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Primordial cardiovascular prevention draws closer
A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, 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.
This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.
“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).
Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.
The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.
A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.
Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.
“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.
Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”
“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.
Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.
“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.
“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.
“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.
Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.
A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, 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.
This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.
“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).
Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.
The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.
A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.
Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.
“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.
Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”
“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.
Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.
“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.
“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.
“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.
Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.
A powerful genetic predisposition to cardiovascular disease was overcome by low lifetime exposure to LDL cholesterol and systolic blood pressure in a naturalistic study conducted in nearly half a million people, Brian A. Ference, 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.
This novel finding potentially opens the door to primordial cardiovascular prevention, the earliest possible form of primary prevention, in which cardiovascular risk factors are curtailed before they can become established.
“It’s important to note that the trajectories of lifetime risk for cardiovascular disease predicted by a PGS [polygenic risk score] are not fixed. At the same level of a PGS for coronary artery disease, participants with lower lifetime exposure to LDL and systolic blood pressure had a lower trajectory of risk for cardiovascular disease. This finding implies that the trajectory of cardiovascular risk predicted by a PGS can be reduced by lowering LDL and blood pressure,” observed Dr. Ference, professor of translational therapeutics and executive director of the Center for Naturally Randomised Trials at the University of Cambridge (England).
Together with an international team of coinvestigators, he analyzed lifetime cardiovascular risk as predicted by a PGS derived by genomic testing in relation to lifetime LDL and systolic blood pressure levels in 445,566 participants in the UK Biobank. Subjects had a mean age of 57.2 years at enrollment and 65.2 years at last follow-up. The primary study outcome, a first major coronary event (MCE) as defined by a fatal or nonfatal MI or coronary revascularization, occurred in 23,032 subjects.
The investigators found a stepwise increase in MCE risk across increasing quintiles of genetic risk as reflected in the PGS, such that participants in the top PGS quintile were at 2.8-fold greater risk of an MCE than those in the first quintile. The risk was essentially the same in men and women.
A key finding was that, at any level of lifetime MCE risk as defined by PGS, the actual event rate varied 10-fold depending upon lifetime exposure to LDL cholesterol and systolic blood pressure (SBP). For example, men in the top PGS quintile with high lifetime SBP and LDL cholesterol had a 93% lifetime MCE risk, but that MCE risk plummeted to 8% in those in the top quintile but with low lifetime SBP and LDL cholesterol.
Small differences in those two cardiovascular risk factors over the course of many decades had a big impact. For example, it took only a 10-mg/dL lower lifetime exposure to LDL cholesterol and a 2–mm Hg lower SBP to blunt the trajectory of lifetime risk for MCE in individuals in the middle quintile of PGS to the more favorable trajectory of those in the lowest PGS quintile. Conversely, with a 10-mg/dL increase in LDL cholesterol and 2–mm Hg greater SBP over the course of a lifetime, the trajectory of risk for people in the middle quintile of PGS became essentially superimposable upon the trajectory associated with the highest PGS quintile, the cardiologist explained.
“Participants with low lifetime exposure to LDL and blood pressure had a low lifetime risk of cardiovascular disease at all levels of PGS for coronary disease. This implies that LDL and blood pressure, which are modifiable, may be more powerful determinants of lifetime risk than polygenic predisposition,” Dr. Ference declared.
Discussant Vera Bittner, MD, professor of medicine at the University of Alabama, Birmingham, said that for her this study carried a heartening take-home message: “The polygenic risk score can stratify the population into different risk groups and, at the same time, lifetime exposure to LDL and blood pressure significantly modifies the risk, suggesting that genetics is not destiny, and we may be able to intervene.”
“To be able to know what your cardiovascular risk is from an early age and to plan therapies to prevent cardiovascular disease would be incredible,” agreed session chair B. Hadley Wilson, MD, of the Sanger Heart and Vascular Institute in Charlotte, N.C.
Sekar Kathiresan, MD, said the study introduces the PGS as a new risk factor for coronary artery disease. Focusing efforts to achieve lifelong low exposure to LDL cholesterol and blood pressure in those individuals in the top 10%-20% in PGS should provide a great absolute reduction in MCE risk.
