease researchers outside the United States face similar challenges. “As you probably are well aware, Spain is now in a complete lockdown. This has affected research centers like ours, the Barcelona Brain Research Center, and the way we work,” José Luís Molinuevo Guix, MD, PhD, told Medscape Medical News.
All participants in observational studies like the ALFA+ study and initiatives, as well as those in trials including PENSA and AB1601, “are not allowed, by law, to come in, hence from a safety perspective we are on good grounds,” added Dr. Molinuevo Guix, who directs the Alzheimer’s disease and other cognitive disorders unit at the Hospital Clinic de Barcelona.
The investigators are creating protocols for communicating with participants during the pandemic and for restarting visits safely after the lockdown has ended.
Stroke studies amended or suspended
A similar situation is occurring in stroke trials. Stroke is “obviously an acute disease, as well as a disease that requires secondary prevention,” Mitchell Elkind, MD, president-elect of the American Heart Association, told Medscape Medical News.
“One could argue that patients with stroke are going to be in the hospital anyway – why not enroll them in a study? They’re not incurring any additional risk,” he said. “But the staff have to come in to see them, and we’re really trying to avoid exposure.”
One ongoing trial, the Atrial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA), stopped randomly assigning new participants to secondary prevention with apixaban or aspirin because of COVID-19. However, Dr. Elkind and colleagues plan to provide medication to the 440 people already in the trial.
“Wherever possible, the study coordinators are shipping the drug to people and doing follow-up visits by phone or video,” said Dr. Elkind, chief of the Division of Neurology Clinical Outcomes Research and Population Sciences at Columbia University in New York City.
Protecting patients, staff, and ultimately society is a “major driving force in stopping the randomizations,” he stressed.
ARCADIA is part of the StrokeNet prevention trials network, run by the NIH’s National Institute of Neurologic Disorders and Stroke (NINDS). Additional pivotal trials include the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and the Multi-arm Optimization of Stroke Thrombolysis (MOST) studies, he said.
Joseph Broderick, MD, director of the national NIH StrokeNet, agreed that safety comes first. “It was the decision of the StrokeNet leadership and the principal investigators of the trials that we needed to hold recruitment of new patients while we worked on adapting processes of enrollment to ensure the safety of both patients and researchers interacting with study patients,” he told Medscape Medical News.
Potential risks vary based on the study intervention and the need for in-person interactions. Trials that include stimulation devices or physical therapy, for example, might be most affected, added Dr. Broderick, professor and director of the UC Gardner Neuroscience Institute at the University of Cincinnati in Ohio.
Nevertheless, “there are potential ways … to move as much as possible toward telemedicine and digital interactions during this time.”
Multiple challenges in multiple sclerosis
At the national level, the COVID-19 pandemic has had an “unprecedented impact on almost all the clinical trials funded by NINDS,” said Clinton Wright, MD, director of the Division of Clinical Research at NINDS. “Investigators have had to adapt quickly.”
Supplementing existing grants with money to conduct research on COVID-19 and pursuing research opportunities from different institutes are “some of the creative approaches [that] have come from the NIH [National Institutes of Health] itself,” Dr. Wright said. “Other creative approaches have come from investigators trying to keep their studies and trials going during the pandemic.”
In clinical trials, “everything from electronic consent to in-home research drug delivery is being brought to bear.”
“A few ongoing trials have been able to modify their protocols to obtain consent and carry out evaluations remotely by telephone or videoconferencing,” Dr. Wright said. “This is especially critical for trials that involve medical management of specific risk factors or conditions, where suspension of the trial could itself have adverse consequences due to reduced engagement with research participants.”
For participants already in MS studies, “each upcoming visit is assessed for whether it’s critical or could be done virtually or just skipped. If a person needs a treatment that cannot be postponed or skipped, they come in,” Jeffrey Cohen, MD, director of the Experimental Therapeutics Program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, told Medscape Medical News.
New study enrollment is largely on hold and study visits for existing participants are limited, said Dr. Cohen, who is also president of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Some of the major ongoing trials in MS are “looking at very fundamental questions in the field,” Dr. Cohen said. The Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS) and Traditional Versus Early Aggressive Therapy for Multiple Sclerosis (TREAT-MS) trials, for example, evaluate whether treatment should be initiated with one of the less efficacious agents with escalation as needed, or whether treatment should begin with a high-efficacy agent.
Both trials are currently on hold because of the pandemic, as is the Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) study.
“There has been a lot of interest in hematopoietic stem cell transplants and where they fit into our overall treatment strategy, and this is intended to provide a more definitive answer,” Dr. Cohen said.
Making the most of down time
“The pandemic has been challenging” in terms of ongoing MS research, said Benjamin M. Segal, MD, chair of the Department of Neurology and director of the Neuroscience Research Institute at the Ohio State University Wexner Medical Center, Columbus.
“With regard to the lab, our animal model experiments have been placed on hold. We have stopped collecting samples from clinical subjects for biomarker studies.
“However, my research team has been taking advantage of the time that has been freed up from bench work by analyzing data sets that had been placed aside, delving more deeply into the literature, and writing new grant proposals and articles,” he added.
Two of Dr. Segal’s trainees are writing review articles on the immunopathogenesis of MS and its treatment. Another postdoctoral candidate is writing a grant proposal to investigate how coinfection with a coronavirus modulates CNS pathology and the clinical course of an animal model of MS.
“I am asking my trainees to plan out experiments further in advance than they ever have before, so they are as prepared as possible to resume their research agendas once we are up and running again,” Dr. Segal said.
Confronting current challenges while planning for a future less disrupted by the pandemic is a common theme that emerges.
“The duration of this [pandemic] will dictate how we analyze the data at the end [for the US POINTER study]. There is a large group of statisticians working on this,” Dr. Snyder said.
Dr. Sperling of Harvard Medical School also remains undeterred. “This is definitely a challenging time, as we must not allow the COVID-19 to interfere with our essential mission to find a successful treatment to prevent cognitive decline in AD. We do need, however, to be as flexible as possible to protect our participants and minimize the impact to our overall study integrity,” she said.
NIH guidance
Dr. Molinuevo Guix, of the Barcelona Brain Research Center, is also determined to continue his Alzheimer’s disease research. “I am aware that after the crisis, there will be less [risk] but still a COVID-19 infection risk, so apart from trying to generate part of our visits virtually, we want to make sure we have all necessary safety measures in place. We remain very active to preserve the work we have done to keep up the fight against Alzheimer’s and dementia,” he said.
Such forward thinking also applies to major stroke trials, said Dr. Broderick of the University of Cincinnati. “As soon as we shut down enrollment in stroke trials, we immediately began to make plans about how and when we can restart our stroke trials,” he explained. “One of our trials can do every step of the trial process remotely without direct in-person interactions and will be able to restart soon.”
An individualized approach is needed, Dr. Broderick added. “For trials involving necessary in-person and hands-on assessments, we will need to consider how best to use protective equipment and expanded testing that will likely match the ongoing clinical care and requirements at a given institution.
“Even if a trial officially reopens enrollment, the decision to enroll locally will need to follow local institutional environment and guidelines. Thus, restart of trial enrollment will not likely be uniform, similar to how trials often start in the first place,” Dr. Broderick said.
The NIH published uniform standards for researchers across its institutes to help guide them during the pandemic. Future contingency plans also are underway at the NINDS.
“As the pandemic wanes and in-person research activities restart, it will be important to have in place safety measures that prevent a resurgence of the virus, such as proper personal protective equipment for staff and research participants, said Dr. Wright, the clinical research director at NINDS.
For clinical trials, NINDS is prepared to provide supplemental funds to trial investigators to help support additional activities undertaken as a result of the pandemic.
“This has been an instructive experience. The pandemic will end, and we will resume much of our old patterns of behavior,” said Ohio State’s Dr. Segal. “But some of the strategies that we have employed to get through this time will continue to influence the way we communicate information, plan experiments, and prioritize research activities in the future, to good effect.”
Drs. Snyder, Sperling, Molinuevo Guix, Elkind, Broderick, Wright, Cohen, and Segal have disclosed no relevant disclosures.
This story first appeared on Medscape.com.
However, researchers remain determined to forge ahead – with many redesigning their studies, at least in part to optimize the safety of their participants and research staff.
Keeping people engaged while protocols are on hold; expanding normal safety considerations; and re-enlisting statisticians to keep their findings as significant as possible are just some of study survival strategies underway.
Alzheimer’s disease research on hold
The pandemic is having a significant impact on Alzheimer’s disease research, and medical research in general, says Heather Snyder, PhD, vice president, Medical & Scientific Relations at the Alzheimer’s Association.
“Many clinical trials worldwide are pausing, changing, or halting the testing of the drug or the intervention,” she told Medscape Medical News. “How the teams have adapted depends on the study,” she added. “As you can imagine, things are changing on a daily basis.”
The US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) trial, for example, is on hold until at least May 31. The Alzheimer’s Association is helping to implement and fund the study along with Wake Forest University Medical Center.
“We’re not randomizing participants at this point in time and the intervention — which is based on a team meeting, and there is a social aspect to that — has been paused,” Dr. Snyder said.
Another pivotal study underway is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (the A4 Study). Investigators are evaluating if an anti-amyloid antibody, solanezumab (Eli Lilly), can slow memory loss among people with amyloid on imaging but no symptoms of cognitive decline at baseline.
“The A4 Study is definitely continuing. However, in an effort to minimize risk to participants, site staff and study integrity, we have implemented an optional study hiatus for both the double-blind and open-label extension phases,” lead investigator Reisa Anne Sperling, MD, told Medscape Medical News.
“We wanted to prioritize the safety of our participants as well as the ability of participants to remain in the study … despite disruptions from the COVID-19 pandemic,” said Dr. Sperling, who is professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.
The ultimate goal is for A4 participants to receive the full number of planned infusions and assessments, even if it takes longer, she added.
Many Alzheimer’s disease researchers outside the United States face similar challenges. “As you probably are well aware, Spain is now in a complete lockdown. This has affected research centers like ours, the Barcelona Brain Research Center, and the way we work,” José Luís Molinuevo Guix, MD, PhD, told Medscape Medical News.
All participants in observational studies like the ALFA+ study and initiatives, as well as those in trials including PENSA and AB1601, “are not allowed, by law, to come in, hence from a safety perspective we are on good grounds,” added Dr. Molinuevo Guix, who directs the Alzheimer’s disease and other cognitive disorders unit at the Hospital Clinic de Barcelona.
The investigators are creating protocols for communicating with participants during the pandemic and for restarting visits safely after the lockdown has ended.
Stroke studies amended or suspended
A similar situation is occurring in stroke trials. Stroke is “obviously an acute disease, as well as a disease that requires secondary prevention,” Mitchell Elkind, MD, president-elect of the American Heart Association, told Medscape Medical News.
“One could argue that patients with stroke are going to be in the hospital anyway – why not enroll them in a study? They’re not incurring any additional risk,” he said. “But the staff have to come in to see them, and we’re really trying to avoid exposure.”
One ongoing trial, the Atrial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA), stopped randomly assigning new participants to secondary prevention with apixaban or aspirin because of COVID-19. However, Dr. Elkind and colleagues plan to provide medication to the 440 people already in the trial.
“Wherever possible, the study coordinators are shipping the drug to people and doing follow-up visits by phone or video,” said Dr. Elkind, chief of the Division of Neurology Clinical Outcomes Research and Population Sciences at Columbia University in New York City.
Protecting patients, staff, and ultimately society is a “major driving force in stopping the randomizations,” he stressed.
ARCADIA is part of the StrokeNet prevention trials network, run by the NIH’s National Institute of Neurologic Disorders and Stroke (NINDS). Additional pivotal trials include the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and the Multi-arm Optimization of Stroke Thrombolysis (MOST) studies, he said.
Joseph Broderick, MD, director of the national NIH StrokeNet, agreed that safety comes first. “It was the decision of the StrokeNet leadership and the principal investigators of the trials that we needed to hold recruitment of new patients while we worked on adapting processes of enrollment to ensure the safety of both patients and researchers interacting with study patients,” he told Medscape Medical News.
Potential risks vary based on the study intervention and the need for in-person interactions. Trials that include stimulation devices or physical therapy, for example, might be most affected, added Dr. Broderick, professor and director of the UC Gardner Neuroscience Institute at the University of Cincinnati in Ohio.
Nevertheless, “there are potential ways … to move as much as possible toward telemedicine and digital interactions during this time.”
Multiple challenges in multiple sclerosis
At the national level, the COVID-19 pandemic has had an “unprecedented impact on almost all the clinical trials funded by NINDS,” said Clinton Wright, MD, director of the Division of Clinical Research at NINDS. “Investigators have had to adapt quickly.”
Supplementing existing grants with money to conduct research on COVID-19 and pursuing research opportunities from different institutes are “some of the creative approaches [that] have come from the NIH [National Institutes of Health] itself,” Dr. Wright said. “Other creative approaches have come from investigators trying to keep their studies and trials going during the pandemic.”
In clinical trials, “everything from electronic consent to in-home research drug delivery is being brought to bear.”
“A few ongoing trials have been able to modify their protocols to obtain consent and carry out evaluations remotely by telephone or videoconferencing,” Dr. Wright said. “This is especially critical for trials that involve medical management of specific risk factors or conditions, where suspension of the trial could itself have adverse consequences due to reduced engagement with research participants.”
For participants already in MS studies, “each upcoming visit is assessed for whether it’s critical or could be done virtually or just skipped. If a person needs a treatment that cannot be postponed or skipped, they come in,” Jeffrey Cohen, MD, director of the Experimental Therapeutics Program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, told Medscape Medical News.
New study enrollment is largely on hold and study visits for existing participants are limited, said Dr. Cohen, who is also president of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Some of the major ongoing trials in MS are “looking at very fundamental questions in the field,” Dr. Cohen said. The Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS) and Traditional Versus Early Aggressive Therapy for Multiple Sclerosis (TREAT-MS) trials, for example, evaluate whether treatment should be initiated with one of the less efficacious agents with escalation as needed, or whether treatment should begin with a high-efficacy agent.
Both trials are currently on hold because of the pandemic, as is the Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) study.
“There has been a lot of interest in hematopoietic stem cell transplants and where they fit into our overall treatment strategy, and this is intended to provide a more definitive answer,” Dr. Cohen said.
Making the most of down time
“The pandemic has been challenging” in terms of ongoing MS research, said Benjamin M. Segal, MD, chair of the Department of Neurology and director of the Neuroscience Research Institute at the Ohio State University Wexner Medical Center, Columbus.
“With regard to the lab, our animal model experiments have been placed on hold. We have stopped collecting samples from clinical subjects for biomarker studies.
“However, my research team has been taking advantage of the time that has been freed up from bench work by analyzing data sets that had been placed aside, delving more deeply into the literature, and writing new grant proposals and articles,” he added.
Two of Dr. Segal’s trainees are writing review articles on the immunopathogenesis of MS and its treatment. Another postdoctoral candidate is writing a grant proposal to investigate how coinfection with a coronavirus modulates CNS pathology and the clinical course of an animal model of MS.
“I am asking my trainees to plan out experiments further in advance than they ever have before, so they are as prepared as possible to resume their research agendas once we are up and running again,” Dr. Segal said.
Confronting current challenges while planning for a future less disrupted by the pandemic is a common theme that emerges.
“The duration of this [pandemic] will dictate how we analyze the data at the end [for the US POINTER study]. There is a large group of statisticians working on this,” Dr. Snyder said.
Dr. Sperling of Harvard Medical School also remains undeterred. “This is definitely a challenging time, as we must not allow the COVID-19 to interfere with our essential mission to find a successful treatment to prevent cognitive decline in AD. We do need, however, to be as flexible as possible to protect our participants and minimize the impact to our overall study integrity,” she said.
NIH guidance
Dr. Molinuevo Guix, of the Barcelona Brain Research Center, is also determined to continue his Alzheimer’s disease research. “I am aware that after the crisis, there will be less [risk] but still a COVID-19 infection risk, so apart from trying to generate part of our visits virtually, we want to make sure we have all necessary safety measures in place. We remain very active to preserve the work we have done to keep up the fight against Alzheimer’s and dementia,” he said.
Such forward thinking also applies to major stroke trials, said Dr. Broderick of the University of Cincinnati. “As soon as we shut down enrollment in stroke trials, we immediately began to make plans about how and when we can restart our stroke trials,” he explained. “One of our trials can do every step of the trial process remotely without direct in-person interactions and will be able to restart soon.”
An individualized approach is needed, Dr. Broderick added. “For trials involving necessary in-person and hands-on assessments, we will need to consider how best to use protective equipment and expanded testing that will likely match the ongoing clinical care and requirements at a given institution.
“Even if a trial officially reopens enrollment, the decision to enroll locally will need to follow local institutional environment and guidelines. Thus, restart of trial enrollment will not likely be uniform, similar to how trials often start in the first place,” Dr. Broderick said.
The NIH published uniform standards for researchers across its institutes to help guide them during the pandemic. Future contingency plans also are underway at the NINDS.
“As the pandemic wanes and in-person research activities restart, it will be important to have in place safety measures that prevent a resurgence of the virus, such as proper personal protective equipment for staff and research participants, said Dr. Wright, the clinical research director at NINDS.
For clinical trials, NINDS is prepared to provide supplemental funds to trial investigators to help support additional activities undertaken as a result of the pandemic.
“This has been an instructive experience. The pandemic will end, and we will resume much of our old patterns of behavior,” said Ohio State’s Dr. Segal. “But some of the strategies that we have employed to get through this time will continue to influence the way we communicate information, plan experiments, and prioritize research activities in the future, to good effect.”
Drs. Snyder, Sperling, Molinuevo Guix, Elkind, Broderick, Wright, Cohen, and Segal have disclosed no relevant disclosures.
This story first appeared on Medscape.com.