“It potentially can give you a 30- or 40-year head start in understanding who’s at risk because the factor can be measured as early as birth,” observed Dr. Kathiresan, a cardiologist who is director of the Center for Genomic Medicine at Massachusetts General Hospital, Boston.
“It’s also very inexpensive: You get the information once, bank it, and use it throughout life,” noted Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Harvard Medical School, Boston.
“A genome-wide scan will give us information not just on cardiovascular risk, but on cancer risk, on risk of kidney disease, and on the risk of a host of other issues. It’s a very different way of thinking about risk presentation across a whole variety of endpoints,” Dr. Ridker added.
Dr. Ference reported receiving fees and/or research grants from Merck, Amgen, Regeneron, Sanofi, Novartis, Pfizer, Eli Lilly, NovoNordisk, The Medicines Company, Mylan, Daiichi Sankyo, Silence Therapeutics, Ionis Pharmaceuticals, dalCOR, CiVi Pharma, KrKa Pharmaceuticals, Medtronic, and Celera.
REPORTING FROM ACC 20
Rivaroxaban plus aspirin safely benefits PAD patients after limb revascularization
A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.
The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 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.
The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.
“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”
“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.
Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.
VOYAGER PAD trial
The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).
Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.
“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.
VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.
SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.
A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.
The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 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.
The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.
“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”
“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.
Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.
VOYAGER PAD trial
The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).
Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.
“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.
VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.
SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.
A combined antithrombotic regimen of rivaroxaban plus aspirin was safe and effective for reducing ischemic events in patients with symptomatic peripheral artery disease who had just undergone peripheral artery revascularization in VOYAGER PAD, a multicenter randomized trial with nearly 6,600 patients.
The study and its results were a groundbreaking advance for this patient population, who until now have had no evidence-based treatment available, Mark P. Bonaca, MD, said on March 28 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.
The study design excluded a small percentage of patients (about 2%) because of their very high bleeding-risk history. Among the treated patients, in those who received a combination of 2.5 mg rivaroxaban twice daily plus 100 mg of aspirin daily, bleeding events were more common, compared with control patients who received aspirin alone. But the patients who received both drugs showed no excess of fatal bleeds or intracranial hemorrhages, and the rate of ischemic events prevented by rivaroxaban plus aspirin exceeded the excess rate of bleeds by three- to sixfold, depending on how bleeding episodes were defined, noted Dr. Bonaca, executive director of CPC Clinical Research and CPC Community Health, an academic research organization affiliated with the University of Colorado at Denver in Aurora.
“This was a much anticipated and important trial. Those of us who treat patients with lower-limb peripheral artery disease have not had much evidence on how to treat these patients, particularly those who have just undergone revascularization. This trial gives us the evidence,” commented Mark A. Creager, MD, professor of medicine and director of the Heart and Vascular Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “The bleeding risk [from adding rivaroxaban treatment] was substantially less than the benefit from preventing major adverse limb events and major adverse cardiovascular events,” producing a “favorable balance” of benefit, compared with risk, Dr. Creager said in an interview. “In the right patients, the benefit greatly outweighed the risk.”
“This was an incredible trial that will advance care,” commented Joshua A. Beckman, MD, professor of medicine and director of Vascular Medicine at Vanderbilt University in Nashville, Tenn. “The treatment was beneficial for patients across a range of symptom severity, from claudication to critical limb ischemia,” and the results expand the range of patients proven to benefit from the rivaroxaban plus aspirin combination from the types of patients with peripheral artery disease (PAD) enrolled in the COMPASS trial. That pivotal trial showed similar benefit from the dual-antithrombotic regimen, but in patients who had both coronary artery disease as well as atherosclerotic disease in at least one additional vascular bed, such as lower-limb arteries (N Engl J Med. 2017 Oct 5;377[14]:1319-30). In addition to “bringing acute limb ischemia to the cardiovascular community,” the results also identified a very useful time point in the clinical presentation of these patients for starting a combined rivaroxaban plus aspirin regimen: when patients are hospitalized for their revascularization procedure, said Dr. Beckman, a designated discussant for the report.
Among the 6,564 patients randomized in the study, about two-thirds underwent endovascular revascularization within 10 days before starting their study treatment, and the remaining third had undergone surgical revascularization. The study focused on patients “with symptomatic PAD but without known coronary artery disease,” noted Dr. Bonaca.