However, researchers remain determined to forge ahead – with many redesigning their studies, at least in part to optimize the safety of their participants and research staff.
Keeping people engaged while protocols are on hold; expanding normal safety considerations; and re-enlisting statisticians to keep their findings as significant as possible are just some of study survival strategies underway.
Alzheimer’s disease research on hold
The pandemic is having a significant impact on Alzheimer’s disease research, and medical research in general, says Heather Snyder, PhD, vice president, Medical & Scientific Relations at the Alzheimer’s Association.
“Many clinical trials worldwide are pausing, changing, or halting the testing of the drug or the intervention,” she told Medscape Medical News. “How the teams have adapted depends on the study,” she added. “As you can imagine, things are changing on a daily basis.”
The US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) trial, for example, is on hold until at least May 31. The Alzheimer’s Association is helping to implement and fund the study along with Wake Forest University Medical Center.
“We’re not randomizing participants at this point in time and the intervention — which is based on a team meeting, and there is a social aspect to that — has been paused,” Dr. Snyder said.
Another pivotal study underway is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (the A4 Study). Investigators are evaluating if an anti-amyloid antibody, solanezumab (Eli Lilly), can slow memory loss among people with amyloid on imaging but no symptoms of cognitive decline at baseline.
“The A4 Study is definitely continuing. However, in an effort to minimize risk to participants, site staff and study integrity, we have implemented an optional study hiatus for both the double-blind and open-label extension phases,” lead investigator Reisa Anne Sperling, MD, told Medscape Medical News.
“We wanted to prioritize the safety of our participants as well as the ability of participants to remain in the study … despite disruptions from the COVID-19 pandemic,” said Dr. Sperling, who is professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.
The ultimate goal is for A4 participants to receive the full number of planned infusions and assessments, even if it takes longer, she added.
Many Alzheimer’s disease researchers outside the United States face similar challenges. “As you probably are well aware, Spain is now in a complete lockdown. This has affected research centers like ours, the Barcelona Brain Research Center, and the way we work,” José Luís Molinuevo Guix, MD, PhD, told Medscape Medical News.
All participants in observational studies like the ALFA+ study and initiatives, as well as those in trials including PENSA and AB1601, “are not allowed, by law, to come in, hence from a safety perspective we are on good grounds,” added Dr. Molinuevo Guix, who directs the Alzheimer’s disease and other cognitive disorders unit at the Hospital Clinic de Barcelona.
The investigators are creating protocols for communicating with participants during the pandemic and for restarting visits safely after the lockdown has ended.
Stroke studies amended or suspended
A similar situation is occurring in stroke trials. Stroke is “obviously an acute disease, as well as a disease that requires secondary prevention,” Mitchell Elkind, MD, president-elect of the American Heart Association, told Medscape Medical News.
“One could argue that patients with stroke are going to be in the hospital anyway – why not enroll them in a study? They’re not incurring any additional risk,” he said. “But the staff have to come in to see them, and we’re really trying to avoid exposure.”
One ongoing trial, the Atrial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA), stopped randomly assigning new participants to secondary prevention with apixaban or aspirin because of COVID-19. However, Dr. Elkind and colleagues plan to provide medication to the 440 people already in the trial.
“Wherever possible, the study coordinators are shipping the drug to people and doing follow-up visits by phone or video,” said Dr. Elkind, chief of the Division of Neurology Clinical Outcomes Research and Population Sciences at Columbia University in New York City.
Protecting patients, staff, and ultimately society is a “major driving force in stopping the randomizations,” he stressed.
ARCADIA is part of the StrokeNet prevention trials network, run by the NIH’s National Institute of Neurologic Disorders and Stroke (NINDS). Additional pivotal trials include the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and the Multi-arm Optimization of Stroke Thrombolysis (MOST) studies, he said.
Joseph Broderick, MD, director of the national NIH StrokeNet, agreed that safety comes first. “It was the decision of the StrokeNet leadership and the principal investigators of the trials that we needed to hold recruitment of new patients while we worked on adapting processes of enrollment to ensure the safety of both patients and researchers interacting with study patients,” he told Medscape Medical News.
Potential risks vary based on the study intervention and the need for in-person interactions. Trials that include stimulation devices or physical therapy, for example, might be most affected, added Dr. Broderick, professor and director of the UC Gardner Neuroscience Institute at the University of Cincinnati in Ohio.
Nevertheless, “there are potential ways … to move as much as possible toward telemedicine and digital interactions during this time.”
Multiple challenges in multiple sclerosis
At the national level, the COVID-19 pandemic has had an “unprecedented impact on almost all the clinical trials funded by NINDS,” said Clinton Wright, MD, director of the Division of Clinical Research at NINDS. “Investigators have had to adapt quickly.”
Supplementing existing grants with money to conduct research on COVID-19 and pursuing research opportunities from different institutes are “some of the creative approaches [that] have come from the NIH [National Institutes of Health] itself,” Dr. Wright said. “Other creative approaches have come from investigators trying to keep their studies and trials going during the pandemic.”
In clinical trials, “everything from electronic consent to in-home research drug delivery is being brought to bear.”
“A few ongoing trials have been able to modify their protocols to obtain consent and carry out evaluations remotely by telephone or videoconferencing,” Dr. Wright said. “This is especially critical for trials that involve medical management of specific risk factors or conditions, where suspension of the trial could itself have adverse consequences due to reduced engagement with research participants.”
For participants already in MS studies, “each upcoming visit is assessed for whether it’s critical or could be done virtually or just skipped. If a person needs a treatment that cannot be postponed or skipped, they come in,” Jeffrey Cohen, MD, director of the Experimental Therapeutics Program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, told Medscape Medical News.
New study enrollment is largely on hold and study visits for existing participants are limited, said Dr. Cohen, who is also president of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
Some of the major ongoing trials in MS are “looking at very fundamental questions in the field,” Dr. Cohen said. The Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS) and Traditional Versus Early Aggressive Therapy for Multiple Sclerosis (TREAT-MS) trials, for example, evaluate whether treatment should be initiated with one of the less efficacious agents with escalation as needed, or whether treatment should begin with a high-efficacy agent.
Both trials are currently on hold because of the pandemic, as is the Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) study.
“There has been a lot of interest in hematopoietic stem cell transplants and where they fit into our overall treatment strategy, and this is intended to provide a more definitive answer,” Dr. Cohen said.
Making the most of down time
“The pandemic has been challenging” in terms of ongoing MS research, said Benjamin M. Segal, MD, chair of the Department of Neurology and director of the Neuroscience Research Institute at the Ohio State University Wexner Medical Center, Columbus.
“With regard to the lab, our animal model experiments have been placed on hold. We have stopped collecting samples from clinical subjects for biomarker studies.
“However, my research team has been taking advantage of the time that has been freed up from bench work by analyzing data sets that had been placed aside, delving more deeply into the literature, and writing new grant proposals and articles,” he added.
Two of Dr. Segal’s trainees are writing review articles on the immunopathogenesis of MS and its treatment. Another postdoctoral candidate is writing a grant proposal to investigate how coinfection with a coronavirus modulates CNS pathology and the clinical course of an animal model of MS.
“I am asking my trainees to plan out experiments further in advance than they ever have before, so they are as prepared as possible to resume their research agendas once we are up and running again,” Dr. Segal said.
Confronting current challenges while planning for a future less disrupted by the pandemic is a common theme that emerges.
“The duration of this [pandemic] will dictate how we analyze the data at the end [for the US POINTER study]. There is a large group of statisticians working on this,” Dr. Snyder said.
Dr. Sperling of Harvard Medical School also remains undeterred. “This is definitely a challenging time, as we must not allow the COVID-19 to interfere with our essential mission to find a successful treatment to prevent cognitive decline in AD. We do need, however, to be as flexible as possible to protect our participants and minimize the impact to our overall study integrity,” she said.
NIH guidance
Dr. Molinuevo Guix, of the Barcelona Brain Research Center, is also determined to continue his Alzheimer’s disease research. “I am aware that after the crisis, there will be less [risk] but still a COVID-19 infection risk, so apart from trying to generate part of our visits virtually, we want to make sure we have all necessary safety measures in place. We remain very active to preserve the work we have done to keep up the fight against Alzheimer’s and dementia,” he said.
Such forward thinking also applies to major stroke trials, said Dr. Broderick of the University of Cincinnati. “As soon as we shut down enrollment in stroke trials, we immediately began to make plans about how and when we can restart our stroke trials,” he explained. “One of our trials can do every step of the trial process remotely without direct in-person interactions and will be able to restart soon.”
An individualized approach is needed, Dr. Broderick added. “For trials involving necessary in-person and hands-on assessments, we will need to consider how best to use protective equipment and expanded testing that will likely match the ongoing clinical care and requirements at a given institution.
“Even if a trial officially reopens enrollment, the decision to enroll locally will need to follow local institutional environment and guidelines. Thus, restart of trial enrollment will not likely be uniform, similar to how trials often start in the first place,” Dr. Broderick said.
The NIH published uniform standards for researchers across its institutes to help guide them during the pandemic. Future contingency plans also are underway at the NINDS.
“As the pandemic wanes and in-person research activities restart, it will be important to have in place safety measures that prevent a resurgence of the virus, such as proper personal protective equipment for staff and research participants, said Dr. Wright, the clinical research director at NINDS.
For clinical trials, NINDS is prepared to provide supplemental funds to trial investigators to help support additional activities undertaken as a result of the pandemic.
“This has been an instructive experience. The pandemic will end, and we will resume much of our old patterns of behavior,” said Ohio State’s Dr. Segal. “But some of the strategies that we have employed to get through this time will continue to influence the way we communicate information, plan experiments, and prioritize research activities in the future, to good effect.”
Drs. Snyder, Sperling, Molinuevo Guix, Elkind, Broderick, Wright, Cohen, and Segal have disclosed no relevant disclosures.
This story first appeared on Medscape.com.
Phytophotodermatitis in a Butterfly Enthusiast Induced by Common Rue
To the Editor:
Phytophotodermatitis is common in dermatology during the summer months, especially in individuals who spend time outdoors; however, identification of the offending plant can be challenging. We report a case of phytophotodermatitis in which the causative plant, common rue, was not identified until it was revealed that the patient was a butterfly enthusiast.
A 60-year-old woman presented to the outpatient dermatology clinic in late summer for a routine skin examination. An eruption was noted over the right thigh and knee that had first appeared approximately 2 weeks prior. The rash started as pruritic blisters but gradually progressed to erythema and then eventually to brown markings, which were observed at the current presentation. Physical examination revealed hyperpigmented, brown, streaky, linear patches and plaques over the right thigh, knee, and lower leg (Figure). When asked about her hobbies, the patient reported an affinity for butterflies and noted that she attracts them with specific species of plants in her garden. She recalled recently planting the herb of grace, or common rue, to attract the giant swallowtail butterfly (Papilio cresphontes). Upon further inquiry, she remembered working in the garden on her knees and digging up roots near the common rue plant while wearing shorts approximately 2 weeks prior to the current presentation. Given the streaky linear pattern of the eruption along with recent sun exposure and exposure to the common rue plant, a diagnosis of phytophotodermatitis was made. No further treatment was sought, as the eruption was not bothersome to her. She was intrigued that the common rue plant had caused the dermatitis and planned on taking proper precautions when working near the plant in the future.
In this case, the observed phototoxic skin findings resulted from exposure to common rue (Ruta graveolens),a pungently scented evergreen shrub native to the Mediterranean region and a member of the Rutaceae family. Extracts have been used in homeopathic practices for bruises, sprains, headache, neck stiffness, rheumatologic pain, neuralgia, stomach problems, and phlebitis, as well as in seasonings, soaps, creams, and perfumes.1 The most commonly encountered plants known to cause phytophotodermatitis belong to the Apiaceae and Rutaceae families.2 Members of Apiaceae include angelica, celery, dill, fennel, hogweed, parsley, and parsnip. Aside from the common rue plant, the Rutaceae family also includes bergamot orange, bitter orange, burning bush (or gas plant), grapefruit, lemon, and lime. Other potential offending agents are fig, mustard, buttercup, St. John’s wort, and scurfpea. The phototoxic properties are due to furocoumarins, which include psoralens and angelicins. They are inert until activated by UVA radiation, which inflicts direct cellular damage, causing vacuolization and apoptosis of keratinocytes, similar to a sunburn.3 Clinical findings typically present 24 hours after sun exposure with erythema, edema, pain, and occasionally vesicles or bullae in severe cases. Unlike sunburn, lesions often present in linear, streaky, or bizarre patterns, reflective of the direct contact with the plant. The lesions eventually transition to hyperpigmentation, which may take months to years to resolve.
Other considerations in cases of suspected phytophotodermatitis include polymorphic light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis, solar urticaria, drug reactions, porphyria, Smith-Lemli-Opitz syndrome, lupus erythematosus, and dermatomyositis.4 Clinicians should suspect phytophotodermatitis with phototoxic findings in bartenders, citrus farm workers, gardeners, chefs, and kitchen workers, especially those handling limes and celery. As in our case, phytophotodermatitis also should be considered in butterfly enthusiasts trying to attract the giant swallowtail butterfly. The caterpillars feed on the leaves of the common rue plant, one of a select few plants that giant swallowtail butterflies use as a host due to its bitter leaves that aid in avoiding predators.5
This case illustrates a unique perspective of phytophotodermatitis, as butterfly enthusiasm is not commonly reported in association with the common rue plant with respect to phytophotodermatitis. This case underscores the importance of inquiring about patients’ professions and hobbies, both in dermatology and other specialties.
- Atta AH, Alkofahi A. Anti-nociceptive and anti-inflammatory effects of some Jordanian medicinal plant extracts. J Ethnopharmacol. 1998;60:117-124.
- McGovern TW. Dermatoses due to plants. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. Edinburgh, Scotland: Mosby; 2007:265-283.
- Hawk JLM, Calonje E. The photosensitivity disorders. In: Elder DE, ed. Lever’s Histopathology of the Skin. 9th ed. Philadelphia, Pennsylvania: Lippincott Williams and Wilkins; 2005:345-353.
- Lim HW. Abnormal responses to ultraviolet radiation: photosensitivity induced by exogenous agents. In: Wolff K, Goldsmith LA, Katz SI, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012:1066-1074.
- McAuslane H. Giant swallowtail. University of Florida Department of Entomology and Nematology Featured Creatures website. http://entnemdept.ufl.edu/creatures/citrus/giantswallowtail.htm. Revised January 2018. Accessed April 10, 2020.
To the Editor:
Phytophotodermatitis is common in dermatology during the summer months, especially in individuals who spend time outdoors; however, identification of the offending plant can be challenging. We report a case of phytophotodermatitis in which the causative plant, common rue, was not identified until it was revealed that the patient was a butterfly enthusiast.
A 60-year-old woman presented to the outpatient dermatology clinic in late summer for a routine skin examination. An eruption was noted over the right thigh and knee that had first appeared approximately 2 weeks prior. The rash started as pruritic blisters but gradually progressed to erythema and then eventually to brown markings, which were observed at the current presentation. Physical examination revealed hyperpigmented, brown, streaky, linear patches and plaques over the right thigh, knee, and lower leg (Figure). When asked about her hobbies, the patient reported an affinity for butterflies and noted that she attracts them with specific species of plants in her garden. She recalled recently planting the herb of grace, or common rue, to attract the giant swallowtail butterfly (Papilio cresphontes). Upon further inquiry, she remembered working in the garden on her knees and digging up roots near the common rue plant while wearing shorts approximately 2 weeks prior to the current presentation. Given the streaky linear pattern of the eruption along with recent sun exposure and exposure to the common rue plant, a diagnosis of phytophotodermatitis was made. No further treatment was sought, as the eruption was not bothersome to her. She was intrigued that the common rue plant had caused the dermatitis and planned on taking proper precautions when working near the plant in the future.
In this case, the observed phototoxic skin findings resulted from exposure to common rue (Ruta graveolens),a pungently scented evergreen shrub native to the Mediterranean region and a member of the Rutaceae family. Extracts have been used in homeopathic practices for bruises, sprains, headache, neck stiffness, rheumatologic pain, neuralgia, stomach problems, and phlebitis, as well as in seasonings, soaps, creams, and perfumes.1 The most commonly encountered plants known to cause phytophotodermatitis belong to the Apiaceae and Rutaceae families.2 Members of Apiaceae include angelica, celery, dill, fennel, hogweed, parsley, and parsnip. Aside from the common rue plant, the Rutaceae family also includes bergamot orange, bitter orange, burning bush (or gas plant), grapefruit, lemon, and lime. Other potential offending agents are fig, mustard, buttercup, St. John’s wort, and scurfpea. The phototoxic properties are due to furocoumarins, which include psoralens and angelicins. They are inert until activated by UVA radiation, which inflicts direct cellular damage, causing vacuolization and apoptosis of keratinocytes, similar to a sunburn.3 Clinical findings typically present 24 hours after sun exposure with erythema, edema, pain, and occasionally vesicles or bullae in severe cases. Unlike sunburn, lesions often present in linear, streaky, or bizarre patterns, reflective of the direct contact with the plant. The lesions eventually transition to hyperpigmentation, which may take months to years to resolve.
Other considerations in cases of suspected phytophotodermatitis include polymorphic light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis, solar urticaria, drug reactions, porphyria, Smith-Lemli-Opitz syndrome, lupus erythematosus, and dermatomyositis.4 Clinicians should suspect phytophotodermatitis with phototoxic findings in bartenders, citrus farm workers, gardeners, chefs, and kitchen workers, especially those handling limes and celery. As in our case, phytophotodermatitis also should be considered in butterfly enthusiasts trying to attract the giant swallowtail butterfly. The caterpillars feed on the leaves of the common rue plant, one of a select few plants that giant swallowtail butterflies use as a host due to its bitter leaves that aid in avoiding predators.5
This case illustrates a unique perspective of phytophotodermatitis, as butterfly enthusiasm is not commonly reported in association with the common rue plant with respect to phytophotodermatitis. This case underscores the importance of inquiring about patients’ professions and hobbies, both in dermatology and other specialties.
To the Editor:
Phytophotodermatitis is common in dermatology during the summer months, especially in individuals who spend time outdoors; however, identification of the offending plant can be challenging. We report a case of phytophotodermatitis in which the causative plant, common rue, was not identified until it was revealed that the patient was a butterfly enthusiast.
A 60-year-old woman presented to the outpatient dermatology clinic in late summer for a routine skin examination. An eruption was noted over the right thigh and knee that had first appeared approximately 2 weeks prior. The rash started as pruritic blisters but gradually progressed to erythema and then eventually to brown markings, which were observed at the current presentation. Physical examination revealed hyperpigmented, brown, streaky, linear patches and plaques over the right thigh, knee, and lower leg (Figure). When asked about her hobbies, the patient reported an affinity for butterflies and noted that she attracts them with specific species of plants in her garden. She recalled recently planting the herb of grace, or common rue, to attract the giant swallowtail butterfly (Papilio cresphontes). Upon further inquiry, she remembered working in the garden on her knees and digging up roots near the common rue plant while wearing shorts approximately 2 weeks prior to the current presentation. Given the streaky linear pattern of the eruption along with recent sun exposure and exposure to the common rue plant, a diagnosis of phytophotodermatitis was made. No further treatment was sought, as the eruption was not bothersome to her. She was intrigued that the common rue plant had caused the dermatitis and planned on taking proper precautions when working near the plant in the future.
In this case, the observed phototoxic skin findings resulted from exposure to common rue (Ruta graveolens),a pungently scented evergreen shrub native to the Mediterranean region and a member of the Rutaceae family. Extracts have been used in homeopathic practices for bruises, sprains, headache, neck stiffness, rheumatologic pain, neuralgia, stomach problems, and phlebitis, as well as in seasonings, soaps, creams, and perfumes.1 The most commonly encountered plants known to cause phytophotodermatitis belong to the Apiaceae and Rutaceae families.2 Members of Apiaceae include angelica, celery, dill, fennel, hogweed, parsley, and parsnip. Aside from the common rue plant, the Rutaceae family also includes bergamot orange, bitter orange, burning bush (or gas plant), grapefruit, lemon, and lime. Other potential offending agents are fig, mustard, buttercup, St. John’s wort, and scurfpea. The phototoxic properties are due to furocoumarins, which include psoralens and angelicins. They are inert until activated by UVA radiation, which inflicts direct cellular damage, causing vacuolization and apoptosis of keratinocytes, similar to a sunburn.3 Clinical findings typically present 24 hours after sun exposure with erythema, edema, pain, and occasionally vesicles or bullae in severe cases. Unlike sunburn, lesions often present in linear, streaky, or bizarre patterns, reflective of the direct contact with the plant. The lesions eventually transition to hyperpigmentation, which may take months to years to resolve.
Other considerations in cases of suspected phytophotodermatitis include polymorphic light eruption, actinic prurigo, hydroa vacciniforme, chronic actinic dermatitis, solar urticaria, drug reactions, porphyria, Smith-Lemli-Opitz syndrome, lupus erythematosus, and dermatomyositis.4 Clinicians should suspect phytophotodermatitis with phototoxic findings in bartenders, citrus farm workers, gardeners, chefs, and kitchen workers, especially those handling limes and celery. As in our case, phytophotodermatitis also should be considered in butterfly enthusiasts trying to attract the giant swallowtail butterfly. The caterpillars feed on the leaves of the common rue plant, one of a select few plants that giant swallowtail butterflies use as a host due to its bitter leaves that aid in avoiding predators.5
This case illustrates a unique perspective of phytophotodermatitis, as butterfly enthusiasm is not commonly reported in association with the common rue plant with respect to phytophotodermatitis. This case underscores the importance of inquiring about patients’ professions and hobbies, both in dermatology and other specialties.
- Atta AH, Alkofahi A. Anti-nociceptive and anti-inflammatory effects of some Jordanian medicinal plant extracts. J Ethnopharmacol. 1998;60:117-124.
- McGovern TW. Dermatoses due to plants. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. Edinburgh, Scotland: Mosby; 2007:265-283.
- Hawk JLM, Calonje E. The photosensitivity disorders. In: Elder DE, ed. Lever’s Histopathology of the Skin. 9th ed. Philadelphia, Pennsylvania: Lippincott Williams and Wilkins; 2005:345-353.
- Lim HW. Abnormal responses to ultraviolet radiation: photosensitivity induced by exogenous agents. In: Wolff K, Goldsmith LA, Katz SI, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012:1066-1074.
- McAuslane H. Giant swallowtail. University of Florida Department of Entomology and Nematology Featured Creatures website. http://entnemdept.ufl.edu/creatures/citrus/giantswallowtail.htm. Revised January 2018. Accessed April 10, 2020.
- Atta AH, Alkofahi A. Anti-nociceptive and anti-inflammatory effects of some Jordanian medicinal plant extracts. J Ethnopharmacol. 1998;60:117-124.
- McGovern TW. Dermatoses due to plants. In: Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. Edinburgh, Scotland: Mosby; 2007:265-283.
- Hawk JLM, Calonje E. The photosensitivity disorders. In: Elder DE, ed. Lever’s Histopathology of the Skin. 9th ed. Philadelphia, Pennsylvania: Lippincott Williams and Wilkins; 2005:345-353.
- Lim HW. Abnormal responses to ultraviolet radiation: photosensitivity induced by exogenous agents. In: Wolff K, Goldsmith LA, Katz SI, et al, eds. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York, NY: McGraw-Hill; 2012:1066-1074.
- McAuslane H. Giant swallowtail. University of Florida Department of Entomology and Nematology Featured Creatures website. http://entnemdept.ufl.edu/creatures/citrus/giantswallowtail.htm. Revised January 2018. Accessed April 10, 2020.
Practice Points
- It is important to inquire about patients’ professions and hobbies, which may lead to the diagnosis, as in this case of a butterfly enthusiast trying to attract the giant swallowtail butterfly with the common rue plant.
- One should suspect phytophotodermatitis with phototoxic findings in bartenders, citrus farm workers, gardeners, chefs, and kitchen workers, especially those handling limes and celery
Remdesivir now ‘standard of care’ for COVID-19, Fauci says
, according to a preliminary data analysis from a U.S.-led randomized, controlled trial.
On the basis of as yet unpublished data, remdesivir “will be the standard of care” for patients with COVID-19, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), said during a press conference at the White House April 29.
The randomized, placebo-controlled international trial was sponsored by NIAID, which is part of the National Institutes of Health, and enrolled 1,063 patients. It began on Feb. 21.
The interim results, discussed in the press conference and in a NIAID press release, show that time to recovery (i.e., being well enough for hospital discharge or to return to normal activity level) was 31% faster for patients who received remdesivir than for those who received placebo (P < .001).
The median time to recovery was 11 days for patients treated with remdesivir, compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir and 11.6% for the patients who received placebo (P = .059).
The study, known as the Adaptive COVID-19 Treatment Trial (ACTT), is the first clinical trial launched in the United States to evaluate an experimental treatment for COVID-19. It is being conducted at 68 sites – 47 in the United States and 21 in countries in Europe and Asia.
The data are being released after an interim review by the independent data safety monitoring board found significant benefit with the drug, Dr. Fauci said.
“The reason we are making the announcement now is something that people don’t fully appreciate: Whenever you have clear-cut evidence that a drug works, you have an ethical obligation to let the people in the placebo group know so they could have access,” he explained.
“When I was looking at the data with our team the other night, it was reminiscent of 34 years ago in 1986 when we were struggling for drugs for HIV,” said Dr. Fauci, who was a key figure in HIV/AIDS research. “We did the first randomized, placebo-controlled trial with AZT. It turned out to have an effect that was modest but that was not the endgame because, building on that, every year after, we did better and better.”
Similarly, new trials of drugs for COVID-19 will build on remdesivir, with other agents being added to block other pathways or viral enzymes, Dr. Fauci said.
The study will be submitted to a journal for peer review, he noted, but the New York Times is reporting that the Food and Drug Administration will approve remdesivir for emergency use soon.
In contrast to the positive results Dr. Fauci described from the NIAID-sponsored trial, a randomized, placebo-controlled clinical trial of remdesivir among hospitalized patients with severe COVID-19 in China was inconclusive.
The study, published online in The Lancet, showed some nonsignificant trends toward benefit but did not meet its primary endpoint.
The study was stopped early after 237 of the intended 453 patients were enrolled, owing to a lack of additional patients who met the eligibility criteria. The trial was thus underpowered.
Results showed that treatment with remdesivir did not significantly speed recovery or reduce deaths from COVID-19, but with regard to prespecified secondary outcomes, time to clinical improvement and duration of invasive mechanical ventilation were shorter among a subgroup of patients who began undergoing treatment with remdesivir within 10 days of showing symptoms, in comparison with patients who received standard care.
“To me, the studies reported here in The Lancet appear to be less promising than some statements released today from the NIH, so the situation is a bit puzzling to me,” said Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, who was not involved in the study. “I would need to look more closely at the data which NIH is looking at to understand the differences.”
Trial details
The published trial was conducted at 10 hospitals in Hubei, China. Enrollment criteria included being admitted to hospital with laboratory-confirmed SARS-CoV-2 infection within 12 days of symptom onset, having oxygen saturation of 94% or less, and having radiologically confirmed pneumonia.
Patients were randomly assigned in a 2:1 ratio to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids.
The primary endpoint was time to clinical improvement to day 28, defined as the time (in days) from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (on that scale, 1 indicated that the patient was discharged, and 6 indicated death) or to the patient’s being discharged alive from hospital, whichever came first.
The trial was stopped early because stringent public health measures used in Wuhan led to marked reductions in new patient presentations and because lack of available hospital beds resulted in most patients being enrolled later in the course of disease.
Between Feb. 6, 2020, and March 12, 2020, 237 patients were enrolled and were randomly assigned to receive either remdesivir (n = 158) or placebo (n = 79).
Results showed that use of remdesivir was not associated with a difference in time to clinical improvement (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.87-1.75).
Although not statistically significant, time to clinical improvement was numerically faster for patients who received remdesivir than for those who received placebo among patients with symptom duration of 10 days or less (median, 18 days vs. 23 days; HR, 1.52; 95% CI, 0.95-2.43).
The mortality rates were similar for the two groups (14% of patients who received remdesivir died vs. 13% of those who received placebo). There was no signal that viral load decreased differentially over time between the two groups.
Adverse events were reported in 66% of remdesivir recipients, vs. 64% of those who received placebo. Remdesivir was stopped early because of adverse events in 12% of patients; it was stopped early for 5% of those who received placebo.
The authors, led by Yeming Wang, MD, China-Japan Friendship Hospital, Beijing, noted that compared with a previous study of compassionate use of remdesivir, the population in the current study was less ill and was treated somewhat earlier in the disease course (median, 10 days vs. 12 days).
Because the study was terminated early, the researchers said they could not adequately assess whether earlier treatment with remdesivir might have provided clinical benefit.
“However, among patients who were treated within 10 days of symptom onset, remdesivir was not a significant factor but was associated with a numerical reduction of 5 days in median time to clinical improvement,” they stated.
They added that remdesivir was adequately tolerated and that no new safety concerns were identified.
In an accompanying comment in The Lancet, John David Norrie, MD, Edinburgh Clinical Trials Unit, United Kingdom, pointed out that this study “has not shown a statistically significant finding that confirms a remdesivir treatment benefit of at least the minimally clinically important difference, nor has it ruled such a benefit out.”
Dr. Norrie was cautious about the fact that the subgroup analysis suggested possible benefit for those treated within 10 days.
Although he said it seems biologically plausible that treating patients earlier could be more effective, he added that “as well as being vigilant against overinterpretation, we need to ensure that hypotheses generated in efficacy-based trials, even in subgroups, are confirmed or refuted in subsequent adequately powered trials or meta-analyses.”
Noting that several other trials of remdesivir are underway, he concluded: “With each individual study at heightened risk of being incomplete, pooling data across possibly several underpowered but high-quality studies looks like our best way to obtain robust insights into what works, safely, and on whom.”
A version of this article originally appeared on Medscape.com.
, according to a preliminary data analysis from a U.S.-led randomized, controlled trial.
On the basis of as yet unpublished data, remdesivir “will be the standard of care” for patients with COVID-19, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), said during a press conference at the White House April 29.
The randomized, placebo-controlled international trial was sponsored by NIAID, which is part of the National Institutes of Health, and enrolled 1,063 patients. It began on Feb. 21.
The interim results, discussed in the press conference and in a NIAID press release, show that time to recovery (i.e., being well enough for hospital discharge or to return to normal activity level) was 31% faster for patients who received remdesivir than for those who received placebo (P < .001).
The median time to recovery was 11 days for patients treated with remdesivir, compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir and 11.6% for the patients who received placebo (P = .059).
The study, known as the Adaptive COVID-19 Treatment Trial (ACTT), is the first clinical trial launched in the United States to evaluate an experimental treatment for COVID-19. It is being conducted at 68 sites – 47 in the United States and 21 in countries in Europe and Asia.
The data are being released after an interim review by the independent data safety monitoring board found significant benefit with the drug, Dr. Fauci said.
“The reason we are making the announcement now is something that people don’t fully appreciate: Whenever you have clear-cut evidence that a drug works, you have an ethical obligation to let the people in the placebo group know so they could have access,” he explained.
“When I was looking at the data with our team the other night, it was reminiscent of 34 years ago in 1986 when we were struggling for drugs for HIV,” said Dr. Fauci, who was a key figure in HIV/AIDS research. “We did the first randomized, placebo-controlled trial with AZT. It turned out to have an effect that was modest but that was not the endgame because, building on that, every year after, we did better and better.”
Similarly, new trials of drugs for COVID-19 will build on remdesivir, with other agents being added to block other pathways or viral enzymes, Dr. Fauci said.
The study will be submitted to a journal for peer review, he noted, but the New York Times is reporting that the Food and Drug Administration will approve remdesivir for emergency use soon.
In contrast to the positive results Dr. Fauci described from the NIAID-sponsored trial, a randomized, placebo-controlled clinical trial of remdesivir among hospitalized patients with severe COVID-19 in China was inconclusive.
The study, published online in The Lancet, showed some nonsignificant trends toward benefit but did not meet its primary endpoint.
The study was stopped early after 237 of the intended 453 patients were enrolled, owing to a lack of additional patients who met the eligibility criteria. The trial was thus underpowered.
Results showed that treatment with remdesivir did not significantly speed recovery or reduce deaths from COVID-19, but with regard to prespecified secondary outcomes, time to clinical improvement and duration of invasive mechanical ventilation were shorter among a subgroup of patients who began undergoing treatment with remdesivir within 10 days of showing symptoms, in comparison with patients who received standard care.
“To me, the studies reported here in The Lancet appear to be less promising than some statements released today from the NIH, so the situation is a bit puzzling to me,” said Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, who was not involved in the study. “I would need to look more closely at the data which NIH is looking at to understand the differences.”
Trial details
The published trial was conducted at 10 hospitals in Hubei, China. Enrollment criteria included being admitted to hospital with laboratory-confirmed SARS-CoV-2 infection within 12 days of symptom onset, having oxygen saturation of 94% or less, and having radiologically confirmed pneumonia.
Patients were randomly assigned in a 2:1 ratio to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids.
The primary endpoint was time to clinical improvement to day 28, defined as the time (in days) from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (on that scale, 1 indicated that the patient was discharged, and 6 indicated death) or to the patient’s being discharged alive from hospital, whichever came first.
The trial was stopped early because stringent public health measures used in Wuhan led to marked reductions in new patient presentations and because lack of available hospital beds resulted in most patients being enrolled later in the course of disease.
Between Feb. 6, 2020, and March 12, 2020, 237 patients were enrolled and were randomly assigned to receive either remdesivir (n = 158) or placebo (n = 79).
Results showed that use of remdesivir was not associated with a difference in time to clinical improvement (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.87-1.75).
Although not statistically significant, time to clinical improvement was numerically faster for patients who received remdesivir than for those who received placebo among patients with symptom duration of 10 days or less (median, 18 days vs. 23 days; HR, 1.52; 95% CI, 0.95-2.43).
The mortality rates were similar for the two groups (14% of patients who received remdesivir died vs. 13% of those who received placebo). There was no signal that viral load decreased differentially over time between the two groups.
Adverse events were reported in 66% of remdesivir recipients, vs. 64% of those who received placebo. Remdesivir was stopped early because of adverse events in 12% of patients; it was stopped early for 5% of those who received placebo.
The authors, led by Yeming Wang, MD, China-Japan Friendship Hospital, Beijing, noted that compared with a previous study of compassionate use of remdesivir, the population in the current study was less ill and was treated somewhat earlier in the disease course (median, 10 days vs. 12 days).
Because the study was terminated early, the researchers said they could not adequately assess whether earlier treatment with remdesivir might have provided clinical benefit.
“However, among patients who were treated within 10 days of symptom onset, remdesivir was not a significant factor but was associated with a numerical reduction of 5 days in median time to clinical improvement,” they stated.
They added that remdesivir was adequately tolerated and that no new safety concerns were identified.
In an accompanying comment in The Lancet, John David Norrie, MD, Edinburgh Clinical Trials Unit, United Kingdom, pointed out that this study “has not shown a statistically significant finding that confirms a remdesivir treatment benefit of at least the minimally clinically important difference, nor has it ruled such a benefit out.”
Dr. Norrie was cautious about the fact that the subgroup analysis suggested possible benefit for those treated within 10 days.