VOYAGER PAD trial
The VOYAGER PAD (Vascular Outcomes Study of Acetylsalicylic Acid Along With Rivaroxaban in Endovascular Or Surgical Limb Revascularization for Peripheral Artery Disease) trial enrolled patients during 2015-2018 at 534 sites in 34 countries. The study’s primary endpoint was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes, and was reduced during a median follow-up of 28 months from 19.9% with aspirin alone to 17.3% on the combined regimen, a 2.6% absolute difference and a 15% relative risk reduction that was statistically significant, an endpoint primarily driven by a reduction in acute limb ischemia. The primary safety endpoint was the rate of TIMI (Thrombolysis in Myocardial Infarction) major bleeds, which was 0.8% higher in the patients who received the anticoagulant, a 43% relative increase that just missed statistical significance. But that result demonstrated the small but important increased risk for bleeding events that the dual regimen produced in these patients, Dr. Bonaca said. Simultaneously with his report the findings also appeared in an article published online (N Engl J Med. 2020 Mar 28. doi: 10.1056/NEJMoa2000052).
Dr. Bonaca cautioned that one limitation of his report on the primary outcome of VOYAGER PAD is that the results of an important subgroup analysis won’t be known until a second report during the ACC online sessions on March 29, which will examine the impact that treatment with the antiplatelet drug clopidogrel had on both the efficacy and safety outcomes. Half of the enrolled patients received clopidogrel at the discretion of their treating physicians; addition or exclusion of concurrent clopidogrel treatment was outside of the study’s design. “Is efficacy the same with or without clopidogrel, and what is the bleeding cost,” especially in patients who receive three antithrombotic drugs? “It will be very important to understand,” Dr. Bonaca said.
“Until now, we had no idea of what was the best antithrombotic strategy for patients after a successful peripheral vascular intervention.” VOYAGER PAD was “an unprecedented vascular study that addressed an unmet patient need,” commented Roxana Mehran, MD, a designated discussant for the study and professor of medicine and director of Interventional Cardiovascular Research at Mount Sinai Medical Center in New York.
VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.
SOURCE: Bonaca MP et al. ACC 20, Abstract 402-10.
REPORTING FROM ACC 20
Key clinical point: Combined treatment with rivaroxaban plus aspirin safely reduced a composite measure of adverse ischemic events in PAD patients following lower-limb revascularization.
Major finding: The primary event outcome occurred in 17.3% of patients on rivaroxaban plus aspirin, and in 19.9% on aspirin alone.
Study details: VOYAGER PAD, a multicenter, international randomized trial with 6,564 patients.
Disclosures: VOYAGER PAD was sponsored by Bayer and Janssen, the companies that market rivaroxaban (Xarelto). The institution that Dr. Bonaca directs has received research funding from Bayer and Janssen, and also from Amgen, Aralez, AstraZeneca, Merck, Novo Nordisk, Pfizer, and Sanofi. Dr. Creager had no disclosures. Dr. Beckman has served as a data safety monitor for Bayer and for Novartis, and has been a consultant to Amgen, AstraZeneca, JanOne and Sanofi. Dr. Mehran has received research funding from Bayer and has been a consultant to Janssen, and she has also received research funding or been a consultant to several other companies.
Source: Bonaca MP. ACC 20, Abstract 402-10.
Before the COVID-19 surge hits your facility, take steps to boost capacity
, according to a physician leader and a health workforce expert.
Polly Pittman, PhD, is hearing a lot of concern among health care workers that it’s difficult to find definitive and accurate information about how best to protect themselves and their families, she said during a webinar by the Alliance for Health Policy titled Health System Capacity: Protecting Frontline Health Workers. “The knowledge base is evolving very quickly,” said Dr. Pittman, Fitzhugh Mullan Professor of Health Workforce Equity at the Milken Institute School of Public Health, George Washington University, Washington.
Stephen Parodi, MD, agreed that effective communication is job one in the health care workplace during the crisis. “I can’t stress enough ... that communications are paramount and you can’t overcommunicate,” said Dr. Parodi, executive vice president of external affairs, communications, and brand at the Permanente Federation and associate executive director of the Permanente Medical Group, Vallejo, Calif.