Although he said it seems biologically plausible that treating patients earlier could be more effective, he added that “as well as being vigilant against overinterpretation, we need to ensure that hypotheses generated in efficacy-based trials, even in subgroups, are confirmed or refuted in subsequent adequately powered trials or meta-analyses.”
Noting that several other trials of remdesivir are underway, he concluded: “With each individual study at heightened risk of being incomplete, pooling data across possibly several underpowered but high-quality studies looks like our best way to obtain robust insights into what works, safely, and on whom.”
A version of this article originally appeared on Medscape.com.
, according to a preliminary data analysis from a U.S.-led randomized, controlled trial.
On the basis of as yet unpublished data, remdesivir “will be the standard of care” for patients with COVID-19, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), said during a press conference at the White House April 29.
The randomized, placebo-controlled international trial was sponsored by NIAID, which is part of the National Institutes of Health, and enrolled 1,063 patients. It began on Feb. 21.
The interim results, discussed in the press conference and in a NIAID press release, show that time to recovery (i.e., being well enough for hospital discharge or to return to normal activity level) was 31% faster for patients who received remdesivir than for those who received placebo (P < .001).
The median time to recovery was 11 days for patients treated with remdesivir, compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir and 11.6% for the patients who received placebo (P = .059).
The study, known as the Adaptive COVID-19 Treatment Trial (ACTT), is the first clinical trial launched in the United States to evaluate an experimental treatment for COVID-19. It is being conducted at 68 sites – 47 in the United States and 21 in countries in Europe and Asia.
The data are being released after an interim review by the independent data safety monitoring board found significant benefit with the drug, Dr. Fauci said.
“The reason we are making the announcement now is something that people don’t fully appreciate: Whenever you have clear-cut evidence that a drug works, you have an ethical obligation to let the people in the placebo group know so they could have access,” he explained.
“When I was looking at the data with our team the other night, it was reminiscent of 34 years ago in 1986 when we were struggling for drugs for HIV,” said Dr. Fauci, who was a key figure in HIV/AIDS research. “We did the first randomized, placebo-controlled trial with AZT. It turned out to have an effect that was modest but that was not the endgame because, building on that, every year after, we did better and better.”
Similarly, new trials of drugs for COVID-19 will build on remdesivir, with other agents being added to block other pathways or viral enzymes, Dr. Fauci said.
The study will be submitted to a journal for peer review, he noted, but the New York Times is reporting that the Food and Drug Administration will approve remdesivir for emergency use soon.
In contrast to the positive results Dr. Fauci described from the NIAID-sponsored trial, a randomized, placebo-controlled clinical trial of remdesivir among hospitalized patients with severe COVID-19 in China was inconclusive.
The study, published online in The Lancet, showed some nonsignificant trends toward benefit but did not meet its primary endpoint.
The study was stopped early after 237 of the intended 453 patients were enrolled, owing to a lack of additional patients who met the eligibility criteria. The trial was thus underpowered.
Results showed that treatment with remdesivir did not significantly speed recovery or reduce deaths from COVID-19, but with regard to prespecified secondary outcomes, time to clinical improvement and duration of invasive mechanical ventilation were shorter among a subgroup of patients who began undergoing treatment with remdesivir within 10 days of showing symptoms, in comparison with patients who received standard care.
“To me, the studies reported here in The Lancet appear to be less promising than some statements released today from the NIH, so the situation is a bit puzzling to me,” said Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, who was not involved in the study. “I would need to look more closely at the data which NIH is looking at to understand the differences.”
Trial details
The published trial was conducted at 10 hospitals in Hubei, China. Enrollment criteria included being admitted to hospital with laboratory-confirmed SARS-CoV-2 infection within 12 days of symptom onset, having oxygen saturation of 94% or less, and having radiologically confirmed pneumonia.
Patients were randomly assigned in a 2:1 ratio to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids.
The primary endpoint was time to clinical improvement to day 28, defined as the time (in days) from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (on that scale, 1 indicated that the patient was discharged, and 6 indicated death) or to the patient’s being discharged alive from hospital, whichever came first.
The trial was stopped early because stringent public health measures used in Wuhan led to marked reductions in new patient presentations and because lack of available hospital beds resulted in most patients being enrolled later in the course of disease.
Between Feb. 6, 2020, and March 12, 2020, 237 patients were enrolled and were randomly assigned to receive either remdesivir (n = 158) or placebo (n = 79).
Results showed that use of remdesivir was not associated with a difference in time to clinical improvement (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.87-1.75).
Although not statistically significant, time to clinical improvement was numerically faster for patients who received remdesivir than for those who received placebo among patients with symptom duration of 10 days or less (median, 18 days vs. 23 days; HR, 1.52; 95% CI, 0.95-2.43).
The mortality rates were similar for the two groups (14% of patients who received remdesivir died vs. 13% of those who received placebo). There was no signal that viral load decreased differentially over time between the two groups.
Adverse events were reported in 66% of remdesivir recipients, vs. 64% of those who received placebo. Remdesivir was stopped early because of adverse events in 12% of patients; it was stopped early for 5% of those who received placebo.
The authors, led by Yeming Wang, MD, China-Japan Friendship Hospital, Beijing, noted that compared with a previous study of compassionate use of remdesivir, the population in the current study was less ill and was treated somewhat earlier in the disease course (median, 10 days vs. 12 days).
Because the study was terminated early, the researchers said they could not adequately assess whether earlier treatment with remdesivir might have provided clinical benefit.
“However, among patients who were treated within 10 days of symptom onset, remdesivir was not a significant factor but was associated with a numerical reduction of 5 days in median time to clinical improvement,” they stated.
They added that remdesivir was adequately tolerated and that no new safety concerns were identified.
In an accompanying comment in The Lancet, John David Norrie, MD, Edinburgh Clinical Trials Unit, United Kingdom, pointed out that this study “has not shown a statistically significant finding that confirms a remdesivir treatment benefit of at least the minimally clinically important difference, nor has it ruled such a benefit out.”
Dr. Norrie was cautious about the fact that the subgroup analysis suggested possible benefit for those treated within 10 days.
Although he said it seems biologically plausible that treating patients earlier could be more effective, he added that “as well as being vigilant against overinterpretation, we need to ensure that hypotheses generated in efficacy-based trials, even in subgroups, are confirmed or refuted in subsequent adequately powered trials or meta-analyses.”
Noting that several other trials of remdesivir are underway, he concluded: “With each individual study at heightened risk of being incomplete, pooling data across possibly several underpowered but high-quality studies looks like our best way to obtain robust insights into what works, safely, and on whom.”
A version of this article originally appeared on Medscape.com.
Purple oral plaques
The papules were clinically consistent with Kaposi sarcoma (KS) and confirmed with a biopsy from the buccal mucosa. The patient had not been given a diagnosis of human immunodeficiency virus (HIV) prior to this presentation. However, the physician confirmed the diagnosis with RNA titers. A CD4 count < 40 cells/mm3 (reference range, 500-1200 cells/mm3) pointed to her progression to AIDS. A chest X-ray revealed multiple nodules; a subsequent biopsy indicated that they were consistent with KS.
KS is a low-grade tumor of vascular origin associated with human herpesvirus-8 (HHV-8). It most often presents on the skin as flat to raised pink to deep purple lesions. It can manifest in the oral mucosa, viscera, and other organs, which can portend a worse prognosis because of the risks associated with bleeding and organ perforation.
There are 4 types of KS.
- Classic KS occurs most often in elderly men of Mediterranean descent.
- HIV-associated KS can occur at any time during HIV infection but is more common as CD4 counts fall. HIV-associated KS increased in frequency dramatically in the United States during the early years of the HIV pandemic prior to effective antiretroviral therapy (ART).
- Endemic KS occurs in equatorial Africa, where there is a natural increased transmission rate of HHV-8.
- Iatrogenic KS can occur following treatment with immunosuppressive therapies.
Our patient was admitted to the Infectious Disease Service and given ART. Chemotherapy was discussed (and sometimes is warranted in extensive visceral disease) but the patient and her specialists opted for ART alone. In addition to ART, she was started on daily trimethoprim-sulfamethoxazole for pneumocystis prophylaxis.
At 6 months’ follow-up with Infectious Disease, the patient’s oral lesions resolved, CD4 count increased above 200 cells/mm3, and HIV RNA titers fell.
Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.
Thariat J, Kirova Y, Sio T, et al. Mucosal Kaposi sarcoma, a Rare Cancer Network study. Rare Tumors. 2012;4:E49.
The papules were clinically consistent with Kaposi sarcoma (KS) and confirmed with a biopsy from the buccal mucosa. The patient had not been given a diagnosis of human immunodeficiency virus (HIV) prior to this presentation. However, the physician confirmed the diagnosis with RNA titers. A CD4 count < 40 cells/mm3 (reference range, 500-1200 cells/mm3) pointed to her progression to AIDS. A chest X-ray revealed multiple nodules; a subsequent biopsy indicated that they were consistent with KS.
KS is a low-grade tumor of vascular origin associated with human herpesvirus-8 (HHV-8). It most often presents on the skin as flat to raised pink to deep purple lesions. It can manifest in the oral mucosa, viscera, and other organs, which can portend a worse prognosis because of the risks associated with bleeding and organ perforation.
There are 4 types of KS.
- Classic KS occurs most often in elderly men of Mediterranean descent.
- HIV-associated KS can occur at any time during HIV infection but is more common as CD4 counts fall. HIV-associated KS increased in frequency dramatically in the United States during the early years of the HIV pandemic prior to effective antiretroviral therapy (ART).
- Endemic KS occurs in equatorial Africa, where there is a natural increased transmission rate of HHV-8.
- Iatrogenic KS can occur following treatment with immunosuppressive therapies.
Our patient was admitted to the Infectious Disease Service and given ART. Chemotherapy was discussed (and sometimes is warranted in extensive visceral disease) but the patient and her specialists opted for ART alone. In addition to ART, she was started on daily trimethoprim-sulfamethoxazole for pneumocystis prophylaxis.
At 6 months’ follow-up with Infectious Disease, the patient’s oral lesions resolved, CD4 count increased above 200 cells/mm3, and HIV RNA titers fell.
Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.
The papules were clinically consistent with Kaposi sarcoma (KS) and confirmed with a biopsy from the buccal mucosa. The patient had not been given a diagnosis of human immunodeficiency virus (HIV) prior to this presentation. However, the physician confirmed the diagnosis with RNA titers. A CD4 count < 40 cells/mm3 (reference range, 500-1200 cells/mm3) pointed to her progression to AIDS. A chest X-ray revealed multiple nodules; a subsequent biopsy indicated that they were consistent with KS.
KS is a low-grade tumor of vascular origin associated with human herpesvirus-8 (HHV-8). It most often presents on the skin as flat to raised pink to deep purple lesions. It can manifest in the oral mucosa, viscera, and other organs, which can portend a worse prognosis because of the risks associated with bleeding and organ perforation.
There are 4 types of KS.
- Classic KS occurs most often in elderly men of Mediterranean descent.
- HIV-associated KS can occur at any time during HIV infection but is more common as CD4 counts fall. HIV-associated KS increased in frequency dramatically in the United States during the early years of the HIV pandemic prior to effective antiretroviral therapy (ART).
- Endemic KS occurs in equatorial Africa, where there is a natural increased transmission rate of HHV-8.
- Iatrogenic KS can occur following treatment with immunosuppressive therapies.
Our patient was admitted to the Infectious Disease Service and given ART. Chemotherapy was discussed (and sometimes is warranted in extensive visceral disease) but the patient and her specialists opted for ART alone. In addition to ART, she was started on daily trimethoprim-sulfamethoxazole for pneumocystis prophylaxis.
At 6 months’ follow-up with Infectious Disease, the patient’s oral lesions resolved, CD4 count increased above 200 cells/mm3, and HIV RNA titers fell.
Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, ME.
Thariat J, Kirova Y, Sio T, et al. Mucosal Kaposi sarcoma, a Rare Cancer Network study. Rare Tumors. 2012;4:E49.
Thariat J, Kirova Y, Sio T, et al. Mucosal Kaposi sarcoma, a Rare Cancer Network study. Rare Tumors. 2012;4:E49.
Remaining connected
Dear colleagues,
We bring you the spring edition of The New Gastroenterologist amid a backdrop of uncertainty in the setting of the novel coronavirus disease 2019 (COVID-19) pandemic. As physicians, we are poised to view this unprecedented situation in modern medicine through a unique lens. At the time of this writing, we are experiencing significant interruptions to our work as gastroenterologists coupled with the possibility of reassignments in order to care for COVID-19 patients to meet the demand of the precipitous rise in cases. Weighing these responsibilities, along with the heightened concern about the threat of exposure to ourselves and our families, is a formidable challenge, but one that we can navigate together.
My sincere hope is that this quarter’s newsletter can provide, at the very least, a brief reprieve from some of these constant stressors. It is during times like this that remaining connected to our colleagues through digital platforms and publications such as The New Gastroenterologist remains of utmost importance.
That being said, I felt it was prudent to first address some common concerns regarding the COVID-19 pandemic, specifically, its implications within gastroenterology. In conjunction with Krishna Rao (University of Michigan), a specialist in infectious diseases, we attempt to shed some light on what is a rapidly evolving situation. For more resources from the American Gastroenterological Association (AGA) on up-to-date clinical guidance and research, you can also visit https://www.gastro.org/practice-guidance/practice-updates/covid-19.
Moving on to our “In Focus” feature, Thangam Ventakesan and Harrison Mooers (Medical College of Wisconsin) provide a comprehensive overview of cyclic vomiting syndrome. This is a valuable read as cyclic vomiting syndrome has been gaining increased recognition among adults, and Dr. Ventakesan and Dr. Mooers elucidate a thorough approach to the diagnosis and treatment of this disorder.
A facet of endoscopy that is extremely important, but frequently overlooked, is ergonomics. Manish Singla and Jared Magee (Walter Reed National Military Medical Center) compile a high-yield list of recommendations on the best practices to preserve our own safety and health as endoscopists.
We continue our medical ethics series with Jennifer Wang and Andrew Aronsohn (University of Chicago) who offer a thought-provoking discussion on the role of early liver transplantation for alcoholic hepatitis, including an analysis of the medical, psychosocial, and ethical considerations.
Also in this issue, Animesh Jain (University of North Carolina) gives us some excellent financial advice on student loan management, outlining a basic strategy of repayment with clear explanations of the available options including refinancing, public service loan forgiveness, and income-driven repayment.
Dilhana Badurdeen (Johns Hopkins), Aline Charabaty Pishvaian (Sibley Memorial Hospital), Miguel Malespin (University of South Florida), Ibironke Oduyebo (Midatlantic Permanente Medical Group), and Sandra Quezada (University of Maryland) give us an in-depth summary of the efforts of the AGA’s Diversity Committee, including publications, events, and future initiatives.
This quarter’s DHPA Private Practice Perspectives series features Paul Berggreen (Arizona Digestive Health), who reviews the advantages and disadvantages of pathology lab ownership as a gastroenterologist. Lastly, Sarah Ordway, Dawn Torres, Manish Singla, and Adam Tritsch (Walter Reed National Military Medical Center) broach the issue of fellowship burnout by providing guidance on how to identify signs and those at risk in addition to providing tangible solutions that any fellowship can incorporate.
Although the cancellation of the upcoming DDW meetings in Chicago is a disappointment, I hope that we can all take this time to prioritize the well-being of ourselves and our communities until we meet again.
As always, if you have interest in contributing or have ideas for future TNG topics, please contact me (vijayarao@medicine.bsd.uchicago.edu), or Ryan Farrell (rfarrell@gastro.org), managing editor of TNG.
Best wishes to stay safe and healthy.
Vijaya L. Rao, MD
Editor in Chief
Dr. Rao is assistant professor of medicine, University of Chicago, section of gastroenterology, hepatology & nutrition.
Dear colleagues,
We bring you the spring edition of The New Gastroenterologist amid a backdrop of uncertainty in the setting of the novel coronavirus disease 2019 (COVID-19) pandemic. As physicians, we are poised to view this unprecedented situation in modern medicine through a unique lens. At the time of this writing, we are experiencing significant interruptions to our work as gastroenterologists coupled with the possibility of reassignments in order to care for COVID-19 patients to meet the demand of the precipitous rise in cases. Weighing these responsibilities, along with the heightened concern about the threat of exposure to ourselves and our families, is a formidable challenge, but one that we can navigate together.
My sincere hope is that this quarter’s newsletter can provide, at the very least, a brief reprieve from some of these constant stressors. It is during times like this that remaining connected to our colleagues through digital platforms and publications such as The New Gastroenterologist remains of utmost importance.
That being said, I felt it was prudent to first address some common concerns regarding the COVID-19 pandemic, specifically, its implications within gastroenterology. In conjunction with Krishna Rao (University of Michigan), a specialist in infectious diseases, we attempt to shed some light on what is a rapidly evolving situation. For more resources from the American Gastroenterological Association (AGA) on up-to-date clinical guidance and research, you can also visit https://www.gastro.org/practice-guidance/practice-updates/covid-19.
Moving on to our “In Focus” feature, Thangam Ventakesan and Harrison Mooers (Medical College of Wisconsin) provide a comprehensive overview of cyclic vomiting syndrome. This is a valuable read as cyclic vomiting syndrome has been gaining increased recognition among adults, and Dr. Ventakesan and Dr. Mooers elucidate a thorough approach to the diagnosis and treatment of this disorder.
A facet of endoscopy that is extremely important, but frequently overlooked, is ergonomics. Manish Singla and Jared Magee (Walter Reed National Military Medical Center) compile a high-yield list of recommendations on the best practices to preserve our own safety and health as endoscopists.
We continue our medical ethics series with Jennifer Wang and Andrew Aronsohn (University of Chicago) who offer a thought-provoking discussion on the role of early liver transplantation for alcoholic hepatitis, including an analysis of the medical, psychosocial, and ethical considerations.
Also in this issue, Animesh Jain (University of North Carolina) gives us some excellent financial advice on student loan management, outlining a basic strategy of repayment with clear explanations of the available options including refinancing, public service loan forgiveness, and income-driven repayment.
Dilhana Badurdeen (Johns Hopkins), Aline Charabaty Pishvaian (Sibley Memorial Hospital), Miguel Malespin (University of South Florida), Ibironke Oduyebo (Midatlantic Permanente Medical Group), and Sandra Quezada (University of Maryland) give us an in-depth summary of the efforts of the AGA’s Diversity Committee, including publications, events, and future initiatives.
This quarter’s DHPA Private Practice Perspectives series features Paul Berggreen (Arizona Digestive Health), who reviews the advantages and disadvantages of pathology lab ownership as a gastroenterologist. Lastly, Sarah Ordway, Dawn Torres, Manish Singla, and Adam Tritsch (Walter Reed National Military Medical Center) broach the issue of fellowship burnout by providing guidance on how to identify signs and those at risk in addition to providing tangible solutions that any fellowship can incorporate.
Although the cancellation of the upcoming DDW meetings in Chicago is a disappointment, I hope that we can all take this time to prioritize the well-being of ourselves and our communities until we meet again.
As always, if you have interest in contributing or have ideas for future TNG topics, please contact me (vijayarao@medicine.bsd.uchicago.edu), or Ryan Farrell (rfarrell@gastro.org), managing editor of TNG.
Best wishes to stay safe and healthy.
Vijaya L. Rao, MD
Editor in Chief
Dr. Rao is assistant professor of medicine, University of Chicago, section of gastroenterology, hepatology & nutrition.
Dear colleagues,
We bring you the spring edition of The New Gastroenterologist amid a backdrop of uncertainty in the setting of the novel coronavirus disease 2019 (COVID-19) pandemic. As physicians, we are poised to view this unprecedented situation in modern medicine through a unique lens. At the time of this writing, we are experiencing significant interruptions to our work as gastroenterologists coupled with the possibility of reassignments in order to care for COVID-19 patients to meet the demand of the precipitous rise in cases. Weighing these responsibilities, along with the heightened concern about the threat of exposure to ourselves and our families, is a formidable challenge, but one that we can navigate together.
My sincere hope is that this quarter’s newsletter can provide, at the very least, a brief reprieve from some of these constant stressors. It is during times like this that remaining connected to our colleagues through digital platforms and publications such as The New Gastroenterologist remains of utmost importance.
That being said, I felt it was prudent to first address some common concerns regarding the COVID-19 pandemic, specifically, its implications within gastroenterology. In conjunction with Krishna Rao (University of Michigan), a specialist in infectious diseases, we attempt to shed some light on what is a rapidly evolving situation. For more resources from the American Gastroenterological Association (AGA) on up-to-date clinical guidance and research, you can also visit https://www.gastro.org/practice-guidance/practice-updates/covid-19.
Moving on to our “In Focus” feature, Thangam Ventakesan and Harrison Mooers (Medical College of Wisconsin) provide a comprehensive overview of cyclic vomiting syndrome. This is a valuable read as cyclic vomiting syndrome has been gaining increased recognition among adults, and Dr. Ventakesan and Dr. Mooers elucidate a thorough approach to the diagnosis and treatment of this disorder.
A facet of endoscopy that is extremely important, but frequently overlooked, is ergonomics. Manish Singla and Jared Magee (Walter Reed National Military Medical Center) compile a high-yield list of recommendations on the best practices to preserve our own safety and health as endoscopists.
We continue our medical ethics series with Jennifer Wang and Andrew Aronsohn (University of Chicago) who offer a thought-provoking discussion on the role of early liver transplantation for alcoholic hepatitis, including an analysis of the medical, psychosocial, and ethical considerations.
Also in this issue, Animesh Jain (University of North Carolina) gives us some excellent financial advice on student loan management, outlining a basic strategy of repayment with clear explanations of the available options including refinancing, public service loan forgiveness, and income-driven repayment.
Dilhana Badurdeen (Johns Hopkins), Aline Charabaty Pishvaian (Sibley Memorial Hospital), Miguel Malespin (University of South Florida), Ibironke Oduyebo (Midatlantic Permanente Medical Group), and Sandra Quezada (University of Maryland) give us an in-depth summary of the efforts of the AGA’s Diversity Committee, including publications, events, and future initiatives.
This quarter’s DHPA Private Practice Perspectives series features Paul Berggreen (Arizona Digestive Health), who reviews the advantages and disadvantages of pathology lab ownership as a gastroenterologist. Lastly, Sarah Ordway, Dawn Torres, Manish Singla, and Adam Tritsch (Walter Reed National Military Medical Center) broach the issue of fellowship burnout by providing guidance on how to identify signs and those at risk in addition to providing tangible solutions that any fellowship can incorporate.
Although the cancellation of the upcoming DDW meetings in Chicago is a disappointment, I hope that we can all take this time to prioritize the well-being of ourselves and our communities until we meet again.
As always, if you have interest in contributing or have ideas for future TNG topics, please contact me (vijayarao@medicine.bsd.uchicago.edu), or Ryan Farrell (rfarrell@gastro.org), managing editor of TNG.
Best wishes to stay safe and healthy.
Vijaya L. Rao, MD
Editor in Chief
Dr. Rao is assistant professor of medicine, University of Chicago, section of gastroenterology, hepatology & nutrition.
Cyclic vomiting syndrome: A GI primer
Introduction
Cyclic vomiting syndrome (CVS) is a chronic disorder of gut-brain interaction (DGBI) and is characterized by recurrent episodes of severe nausea, vomiting, and often, abdominal pain. Patients are usually asymptomatic in between episodes.1 CVS was considered a pediatric disease but is now known to be as common in adults. The prevalence of CVS in adults was 2% in a recent population-based study.2 Patients are predominantly white. Both males and females are affected with some studies showing a female preponderance. The mean age of onset is 5 years in children and 35 years in adults.3
The etiology of CVS is not known, but various hypotheses have been proposed. Zaki et al. showed that two mitochondrial DNA polymorphisms 16519T and 3010A were associated with a 17-fold increased odds of having CVS in children.4 These polymorphisms were not associated with CVS in adults.5 Alterations in the brain-gut axis also have been shown in CVS. Functional neuroimaging studies demonstrate that patients with CVS displayed increased connectivity between insula and salience networks with concomitant decrease in connectivity to somatosensory networks.6 Recent data also indicate that the endocannabinoid system (ECS) and the hypothalamic-pituitary-adrenal axis are implicated in CVS with an increase in serum endocannabinoid concentration during an episode.7 The same study also showed a significant increase in salivary cortisol in CVS patients who used cannabis. Further, single nucleotide polymorphisms (SNPs) in the gene that encodes for the cannabinoid receptor type 1 (CB1R) are implicated in CVS.8 The CB1R is part of the ECS and is densely expressed in brain areas involved in emesis, such as the dorsal vagal complex consisting of the area postrema (AP), nucleus of the solitary tract (NTS), and also the dorsal motor nucleus of the vagus.9 Wasilewski et al. showed an increased risk of CVS among individuals with AG and GG genotypes of CNR1 rs806380 (P less than .01), whereas the CC genotype of CNR1 rs806368 was associated with a decreased risk of CVS (P less than .05).8 CB1R agonists – endocannabinoids and tetrahydrocannabinol (THC) – have acute antiemetic and anxiolytic effects.9-11 The apparent paradoxical effects of cannabis in this patient population are yet to be explained and need further study.
Diagnosis and clinical features of CVS
Figure 1: Phases of Cyclic Vomiting Syndrome12
Adapted from Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ. Cyclic Vomiting Syndrome in 41 adults: The illness, the patients, and problems of management. BMC Med 2005;3:20. This work is licensed under the Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, modification, and reproduction in any medium.
CVS consists of four phases which include the a) prodromal phase, b) the episodic phase, c) recovery phase, and d) the interepisodic phase; and was first described by David Fleisher.12 The phases of CVS are important for clinicians and patients alike as they have therapeutic implications. The administration of abortive medications during a prodrome can terminate an episode. The phases of CVS are shown above.
Most patients (~ 93%) have a prodromal phase. Symptoms during this phase can include nausea, abdominal pain, diaphoresis, fatigue, weakness, hot flashes, chills, shivering, increased thirst, loss of appetite, burping, lightheadedness, and paresthesia.13 Some patients report a sense of impending doom and many have symptoms consistent with panic. If untreated, this progresses to the emetic phase and patients have unrelenting nausea, retching, vomiting, and other symptoms. During an episode, patients may vomit up to 20 times per hour and the episode may last several hours to days. During this phase, patients are sometimes described as being in a “conscious coma” and exhibit lethargy, listlessness, withdrawal, and sometimes disorientation.14,15 The emetic phase is followed by the recovery phase, during which symptoms subside and patients are able to resume oral intake. Patients are usually asymptomatic between episodes but ~ 30% can have interepisodic nausea and dyspepsia. In some patients, episodes become progressively longer and the interepisodic phase is considerably shortened and patients have a “coalescence of symptoms.”12 It is important to elicit a thorough history in all patients with vomiting in order to make an accurate diagnosis of CVS since coalescence of symptoms only occurs over a period of time. Episodes often are triggered by psychological stress, both positive and negative. Common triggers can include positive events such as birthdays, holidays, and negative ones like examinations, the death of a loved one, etc. Sleep deprivation and physical exhaustion also can trigger an episode.12
CVS remains a clinical diagnosis since there are no biomarkers. While there is a lack of data on the optimal work-up in these patients, experts recommend an upper endoscopy or upper GI series in order to rule out alternative gastric and intestinal pathology (e.g., malrotation with volvulus).16 Of note, a gastric-emptying study is not recommended as part of the routine work-up as per recent guidelines because of the poor specificity of this test in establishing a diagnosis of CVS.16 Biochemical testing including a complete blood count, serum electrolytes, serum glucose, liver panel, and urinalysis is also warranted. Any additional testing is indicated when clinical features suggest an alternative diagnosis. For instance, neurologic symptoms might warrant a cranial MRI to exclude an intracerebral tumor or other lesions of the brain.
The severity and unpredictable nature of symptoms makes it difficult for some patients to attend school or work; one study found that 32% of patients with CVS were completely disabled.12 Despite increasing awareness of this disorder, patients often are misdiagnosed. The prevalence of CVS in an outpatient gastroenterology clinic in the United Kingdom was 11% and was markedly underdiagnosed in the community.17 Only 5% of patients who were subsequently diagnosed with CVS were initially diagnosed accurately by their referring physician despite meeting criteria for the disorder.17 A subset of patients with CVS even undergo futile surgeries.13 Fleisher et al. noted that 30% of a 41-patient cohort underwent cholecystectomy for CVS symptoms without any improvement in disease.12 Prompt diagnosis and appropriate therapy is essential to improve patient outcomes and improve quality of life.
CVS is associated with various comorbidities such as migraine, anxiety, depression and dysautonomia, which can further impair quality of life.18,19 Approximately 70% of CVS patients report a personal or family history of migraine. Anxiety and depression affects nearly half of patients with CVS.13 Cannabis use is significantly more prevalent among patients with CVS than patients without CVS.20
Role of cannabis in CVS
The role of cannabis in the pathogenesis of symptoms in CVS is controversial. While cannabis has antiemetic properties, there is a strong link between its use and CVS. The use of cannabis has increased over the past decade with increasing legalization.21 Several studies have shown that 40%-80% of patients with CVS use cannabis.22,23 Following this, cannabinoid hyperemesis syndrome (CHS) was coined as a separate entity based on this statistical association, though there are no data to support the notion that cannabis causes vomiting.24,25 CHS has clinical features that are indistinguishable from CVS except for the chronic heavy cannabis use. A peculiar bathing behavior called “compulsive hot-water bathing” has been described and was thought to be pathognomonic of cannabis use.26 During an episode, patients will take multiple hot showers/baths, which temporarily alleviate their symptoms. Many patients even report running out of hot water and sometimes check into a hotel for a continuous supply of hot water. A small number of patients may sustain burns from the hot-water bathing. However, studies show that this hot-water bathing behavior also is seen in about 50% of patents with CVS who do not use cannabis.22
CHS is now defined by Rome IV criteria, which include episodes of nausea and vomiting similar to CVS preceded by chronic, heavy cannabis use. Patients must have complete resolution of symptoms following cessation.1 A recent systematic review of 376 cases of purported CHS showed that only 59 (15.7%) met Rome IV criteria for this disorder.27 This is because of considerable heterogeneity in how the diagnosis of CHS was made and the lack of standard diagnostic criteria at the time. Some cases of CHS were diagnosed merely based on an association of vomiting, hot-water bathing, and cannabis use.28 Only a minority of patients (71,19%) had a duration of follow-up more than 4 weeks, which would make it impossible to establish a diagnosis of CHS. A period of at least a year or a duration of time that spans at least three episodes is generally recommended to determine if abstinence from cannabis causes a true resolution of symptoms.27 Whether CHS is a separate entity or a subtype of CVS remains to be determined. The paradoxical effects of cannabis may happen because of the use of highly potent cannabis products that are currently in use. A complete discussion of the role of cannabis in CVS is beyond the scope of this article, and the reader is referred to a recent systematic review and discussion.27
Treatment
CVS should be treated based on a biopsychosocial model with a multidisciplinary team that includes a gastroenterologist with knowledge of CVS, primary care physician, psychologist, psychiatrist, and sleep specialist if needed.16 Initiating prophylactic treatment is based on the severity of disease. An algorithm for the treatment of CVS based on severity of symptoms is shown below.
Figure 2. Adapted and reprinted by permission from the Licensor: Springer Nature, Current Treatment Options in Gastroenterology, Bhandari S, Venkatesan T. Novel Treatments for Cyclic Vomiting Syndrome: Beyond Ondansetron and Amitriptyline, 14:495-506, Copyright 2016.
Patients who have mild disease (defined as fewer than four episodes/year, episodes lasting up to 2 days, quick recovery from episodes, or episodes not requiring ED care or hospitalization) are usually prescribed abortive medications.16 These medications are best administered during the prodromal phase and can prevent progression to the emetic phase. Medications used for aborting episodes include sumatriptan (20 mg intranasal or 6 mg subcutaneous), ondansetron (8 mg sublingual), and diphenhydramine (25-50 mg).30,31 This combination can help abort symptoms and potentially avoid ED visits or hospitalizations. Patients with moderate-to-severe CVS are offered prophylactic therapy in addition to abortive therapy.16
Recent guidelines recommend tricyclic antidepressants (TCAs) as the first-line agent in the prophylaxis of CVS episodes. Data from 14 studies determined that 70% (413/600) of patients responded partially or completely to TCAs.16 An open-label study of 46 patients by Hejazi et al. noted a decline in the number of CVS episodes from 17 to 3, in the duration of a CVS episode from 6 to 2 days, and in the number of ED visits/ hospitalizations from 15 to 3.3.32Amitriptyline should be started at 25 mg at night and titrated up by 10-25 mg each week to minimize emergence of side effects. The mean effective dose is 75-100 mg or 1.0-1.5 mg/kg. An EKG should be checked at baseline and during titration to monitor the QT interval. Unfortunately, side effects from TCAs are quite common and include cognitive impairment, drowsiness, dryness of mouth, weight gain, constipation, and mood changes, which may warrant dose reduction or discontinuation. Antiepileptics such as topiramate, mitochondrial supplements such as Coenzyme Q10 and riboflavin are alternative prophylactic agents in CVS.33 Aprepitant, a newer NK1 receptor antagonist has been found to be effective in refractory CVS.34 In addition to pharmacotherapy, addressing comorbid conditions such as anxiety and depression and counseling patients to abstain from heavy cannabis use is also important to achieve good health care outcomes.
In summary, CVS is a common, chronic functional GI disorder with episodic nausea, vomiting, and often, abdominal pain. Symptoms can be disabling, and prompt diagnosis and therapy is important. CVS is associated with multiple comorbid conditions such as migraine, anxiety and depression, and a biopsychosocial model of care is essential. Medications such as amitriptyline are effective in the prophylaxis of CVS, but side effects hamper their use. Recent recommendations for management of CVS have been published.16 Cannabis is frequently used by patients for symptom relief but use of high potency products may cause worsening of symptoms or unmask symptoms in genetically predisposed individuals.23 Studies to elucidate the pathophysiology of CVS should help in the development of better therapies.
Dr. Mooers is PGY-2, an internal medicine resident in the department of medicine, Medical College of Wisconsin, Milwaukee; Dr. Venkatesan is professor of medicine, division of gastroenterology and hepatology, department of medicine, Medical College of Wisconsin, Milwaukee. The authors have no conflicts to disclose.
References
1. Stanghellini V et al. Gastroenterology. 2016;150:1380-92.
2. Aziz I et al. Clin Gastroenterol Hepatol. 2019 Apr;17(5):878-86.
3. Kovacic K et al. Curr Gastroenterol Rep. 2018;20(10):46.
4. Zaki EA et al. Cephalalgia. 2009;29:719-28.
5. Venkatesan T et al. BMC Gastroenterol. 2014;14:181.
6. Ellingsen DM et al. Neurogastroenterol Motil. 2017;29 (6)e13004 9.
7. Venkatesan T et al. Neurogastroenterol Motil. 2016;28:1409-18.
8. Wasilewski A et al. Am J Gastroenterol. 2017;112:933-9.
9. van Sickle MD et al. Am J Physiol Gastrointest Liver Physiol 2003;285:G566-76.
10. Parker LA et al. Br J Pharmacol. 2011;163:1411-22.
11. van Sickle MD et al. Gastroenterology. 2001;121:767-74.