“We’re in a situation of confusion and improvisation right now,” regarding protection of health care workers, said Dr. Pittman. The potential exists for “a downward spiral where you have the lack of training, the shortages in terms of protective gear, weakening of guidelines, and confusion regarding guidelines at federal level, creating a potential cascade” that may result in “moral distress and fatigue. ... That’s not occurring now, but that’s the danger” unless the personal protective equipment (PPE) situation is adequately addressed very soon, she said.
Dr. Pittman also pointed out the concerns that many of the 18 million U.S. health care workers have for their families should they themselves fall ill or transmit coronavirus to family members. “The danger exists of a mass exodus. People don’t have to show up at work, and they won’t show up at work if they don’t feel supported and safe.”
Dr. Parodi said that the Permanente organization is on a better footing than many workplaces. “We actually had an early experience because of the work that we did to support the Diamond Princess cruise ship evacuees from Yokahama in February.” That ship was quarantined upon arrival in Yokahama on Feb. 3 because a passenger had a confirmed test for SARS-CoV-2 infection, and a quarter of the 428 Americans on board subsequently tested positive. Most of them were evacuated to California or Texas. “That actually gave us the experience for providing care within the hospital setting – and also for containment strategies,” he said.
“We quickly understood that we needed to move to a mitigation strategy,” said Dr. Parodi. Use of PPE has been “tailored for how the virus is spread.” In the absence of the risk of aerosol transmission from certain procedures, health care workers use gowns, gloves, surgical masks, and goggles.
Because of anticipated “supply chain shortfalls,” Dr. Parodi said that his organization implemented Centers for Disease Control and Prevention guidelines for reuse and extended use of N95 respirators early on. “Even if you’re not in a locale that’s been hit, you need to be on wartime footing for preserving PPE.”
Telehealth, said Dr. Parodi, has been implemented “in a huge way” throughout the Permanente system. “We have reduced primary care visits by 90% in the past week, and also subspecialty visits by 50%. … A large amount of the workforce can work from home. We turned off elective surgeries more than a week ago to reduce the number of patients who are requiring intensive care.” Making these changes means the organization is more prepared now for a surge they expect in the coming weeks.
Dr. Pittman voiced an opinion widely shared by those who are implementing large-scale telehealth efforts “We’re going to learn a lot. Many of the traditional doctor-patient visits can be done by telemedicine in the future.”
Knowledge about local trends in infection rates is key to preparedness. “We’ve ramped up testing, to understand what’s happening in the community,” said Dr. Parodi, noting that test turnaround time is currently running 8-24 hours. Tightening up this window can free up resources when an admitted patient’s test is negative.
Still, some national projections forecast a need for hospital beds at two to three times current capacity – or even more, said Dr. Parodi.
He noted that Permanente is “working hand in glove with state authorities throughout the country.” Efforts include establishing alternative sites for assessment and testing, as well as opening up closed hospitals and working with the National Guard and the Department of Defense to prepare mobile hospital units that can be deployed in areas with peak infection rates. “Having all of those options available to us is critically important,” he said.
To mitigate potential provider shortages, Dr. Pittman said, “All members of the care team could potentially do more” than their current licenses allow. Expanding the scope of practice for pharmacists, clinical laboratory staff, licensed practical nurses, and medical assistants can help with efficient care delivery.
Other measures include expedited licensing for near-graduates and nonpracticing foreign medical graduates, as well as relicensing for retired health care personnel and those who are not currently working directly with patients, she said.
Getting these things done “requires leadership on behalf of the licensing bodies,” as well as coordination with state regulatory authorities, Dr. Pittman pointed out.
Dr. Parodi called for state and federal governments to implement emergency declarations that suspend some existing health codes to achieve repurposing of staff. Getting these measures in place now will allow facilities “to be able to provide that in-time training now before the surge occurs. ... We are actively developing plans knowing that there’s going to be a need for more critical care.”
The game plan at Permanente, he said, is to repurpose critical care physicians to provide consultations to multiple hospitalists who are providing the bulk of frontline care. At the same time, they plan to repurpose other specialists to backfill the hospitalists, and to repurpose family medicine physicians to supplement staff in emergency departments and other frontline intake areas.