12. Fleisher DR et al. BMC Med. 2005;3:20.
13. Kumar N et al. BMC Gastroenterol. 2012;12:52.
14. Li BU et al. J Pediatr Gastroenterol Nutr. 2008;47:379-93.
15. Bhandari S et al. Clin Auton Res. 2018 Apr;28(2):203-9.
16. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13604. doi: 10.1111/nmo.13604.
17. Sagar RC et al. Neurogastroenterol Motil. 2018;30. doi: 10.1111/nmo.13174.
18. Taranukha T et al. Neurogastroenterol Motil. 2018 Apr;30(4):e13245. doi: 10.1111/nmo.13245.
19. Bhandari S and Venkatesan T. Dig Dis Sci. 2017;62:2035-44.
20. Choung RS et al. Neurogastroenterol Motil. 2012;24:20-6, e21. doi: 10.1111/j.1365-2982.2011.01791.x.
21. Bhandari S et al. Intern Med J. 2019 May;49(5):649-55.
22. Venkatesan T et al. Exp Brain Res. 2014; 232:2563-70.
23. Venkatesan T et al. Clin Gastroenterol Hepatol. 2019 Jul 25. doi: 10.1016/j.cgh.2019.07.039.
24. Simonetto DA et al. Mayo Clin Proc. 2012;87:114-9.
25. Wallace EA et al. South Med J. 2011;104:659-64.
26. Allen JH et al. Gut. 2004;53:1566-70.
27. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13606. doi: 10.1111/nmo.13606.
28. Habboushe J et al. Basic Clin Pharmacol Toxicol. 2018;122:660-2.
29. Bhandari S and Venkatesan T. Curr Treat Options Gastroenterol. 2016;14:495-506.
30. Hikita T et al. Cephalalgia. 2011;31:504-7.
31. Fuseau E et al. Clin Pharmacokinet 2002;41:801-11.
32. Hejazi RA et al. J Clin Gastroenterol. 2010;44:18-21.
33. Sezer OB and Sezer T. J Neurogastroenterol Motil. 2016;22:656-60.
34. Cristofori F et al. Aliment Pharmacol Ther. 2014;40:309-17.
Introduction
Cyclic vomiting syndrome (CVS) is a chronic disorder of gut-brain interaction (DGBI) and is characterized by recurrent episodes of severe nausea, vomiting, and often, abdominal pain. Patients are usually asymptomatic in between episodes.1 CVS was considered a pediatric disease but is now known to be as common in adults. The prevalence of CVS in adults was 2% in a recent population-based study.2 Patients are predominantly white. Both males and females are affected with some studies showing a female preponderance. The mean age of onset is 5 years in children and 35 years in adults.3
The etiology of CVS is not known, but various hypotheses have been proposed. Zaki et al. showed that two mitochondrial DNA polymorphisms 16519T and 3010A were associated with a 17-fold increased odds of having CVS in children.4 These polymorphisms were not associated with CVS in adults.5 Alterations in the brain-gut axis also have been shown in CVS. Functional neuroimaging studies demonstrate that patients with CVS displayed increased connectivity between insula and salience networks with concomitant decrease in connectivity to somatosensory networks.6 Recent data also indicate that the endocannabinoid system (ECS) and the hypothalamic-pituitary-adrenal axis are implicated in CVS with an increase in serum endocannabinoid concentration during an episode.7 The same study also showed a significant increase in salivary cortisol in CVS patients who used cannabis. Further, single nucleotide polymorphisms (SNPs) in the gene that encodes for the cannabinoid receptor type 1 (CB1R) are implicated in CVS.8 The CB1R is part of the ECS and is densely expressed in brain areas involved in emesis, such as the dorsal vagal complex consisting of the area postrema (AP), nucleus of the solitary tract (NTS), and also the dorsal motor nucleus of the vagus.9 Wasilewski et al. showed an increased risk of CVS among individuals with AG and GG genotypes of CNR1 rs806380 (P less than .01), whereas the CC genotype of CNR1 rs806368 was associated with a decreased risk of CVS (P less than .05).8 CB1R agonists – endocannabinoids and tetrahydrocannabinol (THC) – have acute antiemetic and anxiolytic effects.9-11 The apparent paradoxical effects of cannabis in this patient population are yet to be explained and need further study.
Diagnosis and clinical features of CVS
Figure 1: Phases of Cyclic Vomiting Syndrome12
Adapted from Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ. Cyclic Vomiting Syndrome in 41 adults: The illness, the patients, and problems of management. BMC Med 2005;3:20. This work is licensed under the Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, modification, and reproduction in any medium.
CVS consists of four phases which include the a) prodromal phase, b) the episodic phase, c) recovery phase, and d) the interepisodic phase; and was first described by David Fleisher.12 The phases of CVS are important for clinicians and patients alike as they have therapeutic implications. The administration of abortive medications during a prodrome can terminate an episode. The phases of CVS are shown above.
Most patients (~ 93%) have a prodromal phase. Symptoms during this phase can include nausea, abdominal pain, diaphoresis, fatigue, weakness, hot flashes, chills, shivering, increased thirst, loss of appetite, burping, lightheadedness, and paresthesia.13 Some patients report a sense of impending doom and many have symptoms consistent with panic. If untreated, this progresses to the emetic phase and patients have unrelenting nausea, retching, vomiting, and other symptoms. During an episode, patients may vomit up to 20 times per hour and the episode may last several hours to days. During this phase, patients are sometimes described as being in a “conscious coma” and exhibit lethargy, listlessness, withdrawal, and sometimes disorientation.14,15 The emetic phase is followed by the recovery phase, during which symptoms subside and patients are able to resume oral intake. Patients are usually asymptomatic between episodes but ~ 30% can have interepisodic nausea and dyspepsia. In some patients, episodes become progressively longer and the interepisodic phase is considerably shortened and patients have a “coalescence of symptoms.”12 It is important to elicit a thorough history in all patients with vomiting in order to make an accurate diagnosis of CVS since coalescence of symptoms only occurs over a period of time. Episodes often are triggered by psychological stress, both positive and negative. Common triggers can include positive events such as birthdays, holidays, and negative ones like examinations, the death of a loved one, etc. Sleep deprivation and physical exhaustion also can trigger an episode.12
CVS remains a clinical diagnosis since there are no biomarkers. While there is a lack of data on the optimal work-up in these patients, experts recommend an upper endoscopy or upper GI series in order to rule out alternative gastric and intestinal pathology (e.g., malrotation with volvulus).16 Of note, a gastric-emptying study is not recommended as part of the routine work-up as per recent guidelines because of the poor specificity of this test in establishing a diagnosis of CVS.16 Biochemical testing including a complete blood count, serum electrolytes, serum glucose, liver panel, and urinalysis is also warranted. Any additional testing is indicated when clinical features suggest an alternative diagnosis. For instance, neurologic symptoms might warrant a cranial MRI to exclude an intracerebral tumor or other lesions of the brain.
The severity and unpredictable nature of symptoms makes it difficult for some patients to attend school or work; one study found that 32% of patients with CVS were completely disabled.12 Despite increasing awareness of this disorder, patients often are misdiagnosed. The prevalence of CVS in an outpatient gastroenterology clinic in the United Kingdom was 11% and was markedly underdiagnosed in the community.17 Only 5% of patients who were subsequently diagnosed with CVS were initially diagnosed accurately by their referring physician despite meeting criteria for the disorder.17 A subset of patients with CVS even undergo futile surgeries.13 Fleisher et al. noted that 30% of a 41-patient cohort underwent cholecystectomy for CVS symptoms without any improvement in disease.12 Prompt diagnosis and appropriate therapy is essential to improve patient outcomes and improve quality of life.
CVS is associated with various comorbidities such as migraine, anxiety, depression and dysautonomia, which can further impair quality of life.18,19 Approximately 70% of CVS patients report a personal or family history of migraine. Anxiety and depression affects nearly half of patients with CVS.13 Cannabis use is significantly more prevalent among patients with CVS than patients without CVS.20
Role of cannabis in CVS
The role of cannabis in the pathogenesis of symptoms in CVS is controversial. While cannabis has antiemetic properties, there is a strong link between its use and CVS. The use of cannabis has increased over the past decade with increasing legalization.21 Several studies have shown that 40%-80% of patients with CVS use cannabis.22,23 Following this, cannabinoid hyperemesis syndrome (CHS) was coined as a separate entity based on this statistical association, though there are no data to support the notion that cannabis causes vomiting.24,25 CHS has clinical features that are indistinguishable from CVS except for the chronic heavy cannabis use. A peculiar bathing behavior called “compulsive hot-water bathing” has been described and was thought to be pathognomonic of cannabis use.26 During an episode, patients will take multiple hot showers/baths, which temporarily alleviate their symptoms. Many patients even report running out of hot water and sometimes check into a hotel for a continuous supply of hot water. A small number of patients may sustain burns from the hot-water bathing. However, studies show that this hot-water bathing behavior also is seen in about 50% of patents with CVS who do not use cannabis.22
CHS is now defined by Rome IV criteria, which include episodes of nausea and vomiting similar to CVS preceded by chronic, heavy cannabis use. Patients must have complete resolution of symptoms following cessation.1 A recent systematic review of 376 cases of purported CHS showed that only 59 (15.7%) met Rome IV criteria for this disorder.27 This is because of considerable heterogeneity in how the diagnosis of CHS was made and the lack of standard diagnostic criteria at the time. Some cases of CHS were diagnosed merely based on an association of vomiting, hot-water bathing, and cannabis use.28 Only a minority of patients (71,19%) had a duration of follow-up more than 4 weeks, which would make it impossible to establish a diagnosis of CHS. A period of at least a year or a duration of time that spans at least three episodes is generally recommended to determine if abstinence from cannabis causes a true resolution of symptoms.27 Whether CHS is a separate entity or a subtype of CVS remains to be determined. The paradoxical effects of cannabis may happen because of the use of highly potent cannabis products that are currently in use. A complete discussion of the role of cannabis in CVS is beyond the scope of this article, and the reader is referred to a recent systematic review and discussion.27
Treatment
CVS should be treated based on a biopsychosocial model with a multidisciplinary team that includes a gastroenterologist with knowledge of CVS, primary care physician, psychologist, psychiatrist, and sleep specialist if needed.16 Initiating prophylactic treatment is based on the severity of disease. An algorithm for the treatment of CVS based on severity of symptoms is shown below.
Figure 2. Adapted and reprinted by permission from the Licensor: Springer Nature, Current Treatment Options in Gastroenterology, Bhandari S, Venkatesan T. Novel Treatments for Cyclic Vomiting Syndrome: Beyond Ondansetron and Amitriptyline, 14:495-506, Copyright 2016.
Patients who have mild disease (defined as fewer than four episodes/year, episodes lasting up to 2 days, quick recovery from episodes, or episodes not requiring ED care or hospitalization) are usually prescribed abortive medications.16 These medications are best administered during the prodromal phase and can prevent progression to the emetic phase. Medications used for aborting episodes include sumatriptan (20 mg intranasal or 6 mg subcutaneous), ondansetron (8 mg sublingual), and diphenhydramine (25-50 mg).30,31 This combination can help abort symptoms and potentially avoid ED visits or hospitalizations. Patients with moderate-to-severe CVS are offered prophylactic therapy in addition to abortive therapy.16
Recent guidelines recommend tricyclic antidepressants (TCAs) as the first-line agent in the prophylaxis of CVS episodes. Data from 14 studies determined that 70% (413/600) of patients responded partially or completely to TCAs.16 An open-label study of 46 patients by Hejazi et al. noted a decline in the number of CVS episodes from 17 to 3, in the duration of a CVS episode from 6 to 2 days, and in the number of ED visits/ hospitalizations from 15 to 3.3.32Amitriptyline should be started at 25 mg at night and titrated up by 10-25 mg each week to minimize emergence of side effects. The mean effective dose is 75-100 mg or 1.0-1.5 mg/kg. An EKG should be checked at baseline and during titration to monitor the QT interval. Unfortunately, side effects from TCAs are quite common and include cognitive impairment, drowsiness, dryness of mouth, weight gain, constipation, and mood changes, which may warrant dose reduction or discontinuation. Antiepileptics such as topiramate, mitochondrial supplements such as Coenzyme Q10 and riboflavin are alternative prophylactic agents in CVS.33 Aprepitant, a newer NK1 receptor antagonist has been found to be effective in refractory CVS.34 In addition to pharmacotherapy, addressing comorbid conditions such as anxiety and depression and counseling patients to abstain from heavy cannabis use is also important to achieve good health care outcomes.
In summary, CVS is a common, chronic functional GI disorder with episodic nausea, vomiting, and often, abdominal pain. Symptoms can be disabling, and prompt diagnosis and therapy is important. CVS is associated with multiple comorbid conditions such as migraine, anxiety and depression, and a biopsychosocial model of care is essential. Medications such as amitriptyline are effective in the prophylaxis of CVS, but side effects hamper their use. Recent recommendations for management of CVS have been published.16 Cannabis is frequently used by patients for symptom relief but use of high potency products may cause worsening of symptoms or unmask symptoms in genetically predisposed individuals.23 Studies to elucidate the pathophysiology of CVS should help in the development of better therapies.
Dr. Mooers is PGY-2, an internal medicine resident in the department of medicine, Medical College of Wisconsin, Milwaukee; Dr. Venkatesan is professor of medicine, division of gastroenterology and hepatology, department of medicine, Medical College of Wisconsin, Milwaukee. The authors have no conflicts to disclose.
References
1. Stanghellini V et al. Gastroenterology. 2016;150:1380-92.
2. Aziz I et al. Clin Gastroenterol Hepatol. 2019 Apr;17(5):878-86.
3. Kovacic K et al. Curr Gastroenterol Rep. 2018;20(10):46.
4. Zaki EA et al. Cephalalgia. 2009;29:719-28.
5. Venkatesan T et al. BMC Gastroenterol. 2014;14:181.
6. Ellingsen DM et al. Neurogastroenterol Motil. 2017;29 (6)e13004 9.
7. Venkatesan T et al. Neurogastroenterol Motil. 2016;28:1409-18.
8. Wasilewski A et al. Am J Gastroenterol. 2017;112:933-9.
9. van Sickle MD et al. Am J Physiol Gastrointest Liver Physiol 2003;285:G566-76.
10. Parker LA et al. Br J Pharmacol. 2011;163:1411-22.
11. van Sickle MD et al. Gastroenterology. 2001;121:767-74.
12. Fleisher DR et al. BMC Med. 2005;3:20.
13. Kumar N et al. BMC Gastroenterol. 2012;12:52.
14. Li BU et al. J Pediatr Gastroenterol Nutr. 2008;47:379-93.
15. Bhandari S et al. Clin Auton Res. 2018 Apr;28(2):203-9.
16. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13604. doi: 10.1111/nmo.13604.
17. Sagar RC et al. Neurogastroenterol Motil. 2018;30. doi: 10.1111/nmo.13174.
18. Taranukha T et al. Neurogastroenterol Motil. 2018 Apr;30(4):e13245. doi: 10.1111/nmo.13245.
19. Bhandari S and Venkatesan T. Dig Dis Sci. 2017;62:2035-44.
20. Choung RS et al. Neurogastroenterol Motil. 2012;24:20-6, e21. doi: 10.1111/j.1365-2982.2011.01791.x.
21. Bhandari S et al. Intern Med J. 2019 May;49(5):649-55.
22. Venkatesan T et al. Exp Brain Res. 2014; 232:2563-70.
23. Venkatesan T et al. Clin Gastroenterol Hepatol. 2019 Jul 25. doi: 10.1016/j.cgh.2019.07.039.
24. Simonetto DA et al. Mayo Clin Proc. 2012;87:114-9.
25. Wallace EA et al. South Med J. 2011;104:659-64.
26. Allen JH et al. Gut. 2004;53:1566-70.
27. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13606. doi: 10.1111/nmo.13606.
28. Habboushe J et al. Basic Clin Pharmacol Toxicol. 2018;122:660-2.
29. Bhandari S and Venkatesan T. Curr Treat Options Gastroenterol. 2016;14:495-506.
30. Hikita T et al. Cephalalgia. 2011;31:504-7.
31. Fuseau E et al. Clin Pharmacokinet 2002;41:801-11.
32. Hejazi RA et al. J Clin Gastroenterol. 2010;44:18-21.
33. Sezer OB and Sezer T. J Neurogastroenterol Motil. 2016;22:656-60.
34. Cristofori F et al. Aliment Pharmacol Ther. 2014;40:309-17.
Introduction
Cyclic vomiting syndrome (CVS) is a chronic disorder of gut-brain interaction (DGBI) and is characterized by recurrent episodes of severe nausea, vomiting, and often, abdominal pain. Patients are usually asymptomatic in between episodes.1 CVS was considered a pediatric disease but is now known to be as common in adults. The prevalence of CVS in adults was 2% in a recent population-based study.2 Patients are predominantly white. Both males and females are affected with some studies showing a female preponderance. The mean age of onset is 5 years in children and 35 years in adults.3
The etiology of CVS is not known, but various hypotheses have been proposed. Zaki et al. showed that two mitochondrial DNA polymorphisms 16519T and 3010A were associated with a 17-fold increased odds of having CVS in children.4 These polymorphisms were not associated with CVS in adults.5 Alterations in the brain-gut axis also have been shown in CVS. Functional neuroimaging studies demonstrate that patients with CVS displayed increased connectivity between insula and salience networks with concomitant decrease in connectivity to somatosensory networks.6 Recent data also indicate that the endocannabinoid system (ECS) and the hypothalamic-pituitary-adrenal axis are implicated in CVS with an increase in serum endocannabinoid concentration during an episode.7 The same study also showed a significant increase in salivary cortisol in CVS patients who used cannabis. Further, single nucleotide polymorphisms (SNPs) in the gene that encodes for the cannabinoid receptor type 1 (CB1R) are implicated in CVS.8 The CB1R is part of the ECS and is densely expressed in brain areas involved in emesis, such as the dorsal vagal complex consisting of the area postrema (AP), nucleus of the solitary tract (NTS), and also the dorsal motor nucleus of the vagus.9 Wasilewski et al. showed an increased risk of CVS among individuals with AG and GG genotypes of CNR1 rs806380 (P less than .01), whereas the CC genotype of CNR1 rs806368 was associated with a decreased risk of CVS (P less than .05).8 CB1R agonists – endocannabinoids and tetrahydrocannabinol (THC) – have acute antiemetic and anxiolytic effects.9-11 The apparent paradoxical effects of cannabis in this patient population are yet to be explained and need further study.