All the organizational measures being taken won’t be in vain if they increase preparedness for the long battle ahead, he said. “We need to double down on the work. ... We need to continue social distancing, and we’ve got to ramp up testing. Until we do that we have to hold the line on basic public health measures.”
Dr. Parodi is employed by Permanente. The panelists reported no disclosures relevant to the presentation, which was sponsored by the Alliance for Health Policy, the Commonwealth Fund, and the National Institute for Health Care Management Foundation.
, according to a physician leader and a health workforce expert.
Polly Pittman, PhD, is hearing a lot of concern among health care workers that it’s difficult to find definitive and accurate information about how best to protect themselves and their families, she said during a webinar by the Alliance for Health Policy titled Health System Capacity: Protecting Frontline Health Workers. “The knowledge base is evolving very quickly,” said Dr. Pittman, Fitzhugh Mullan Professor of Health Workforce Equity at the Milken Institute School of Public Health, George Washington University, Washington.
Stephen Parodi, MD, agreed that effective communication is job one in the health care workplace during the crisis. “I can’t stress enough ... that communications are paramount and you can’t overcommunicate,” said Dr. Parodi, executive vice president of external affairs, communications, and brand at the Permanente Federation and associate executive director of the Permanente Medical Group, Vallejo, Calif.
“We’re in a situation of confusion and improvisation right now,” regarding protection of health care workers, said Dr. Pittman. The potential exists for “a downward spiral where you have the lack of training, the shortages in terms of protective gear, weakening of guidelines, and confusion regarding guidelines at federal level, creating a potential cascade” that may result in “moral distress and fatigue. ... That’s not occurring now, but that’s the danger” unless the personal protective equipment (PPE) situation is adequately addressed very soon, she said.
Dr. Pittman also pointed out the concerns that many of the 18 million U.S. health care workers have for their families should they themselves fall ill or transmit coronavirus to family members. “The danger exists of a mass exodus. People don’t have to show up at work, and they won’t show up at work if they don’t feel supported and safe.”
Dr. Parodi said that the Permanente organization is on a better footing than many workplaces. “We actually had an early experience because of the work that we did to support the Diamond Princess cruise ship evacuees from Yokahama in February.” That ship was quarantined upon arrival in Yokahama on Feb. 3 because a passenger had a confirmed test for SARS-CoV-2 infection, and a quarter of the 428 Americans on board subsequently tested positive. Most of them were evacuated to California or Texas. “That actually gave us the experience for providing care within the hospital setting – and also for containment strategies,” he said.
“We quickly understood that we needed to move to a mitigation strategy,” said Dr. Parodi. Use of PPE has been “tailored for how the virus is spread.” In the absence of the risk of aerosol transmission from certain procedures, health care workers use gowns, gloves, surgical masks, and goggles.
Because of anticipated “supply chain shortfalls,” Dr. Parodi said that his organization implemented Centers for Disease Control and Prevention guidelines for reuse and extended use of N95 respirators early on. “Even if you’re not in a locale that’s been hit, you need to be on wartime footing for preserving PPE.”
Telehealth, said Dr. Parodi, has been implemented “in a huge way” throughout the Permanente system. “We have reduced primary care visits by 90% in the past week, and also subspecialty visits by 50%. … A large amount of the workforce can work from home. We turned off elective surgeries more than a week ago to reduce the number of patients who are requiring intensive care.” Making these changes means the organization is more prepared now for a surge they expect in the coming weeks.
Dr. Pittman voiced an opinion widely shared by those who are implementing large-scale telehealth efforts “We’re going to learn a lot. Many of the traditional doctor-patient visits can be done by telemedicine in the future.”
Knowledge about local trends in infection rates is key to preparedness. “We’ve ramped up testing, to understand what’s happening in the community,” said Dr. Parodi, noting that test turnaround time is currently running 8-24 hours. Tightening up this window can free up resources when an admitted patient’s test is negative.
Still, some national projections forecast a need for hospital beds at two to three times current capacity – or even more, said Dr. Parodi.
He noted that Permanente is “working hand in glove with state authorities throughout the country.” Efforts include establishing alternative sites for assessment and testing, as well as opening up closed hospitals and working with the National Guard and the Department of Defense to prepare mobile hospital units that can be deployed in areas with peak infection rates. “Having all of those options available to us is critically important,” he said.