Diagnosis and clinical features of CVS
Figure 1: Phases of Cyclic Vomiting Syndrome12
Adapted from Fleisher DR, Gornowicz B, Adams K, Burch R, Feldman EJ. Cyclic Vomiting Syndrome in 41 adults: The illness, the patients, and problems of management. BMC Med 2005;3:20. This work is licensed under the Creative Commons Attribution 4.0 International License https://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, distribution, modification, and reproduction in any medium.
CVS consists of four phases which include the a) prodromal phase, b) the episodic phase, c) recovery phase, and d) the interepisodic phase; and was first described by David Fleisher.12 The phases of CVS are important for clinicians and patients alike as they have therapeutic implications. The administration of abortive medications during a prodrome can terminate an episode. The phases of CVS are shown above.
Most patients (~ 93%) have a prodromal phase. Symptoms during this phase can include nausea, abdominal pain, diaphoresis, fatigue, weakness, hot flashes, chills, shivering, increased thirst, loss of appetite, burping, lightheadedness, and paresthesia.13 Some patients report a sense of impending doom and many have symptoms consistent with panic. If untreated, this progresses to the emetic phase and patients have unrelenting nausea, retching, vomiting, and other symptoms. During an episode, patients may vomit up to 20 times per hour and the episode may last several hours to days. During this phase, patients are sometimes described as being in a “conscious coma” and exhibit lethargy, listlessness, withdrawal, and sometimes disorientation.14,15 The emetic phase is followed by the recovery phase, during which symptoms subside and patients are able to resume oral intake. Patients are usually asymptomatic between episodes but ~ 30% can have interepisodic nausea and dyspepsia. In some patients, episodes become progressively longer and the interepisodic phase is considerably shortened and patients have a “coalescence of symptoms.”12 It is important to elicit a thorough history in all patients with vomiting in order to make an accurate diagnosis of CVS since coalescence of symptoms only occurs over a period of time. Episodes often are triggered by psychological stress, both positive and negative. Common triggers can include positive events such as birthdays, holidays, and negative ones like examinations, the death of a loved one, etc. Sleep deprivation and physical exhaustion also can trigger an episode.12
CVS remains a clinical diagnosis since there are no biomarkers. While there is a lack of data on the optimal work-up in these patients, experts recommend an upper endoscopy or upper GI series in order to rule out alternative gastric and intestinal pathology (e.g., malrotation with volvulus).16 Of note, a gastric-emptying study is not recommended as part of the routine work-up as per recent guidelines because of the poor specificity of this test in establishing a diagnosis of CVS.16 Biochemical testing including a complete blood count, serum electrolytes, serum glucose, liver panel, and urinalysis is also warranted. Any additional testing is indicated when clinical features suggest an alternative diagnosis. For instance, neurologic symptoms might warrant a cranial MRI to exclude an intracerebral tumor or other lesions of the brain.
The severity and unpredictable nature of symptoms makes it difficult for some patients to attend school or work; one study found that 32% of patients with CVS were completely disabled.12 Despite increasing awareness of this disorder, patients often are misdiagnosed. The prevalence of CVS in an outpatient gastroenterology clinic in the United Kingdom was 11% and was markedly underdiagnosed in the community.17 Only 5% of patients who were subsequently diagnosed with CVS were initially diagnosed accurately by their referring physician despite meeting criteria for the disorder.17 A subset of patients with CVS even undergo futile surgeries.13 Fleisher et al. noted that 30% of a 41-patient cohort underwent cholecystectomy for CVS symptoms without any improvement in disease.12 Prompt diagnosis and appropriate therapy is essential to improve patient outcomes and improve quality of life.
CVS is associated with various comorbidities such as migraine, anxiety, depression and dysautonomia, which can further impair quality of life.18,19 Approximately 70% of CVS patients report a personal or family history of migraine. Anxiety and depression affects nearly half of patients with CVS.13 Cannabis use is significantly more prevalent among patients with CVS than patients without CVS.20
Role of cannabis in CVS
The role of cannabis in the pathogenesis of symptoms in CVS is controversial. While cannabis has antiemetic properties, there is a strong link between its use and CVS. The use of cannabis has increased over the past decade with increasing legalization.21 Several studies have shown that 40%-80% of patients with CVS use cannabis.22,23 Following this, cannabinoid hyperemesis syndrome (CHS) was coined as a separate entity based on this statistical association, though there are no data to support the notion that cannabis causes vomiting.24,25 CHS has clinical features that are indistinguishable from CVS except for the chronic heavy cannabis use. A peculiar bathing behavior called “compulsive hot-water bathing” has been described and was thought to be pathognomonic of cannabis use.26 During an episode, patients will take multiple hot showers/baths, which temporarily alleviate their symptoms. Many patients even report running out of hot water and sometimes check into a hotel for a continuous supply of hot water. A small number of patients may sustain burns from the hot-water bathing. However, studies show that this hot-water bathing behavior also is seen in about 50% of patents with CVS who do not use cannabis.22
CHS is now defined by Rome IV criteria, which include episodes of nausea and vomiting similar to CVS preceded by chronic, heavy cannabis use. Patients must have complete resolution of symptoms following cessation.1 A recent systematic review of 376 cases of purported CHS showed that only 59 (15.7%) met Rome IV criteria for this disorder.27 This is because of considerable heterogeneity in how the diagnosis of CHS was made and the lack of standard diagnostic criteria at the time. Some cases of CHS were diagnosed merely based on an association of vomiting, hot-water bathing, and cannabis use.28 Only a minority of patients (71,19%) had a duration of follow-up more than 4 weeks, which would make it impossible to establish a diagnosis of CHS. A period of at least a year or a duration of time that spans at least three episodes is generally recommended to determine if abstinence from cannabis causes a true resolution of symptoms.27 Whether CHS is a separate entity or a subtype of CVS remains to be determined. The paradoxical effects of cannabis may happen because of the use of highly potent cannabis products that are currently in use. A complete discussion of the role of cannabis in CVS is beyond the scope of this article, and the reader is referred to a recent systematic review and discussion.27
Treatment
CVS should be treated based on a biopsychosocial model with a multidisciplinary team that includes a gastroenterologist with knowledge of CVS, primary care physician, psychologist, psychiatrist, and sleep specialist if needed.16 Initiating prophylactic treatment is based on the severity of disease. An algorithm for the treatment of CVS based on severity of symptoms is shown below.
Figure 2. Adapted and reprinted by permission from the Licensor: Springer Nature, Current Treatment Options in Gastroenterology, Bhandari S, Venkatesan T. Novel Treatments for Cyclic Vomiting Syndrome: Beyond Ondansetron and Amitriptyline, 14:495-506, Copyright 2016.
Patients who have mild disease (defined as fewer than four episodes/year, episodes lasting up to 2 days, quick recovery from episodes, or episodes not requiring ED care or hospitalization) are usually prescribed abortive medications.16 These medications are best administered during the prodromal phase and can prevent progression to the emetic phase. Medications used for aborting episodes include sumatriptan (20 mg intranasal or 6 mg subcutaneous), ondansetron (8 mg sublingual), and diphenhydramine (25-50 mg).30,31 This combination can help abort symptoms and potentially avoid ED visits or hospitalizations. Patients with moderate-to-severe CVS are offered prophylactic therapy in addition to abortive therapy.16
Recent guidelines recommend tricyclic antidepressants (TCAs) as the first-line agent in the prophylaxis of CVS episodes. Data from 14 studies determined that 70% (413/600) of patients responded partially or completely to TCAs.16 An open-label study of 46 patients by Hejazi et al. noted a decline in the number of CVS episodes from 17 to 3, in the duration of a CVS episode from 6 to 2 days, and in the number of ED visits/ hospitalizations from 15 to 3.3.32Amitriptyline should be started at 25 mg at night and titrated up by 10-25 mg each week to minimize emergence of side effects. The mean effective dose is 75-100 mg or 1.0-1.5 mg/kg. An EKG should be checked at baseline and during titration to monitor the QT interval. Unfortunately, side effects from TCAs are quite common and include cognitive impairment, drowsiness, dryness of mouth, weight gain, constipation, and mood changes, which may warrant dose reduction or discontinuation. Antiepileptics such as topiramate, mitochondrial supplements such as Coenzyme Q10 and riboflavin are alternative prophylactic agents in CVS.33 Aprepitant, a newer NK1 receptor antagonist has been found to be effective in refractory CVS.34 In addition to pharmacotherapy, addressing comorbid conditions such as anxiety and depression and counseling patients to abstain from heavy cannabis use is also important to achieve good health care outcomes.
In summary, CVS is a common, chronic functional GI disorder with episodic nausea, vomiting, and often, abdominal pain. Symptoms can be disabling, and prompt diagnosis and therapy is important. CVS is associated with multiple comorbid conditions such as migraine, anxiety and depression, and a biopsychosocial model of care is essential. Medications such as amitriptyline are effective in the prophylaxis of CVS, but side effects hamper their use. Recent recommendations for management of CVS have been published.16 Cannabis is frequently used by patients for symptom relief but use of high potency products may cause worsening of symptoms or unmask symptoms in genetically predisposed individuals.23 Studies to elucidate the pathophysiology of CVS should help in the development of better therapies.
Dr. Mooers is PGY-2, an internal medicine resident in the department of medicine, Medical College of Wisconsin, Milwaukee; Dr. Venkatesan is professor of medicine, division of gastroenterology and hepatology, department of medicine, Medical College of Wisconsin, Milwaukee. The authors have no conflicts to disclose.
References
1. Stanghellini V et al. Gastroenterology. 2016;150:1380-92.
2. Aziz I et al. Clin Gastroenterol Hepatol. 2019 Apr;17(5):878-86.
3. Kovacic K et al. Curr Gastroenterol Rep. 2018;20(10):46.
4. Zaki EA et al. Cephalalgia. 2009;29:719-28.
5. Venkatesan T et al. BMC Gastroenterol. 2014;14:181.
6. Ellingsen DM et al. Neurogastroenterol Motil. 2017;29 (6)e13004 9.
7. Venkatesan T et al. Neurogastroenterol Motil. 2016;28:1409-18.
8. Wasilewski A et al. Am J Gastroenterol. 2017;112:933-9.
9. van Sickle MD et al. Am J Physiol Gastrointest Liver Physiol 2003;285:G566-76.
10. Parker LA et al. Br J Pharmacol. 2011;163:1411-22.
11. van Sickle MD et al. Gastroenterology. 2001;121:767-74.
12. Fleisher DR et al. BMC Med. 2005;3:20.
13. Kumar N et al. BMC Gastroenterol. 2012;12:52.
14. Li BU et al. J Pediatr Gastroenterol Nutr. 2008;47:379-93.
15. Bhandari S et al. Clin Auton Res. 2018 Apr;28(2):203-9.
16. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13604. doi: 10.1111/nmo.13604.
17. Sagar RC et al. Neurogastroenterol Motil. 2018;30. doi: 10.1111/nmo.13174.
18. Taranukha T et al. Neurogastroenterol Motil. 2018 Apr;30(4):e13245. doi: 10.1111/nmo.13245.
19. Bhandari S and Venkatesan T. Dig Dis Sci. 2017;62:2035-44.
20. Choung RS et al. Neurogastroenterol Motil. 2012;24:20-6, e21. doi: 10.1111/j.1365-2982.2011.01791.x.
21. Bhandari S et al. Intern Med J. 2019 May;49(5):649-55.
22. Venkatesan T et al. Exp Brain Res. 2014; 232:2563-70.
23. Venkatesan T et al. Clin Gastroenterol Hepatol. 2019 Jul 25. doi: 10.1016/j.cgh.2019.07.039.
24. Simonetto DA et al. Mayo Clin Proc. 2012;87:114-9.
25. Wallace EA et al. South Med J. 2011;104:659-64.
26. Allen JH et al. Gut. 2004;53:1566-70.
27. Venkatesan T et al. Neurogastroenterol Motil. 2019;31 Suppl 2:e13606. doi: 10.1111/nmo.13606.
28. Habboushe J et al. Basic Clin Pharmacol Toxicol. 2018;122:660-2.
29. Bhandari S and Venkatesan T. Curr Treat Options Gastroenterol. 2016;14:495-506.
30. Hikita T et al. Cephalalgia. 2011;31:504-7.
31. Fuseau E et al. Clin Pharmacokinet 2002;41:801-11.
32. Hejazi RA et al. J Clin Gastroenterol. 2010;44:18-21.
33. Sezer OB and Sezer T. J Neurogastroenterol Motil. 2016;22:656-60.
34. Cristofori F et al. Aliment Pharmacol Ther. 2014;40:309-17.
EMBRACA shows no overall survival benefit with talazoparib
Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.
The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.
The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).
In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).
“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.
However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
Final overall survival
At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.
The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)
The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”
Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.
Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.
In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.
“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.
She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
Quality of life and safety
Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.
The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.
The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).
At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.
Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.
Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.
She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
Jury’s still out
Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.
She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.
“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”
Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.
The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.
SOURCE: Litton J et al., AACR 20, Abstract CT071.
Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.
The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.
The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).
In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).
“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.
However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
Final overall survival
At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.
The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)
The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”
Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.
Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.
In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.
“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.
She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
Quality of life and safety
Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.
The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.
The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).
At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.
Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.
Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.
She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
Jury’s still out
Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.
She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.
“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”
Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.
The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.
SOURCE: Litton J et al., AACR 20, Abstract CT071.
Talazoparib did not confer an overall survival benefit over chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer, according to a final analysis of the phase 3 EMBRACA trial.
The progression-free survival benefit previously seen with talazoparib did not translate to an overall survival benefit. However, patient-reported quality of life continued to favor talazoparib in the final analysis, Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the AACR virtual meeting I.
The EMBRACA trial enrolled adults with HER2-negative locally advanced or metastatic breast cancer and a deleterious or suspected deleterious germline BRCA mutation. They were randomized to talazoparib at 1 mg daily (n = 287) or to physician’s choice of single-agent chemotherapy (n = 144).
In the primary analysis, talazoparib was associated with significantly improved progression-free survival. The median progression-free survival was 8.6 months in the talazoparib arm and 5.6 months in the chemotherapy arm (hazard ratio, 0.54).
“At the time of the primary analysis, the overall survival data were immature, and the hazard ratio for the interim overall survival was 0.761, which was not statistically significant,” Dr. Litton said.
However, patient-reported outcomes favored talazoparib in the primary analysis, with patients in that arm showing “significant overall improvements with a significant delay in time to clinically meaningful deterioration in multiple cancer-related and breast cancer–specific symptoms, functions, quality of life, and global health,” Dr. Litton said.
Final overall survival
At the final analysis, the median follow-up was 44.9 months for the talazoparib arm and 36.8 months for the chemotherapy arm.
The median overall survival was 19.3 months in the talazoparib arm and 19.5 months in the chemotherapy arm (HR, 0.848; P = .17)
The results were “generally consistent” across patient subgroups,” Dr. Litton said, adding that “the effect of treatment with talazoparib was also similar irrespective of BRCA status, as well as triple-negative or hormone-receptor-positive subtypes.”
Of note, most patients received poststudy therapies. These included PARP inhibitors in 4.5% of patients in the talazoparib arm and 32.6% of patients in the chemotherapy arm, and platinum drugs in 46.3% and 41.7%, respectively.
Patients who received chemotherapy on study but did not receive a subsequent PARP inhibitor or platinum therapy had both shorter total treatment duration and shorter overall survival, compared with patients who did receive subsequent treatment.
In the talazoparib arm, outcomes were similar whether or not patients received a subsequent PARP inhibitor or platinum therapy.
“Interpretation of the overall survival results may have been confounded by subsequent treatment, so two sensitivity analyses accounting for subsequent PARP inhibition or platinum therapy were carried out,” Dr. Litton said.
She noted that adjustment for poststudy treatment lowered the hazard ratio, but there was still no significant difference between the talazoparib and chemotherapy arms. These results suggest “the primary overall survival analysis underestimated the treatment benefit of talazoparib,” Dr. Litton said. She also noted that a longer platinum-free interval prior to study entry was generally associated with a longer duration of survival, particularly in the talazoparib arm.
Quality of life and safety
Patient-reported outcomes continued to favor talazoparib with extended follow-up and were consistent with the initial analysis, Dr. Litton noted.
The updated analysis revealed “a significant improvement in estimated overall change from baseline in the global health quality of life scores for those patients receiving talazoparib, while a significant deterioration was observed in patients receiving chemotherapy,” she said.
The estimated overall change in score was a 2.1-point increase in the talazoparib arm and a 5.7-point decrease in the chemotherapy arm (P = .001). The median time to clinically meaningful deterioration in global health quality of life scores was 26.3 months in the talazoparib arm and 6.7 months in the chemotherapy arm (HR, 0.385).
At the final analysis, the overall safety profile was consistent with that reported previously. Talazoparib was generally well tolerated, and no new safety signals were identified.
Grade 3/4 serious adverse events occurred in 28.3% of patients in the talazoparib arm and 27% of those in the chemotherapy arm. Adverse events led to treatment discontinuation in 7.7% and 9.5% of patients, respectively.
Most grade 3/4 adverse events were hematologic, and most were successfully managed by supportive care, including transfusions and dose modifications, Dr. Litton said.
She noted that one patient in the chemotherapy arm assigned to receive capecitabine had been diagnosed with acute myeloid leukemia at the time of the first analysis. “And now we report an additional case of [acute myeloid leukemia] in a patient who was randomized to the talazoparib arm,” Dr. Litton said.
Jury’s still out
Based on existing data, including from EMBRACA, the jury is still out on whether PARP inhibition is associated with an overall survival benefit in this setting, said invited discussant Susan Domcheck, MD, of the University of Pennsylvania in Philadelphia.
She suggested that could change with ongoing efforts to identify biomarkers for treatment response and new approaches to treatment, such as earlier lines of therapy and combinations.
“At this time, germline BRCA 1 and 2 pathogenic variants are the best predictor of PARP inhibitor sensitivity in breast cancer,” Dr. Domcheck said. “Not all the tumors are sensitive, but this is true of [estrogen receptor–positive] breast cancer and hormonal therapy, and HER2-positive breast cancer as well.”
Studies investigating approaches to improve survival are “incredibly important, because the progression-free survival is not as long as we would like it to be and there’s not an overwhelming overall survival benefit, for sure,” she said.
The EMBRACA trial was funded by Medivation (Pfizer). Dr. Litton and colleagues disclosed numerous relationships with pharmaceutical companies and other organizations. Dr. Domcheck disclosed relationships with AstraZeneca, Clovis, and Bristol Myers Squibb.
SOURCE: Litton J et al., AACR 20, Abstract CT071.
FROM AACR 2020
Standing orders for vaccines may improve pediatric vaccination rates
The biggest barrier to using standing orders for childhood immunizations is concern that patients will receive the wrong vaccine, according to a survey of pediatricians published in Pediatrics.
The other top reasons pediatricians give for not using standing orders for vaccines are concerns that parents may want to talk to the doctor about the vaccine before their child gets it, and a belief that the doctor should be the one who personally recommends a vaccine for their patient.
But with severe drops in vaccination rates resulting from the COVID-19 pandemic, standing orders may be a valuable tool for ensuring children get their vaccines on time, suggested lead author, Jessica Cataldi, MD, of the University of Colorado and Children’s Hospital Colorado in Aurora.
“As we work to bring more families back to their pediatrician’s office for well-child checks, standing orders are one process that can streamline the visit by saving providers time and increasing vaccine delivery,” she said in an interview. “We will also need use standing orders to support different ways to get children their immunizations during times of social distancing. This could take the form of drive-through immunization clinics or telehealth well-child checks that are paired with a quick immunization-only visit.”
The American Academy of Pediatrics issued guidance April 14 that emphasizes the need to prioritize immunization of children through 2-years-old.
Paul A. Offit, MD, director of the Vaccine Education Center and an attending physician in the division of infectious diseases at Children’s Hospital of Philadelphia, agreed that it’s essential children do not fall behind on the recommended schedule during the pandemic.
“It’s important not to have greater collateral damage from this COVID-19 pandemic by putting children at increased risk from other infections that are circulating, like measles and pertussis,” he said, noting that nearly 1,300 measles cases and more than 15,000 pertussis cases occurred in the United States in 2019.
It’s important “not to delay those primary vaccines because it’s hard to catch up,” he said in an interview
Although “standing orders” may go by other names in non–inpatient settings, the researchers defined them in their survey as “a written or verbal policy that persons other than a medical provider, such as a nurse or medical assistant, may consent and vaccinate a person without speaking with the physician or advanced care provider first.” Further, the “vaccine may be given before or after a physician encounter or in the absence of a physician encounter altogether.”
Research strongly suggests that standing orders for childhood vaccines are cost-effective and increase immunization rates, the authors noted. The Centers for Disease Control and Prevention, its Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the federal National Vaccine Advisory Committee all recommend using standing orders to improve vaccination access and rates.
The authors sought to understand how many pediatricians use standing orders and what reasons stop them from doing so. During June-September 2017, they sent out 471 online and mail surveys to a nationally representative sample of AAP members who spent at least half their time in primary care.
The 372 pediatricians who completed the survey made up a response rate of 79%, with no differences in response based on age, sex, years in practice, practice setting, region or rural/urban location.
More than half the respondents (59%) used standing orders for childhood immunizations. Just over a third of respondents (36%) said they use standing orders for all routinely recommended vaccines, and 23% use them for some vaccines.
Among those who did not use standing orders, 68% cited the concern that patients would get the incorrect vaccine by mistake as a barrier to using them. That came as a surprise to Dr Offit, who would expect standing orders to reduce the likelihood of error.
“The standing order should make things a little more foolproof so that you’re less likely to make a mistake,” Dr Offit said.
No studies have shown that vaccine errors occur more often in clinics that use standing orders for immunizations, but the question merits continued monitoring, Dr Cataldi said.
“It is important for any clinic that is new to the use of standing orders to provide adequate education to providers and other staff about when and how to use standing orders, and to always leave room for staff to bring vaccination questions to the provider,” Dr Cataldi told this newspaper
Nearly as many physicians (62%) believed that families would want to speak to the doctor about a vaccine before getting it, and 57% of respondents who didn’t use standing orders believed they should be the one who recommends a vaccine to their patient’s parents.
All three of these reasons also ranked highest as barriers in responses from all respondents, including those who use standing orders. But those who didn’t use them were significantly more likely to cite these reasons (P less than .0001).
Since the survey occurred in 2017, however, it’s possible the pandemic and the rapid increase in telehealth as a result may influence perceptions moving forward.
“With provider concerns that standing orders remove physicians from the vaccination conversation, it may be that those conversations become less crucial as some families may start to value and accept immunizations more as a result of this pandemic,” Dr Cataldi said. “Or for families with vaccine questions, telehealth might support those conversations with a provider well.”
After adjusting for potential confounders, the only practice or physician factor significantly associated with not using standing orders for vaccines was physicians’ having a higher “physician responsibility score.” Doctors with these higher scores also were marginally more likely to make independent decisions about vaccines than counterparts working at practices where system-level decisions occur.
“Perhaps physicians who feel more personal responsibility about their role in vaccination are more likely to choose practice settings where they have more independent decision-making ability,” the authors wrote. “Alternatively, knowing the level of decision-making about vaccines in the practice may influence the amount of personal responsibility that pediatricians feel about their role in vaccine delivery.”
Again, attitudes may have shifted since the coronavirus pandemic began. The biggest risk to children in terms of immunizations is not getting them, Dr Offit said.
“The parents are scared, and the doctors are scared,” he said. “They feel that going to a doctor’s office is going to a concentrated area where they’re more likely to pick up this virus.”
He’s expressed uncertainty about whether standing orders could play a role in alleviating that anxiety. But Dr Cataldi suggests it’s possible.
“I think standing orders will be important to increasing vaccination rates during a pandemic as they can be used to support delivery of vaccines through public health departments and through vaccine-only nurse visits,” she said.
The research was funded by the Centers for Disease Control and Prevention. The authors had no relevant financial disclosures.
SOURCE: Cataldi J et al. Pediatrics. 2020 Apr;e20191855.
The biggest barrier to using standing orders for childhood immunizations is concern that patients will receive the wrong vaccine, according to a survey of pediatricians published in Pediatrics.
The other top reasons pediatricians give for not using standing orders for vaccines are concerns that parents may want to talk to the doctor about the vaccine before their child gets it, and a belief that the doctor should be the one who personally recommends a vaccine for their patient.
But with severe drops in vaccination rates resulting from the COVID-19 pandemic, standing orders may be a valuable tool for ensuring children get their vaccines on time, suggested lead author, Jessica Cataldi, MD, of the University of Colorado and Children’s Hospital Colorado in Aurora.
“As we work to bring more families back to their pediatrician’s office for well-child checks, standing orders are one process that can streamline the visit by saving providers time and increasing vaccine delivery,” she said in an interview. “We will also need use standing orders to support different ways to get children their immunizations during times of social distancing. This could take the form of drive-through immunization clinics or telehealth well-child checks that are paired with a quick immunization-only visit.”
The American Academy of Pediatrics issued guidance April 14 that emphasizes the need to prioritize immunization of children through 2-years-old.
Paul A. Offit, MD, director of the Vaccine Education Center and an attending physician in the division of infectious diseases at Children’s Hospital of Philadelphia, agreed that it’s essential children do not fall behind on the recommended schedule during the pandemic.
“It’s important not to have greater collateral damage from this COVID-19 pandemic by putting children at increased risk from other infections that are circulating, like measles and pertussis,” he said, noting that nearly 1,300 measles cases and more than 15,000 pertussis cases occurred in the United States in 2019.
It’s important “not to delay those primary vaccines because it’s hard to catch up,” he said in an interview
Although “standing orders” may go by other names in non–inpatient settings, the researchers defined them in their survey as “a written or verbal policy that persons other than a medical provider, such as a nurse or medical assistant, may consent and vaccinate a person without speaking with the physician or advanced care provider first.” Further, the “vaccine may be given before or after a physician encounter or in the absence of a physician encounter altogether.”
Research strongly suggests that standing orders for childhood vaccines are cost-effective and increase immunization rates, the authors noted. The Centers for Disease Control and Prevention, its Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the federal National Vaccine Advisory Committee all recommend using standing orders to improve vaccination access and rates.
The authors sought to understand how many pediatricians use standing orders and what reasons stop them from doing so. During June-September 2017, they sent out 471 online and mail surveys to a nationally representative sample of AAP members who spent at least half their time in primary care.
The 372 pediatricians who completed the survey made up a response rate of 79%, with no differences in response based on age, sex, years in practice, practice setting, region or rural/urban location.
More than half the respondents (59%) used standing orders for childhood immunizations. Just over a third of respondents (36%) said they use standing orders for all routinely recommended vaccines, and 23% use them for some vaccines.
Among those who did not use standing orders, 68% cited the concern that patients would get the incorrect vaccine by mistake as a barrier to using them. That came as a surprise to Dr Offit, who would expect standing orders to reduce the likelihood of error.
“The standing order should make things a little more foolproof so that you’re less likely to make a mistake,” Dr Offit said.
No studies have shown that vaccine errors occur more often in clinics that use standing orders for immunizations, but the question merits continued monitoring, Dr Cataldi said.
“It is important for any clinic that is new to the use of standing orders to provide adequate education to providers and other staff about when and how to use standing orders, and to always leave room for staff to bring vaccination questions to the provider,” Dr Cataldi told this newspaper
Nearly as many physicians (62%) believed that families would want to speak to the doctor about a vaccine before getting it, and 57% of respondents who didn’t use standing orders believed they should be the one who recommends a vaccine to their patient’s parents.
All three of these reasons also ranked highest as barriers in responses from all respondents, including those who use standing orders. But those who didn’t use them were significantly more likely to cite these reasons (P less than .0001).
Since the survey occurred in 2017, however, it’s possible the pandemic and the rapid increase in telehealth as a result may influence perceptions moving forward.
“With provider concerns that standing orders remove physicians from the vaccination conversation, it may be that those conversations become less crucial as some families may start to value and accept immunizations more as a result of this pandemic,” Dr Cataldi said. “Or for families with vaccine questions, telehealth might support those conversations with a provider well.”
After adjusting for potential confounders, the only practice or physician factor significantly associated with not using standing orders for vaccines was physicians’ having a higher “physician responsibility score.” Doctors with these higher scores also were marginally more likely to make independent decisions about vaccines than counterparts working at practices where system-level decisions occur.
“Perhaps physicians who feel more personal responsibility about their role in vaccination are more likely to choose practice settings where they have more independent decision-making ability,” the authors wrote. “Alternatively, knowing the level of decision-making about vaccines in the practice may influence the amount of personal responsibility that pediatricians feel about their role in vaccine delivery.”
Again, attitudes may have shifted since the coronavirus pandemic began. The biggest risk to children in terms of immunizations is not getting them, Dr Offit said.
“The parents are scared, and the doctors are scared,” he said. “They feel that going to a doctor’s office is going to a concentrated area where they’re more likely to pick up this virus.”
He’s expressed uncertainty about whether standing orders could play a role in alleviating that anxiety. But Dr Cataldi suggests it’s possible.
“I think standing orders will be important to increasing vaccination rates during a pandemic as they can be used to support delivery of vaccines through public health departments and through vaccine-only nurse visits,” she said.
The research was funded by the Centers for Disease Control and Prevention. The authors had no relevant financial disclosures.
SOURCE: Cataldi J et al. Pediatrics. 2020 Apr;e20191855.
The biggest barrier to using standing orders for childhood immunizations is concern that patients will receive the wrong vaccine, according to a survey of pediatricians published in Pediatrics.
The other top reasons pediatricians give for not using standing orders for vaccines are concerns that parents may want to talk to the doctor about the vaccine before their child gets it, and a belief that the doctor should be the one who personally recommends a vaccine for their patient.
But with severe drops in vaccination rates resulting from the COVID-19 pandemic, standing orders may be a valuable tool for ensuring children get their vaccines on time, suggested lead author, Jessica Cataldi, MD, of the University of Colorado and Children’s Hospital Colorado in Aurora.
“As we work to bring more families back to their pediatrician’s office for well-child checks, standing orders are one process that can streamline the visit by saving providers time and increasing vaccine delivery,” she said in an interview. “We will also need use standing orders to support different ways to get children their immunizations during times of social distancing. This could take the form of drive-through immunization clinics or telehealth well-child checks that are paired with a quick immunization-only visit.”
The American Academy of Pediatrics issued guidance April 14 that emphasizes the need to prioritize immunization of children through 2-years-old.
Paul A. Offit, MD, director of the Vaccine Education Center and an attending physician in the division of infectious diseases at Children’s Hospital of Philadelphia, agreed that it’s essential children do not fall behind on the recommended schedule during the pandemic.
“It’s important not to have greater collateral damage from this COVID-19 pandemic by putting children at increased risk from other infections that are circulating, like measles and pertussis,” he said, noting that nearly 1,300 measles cases and more than 15,000 pertussis cases occurred in the United States in 2019.
It’s important “not to delay those primary vaccines because it’s hard to catch up,” he said in an interview
Although “standing orders” may go by other names in non–inpatient settings, the researchers defined them in their survey as “a written or verbal policy that persons other than a medical provider, such as a nurse or medical assistant, may consent and vaccinate a person without speaking with the physician or advanced care provider first.” Further, the “vaccine may be given before or after a physician encounter or in the absence of a physician encounter altogether.”
Research strongly suggests that standing orders for childhood vaccines are cost-effective and increase immunization rates, the authors noted. The Centers for Disease Control and Prevention, its Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the federal National Vaccine Advisory Committee all recommend using standing orders to improve vaccination access and rates.
The authors sought to understand how many pediatricians use standing orders and what reasons stop them from doing so. During June-September 2017, they sent out 471 online and mail surveys to a nationally representative sample of AAP members who spent at least half their time in primary care.
The 372 pediatricians who completed the survey made up a response rate of 79%, with no differences in response based on age, sex, years in practice, practice setting, region or rural/urban location.
More than half the respondents (59%) used standing orders for childhood immunizations. Just over a third of respondents (36%) said they use standing orders for all routinely recommended vaccines, and 23% use them for some vaccines.
Among those who did not use standing orders, 68% cited the concern that patients would get the incorrect vaccine by mistake as a barrier to using them. That came as a surprise to Dr Offit, who would expect standing orders to reduce the likelihood of error.
“The standing order should make things a little more foolproof so that you’re less likely to make a mistake,” Dr Offit said.
No studies have shown that vaccine errors occur more often in clinics that use standing orders for immunizations, but the question merits continued monitoring, Dr Cataldi said.
“It is important for any clinic that is new to the use of standing orders to provide adequate education to providers and other staff about when and how to use standing orders, and to always leave room for staff to bring vaccination questions to the provider,” Dr Cataldi told this newspaper
Nearly as many physicians (62%) believed that families would want to speak to the doctor about a vaccine before getting it, and 57% of respondents who didn’t use standing orders believed they should be the one who recommends a vaccine to their patient’s parents.
All three of these reasons also ranked highest as barriers in responses from all respondents, including those who use standing orders. But those who didn’t use them were significantly more likely to cite these reasons (P less than .0001).
Since the survey occurred in 2017, however, it’s possible the pandemic and the rapid increase in telehealth as a result may influence perceptions moving forward.
“With provider concerns that standing orders remove physicians from the vaccination conversation, it may be that those conversations become less crucial as some families may start to value and accept immunizations more as a result of this pandemic,” Dr Cataldi said. “Or for families with vaccine questions, telehealth might support those conversations with a provider well.”
After adjusting for potential confounders, the only practice or physician factor significantly associated with not using standing orders for vaccines was physicians’ having a higher “physician responsibility score.” Doctors with these higher scores also were marginally more likely to make independent decisions about vaccines than counterparts working at practices where system-level decisions occur.
“Perhaps physicians who feel more personal responsibility about their role in vaccination are more likely to choose practice settings where they have more independent decision-making ability,” the authors wrote. “Alternatively, knowing the level of decision-making about vaccines in the practice may influence the amount of personal responsibility that pediatricians feel about their role in vaccine delivery.”
Again, attitudes may have shifted since the coronavirus pandemic began. The biggest risk to children in terms of immunizations is not getting them, Dr Offit said.
“The parents are scared, and the doctors are scared,” he said. “They feel that going to a doctor’s office is going to a concentrated area where they’re more likely to pick up this virus.”
He’s expressed uncertainty about whether standing orders could play a role in alleviating that anxiety. But Dr Cataldi suggests it’s possible.
“I think standing orders will be important to increasing vaccination rates during a pandemic as they can be used to support delivery of vaccines through public health departments and through vaccine-only nurse visits,” she said.
The research was funded by the Centers for Disease Control and Prevention. The authors had no relevant financial disclosures.
SOURCE: Cataldi J et al. Pediatrics. 2020 Apr;e20191855.
FROM PEDIATRICS