To mitigate potential provider shortages, Dr. Pittman said, “All members of the care team could potentially do more” than their current licenses allow. Expanding the scope of practice for pharmacists, clinical laboratory staff, licensed practical nurses, and medical assistants can help with efficient care delivery.
Other measures include expedited licensing for near-graduates and nonpracticing foreign medical graduates, as well as relicensing for retired health care personnel and those who are not currently working directly with patients, she said.
Getting these things done “requires leadership on behalf of the licensing bodies,” as well as coordination with state regulatory authorities, Dr. Pittman pointed out.
Dr. Parodi called for state and federal governments to implement emergency declarations that suspend some existing health codes to achieve repurposing of staff. Getting these measures in place now will allow facilities “to be able to provide that in-time training now before the surge occurs. ... We are actively developing plans knowing that there’s going to be a need for more critical care.”
The game plan at Permanente, he said, is to repurpose critical care physicians to provide consultations to multiple hospitalists who are providing the bulk of frontline care. At the same time, they plan to repurpose other specialists to backfill the hospitalists, and to repurpose family medicine physicians to supplement staff in emergency departments and other frontline intake areas.
All the organizational measures being taken won’t be in vain if they increase preparedness for the long battle ahead, he said. “We need to double down on the work. ... We need to continue social distancing, and we’ve got to ramp up testing. Until we do that we have to hold the line on basic public health measures.”
Dr. Parodi is employed by Permanente. The panelists reported no disclosures relevant to the presentation, which was sponsored by the Alliance for Health Policy, the Commonwealth Fund, and the National Institute for Health Care Management Foundation.
, according to a physician leader and a health workforce expert.
Polly Pittman, PhD, is hearing a lot of concern among health care workers that it’s difficult to find definitive and accurate information about how best to protect themselves and their families, she said during a webinar by the Alliance for Health Policy titled Health System Capacity: Protecting Frontline Health Workers. “The knowledge base is evolving very quickly,” said Dr. Pittman, Fitzhugh Mullan Professor of Health Workforce Equity at the Milken Institute School of Public Health, George Washington University, Washington.
Stephen Parodi, MD, agreed that effective communication is job one in the health care workplace during the crisis. “I can’t stress enough ... that communications are paramount and you can’t overcommunicate,” said Dr. Parodi, executive vice president of external affairs, communications, and brand at the Permanente Federation and associate executive director of the Permanente Medical Group, Vallejo, Calif.
“We’re in a situation of confusion and improvisation right now,” regarding protection of health care workers, said Dr. Pittman. The potential exists for “a downward spiral where you have the lack of training, the shortages in terms of protective gear, weakening of guidelines, and confusion regarding guidelines at federal level, creating a potential cascade” that may result in “moral distress and fatigue. ... That’s not occurring now, but that’s the danger” unless the personal protective equipment (PPE) situation is adequately addressed very soon, she said.
Dr. Pittman also pointed out the concerns that many of the 18 million U.S. health care workers have for their families should they themselves fall ill or transmit coronavirus to family members. “The danger exists of a mass exodus. People don’t have to show up at work, and they won’t show up at work if they don’t feel supported and safe.”
Dr. Parodi said that the Permanente organization is on a better footing than many workplaces. “We actually had an early experience because of the work that we did to support the Diamond Princess cruise ship evacuees from Yokahama in February.” That ship was quarantined upon arrival in Yokahama on Feb. 3 because a passenger had a confirmed test for SARS-CoV-2 infection, and a quarter of the 428 Americans on board subsequently tested positive. Most of them were evacuated to California or Texas. “That actually gave us the experience for providing care within the hospital setting – and also for containment strategies,” he said.
“We quickly understood that we needed to move to a mitigation strategy,” said Dr. Parodi. Use of PPE has been “tailored for how the virus is spread.” In the absence of the risk of aerosol transmission from certain procedures, health care workers use gowns, gloves, surgical masks, and goggles.
Because of anticipated “supply chain shortfalls,” Dr. Parodi said that his organization implemented Centers for Disease Control and Prevention guidelines for reuse and extended use of N95 respirators early on. “Even if you’re not in a locale that’s been hit, you need to be on wartime footing for preserving PPE.”
Telehealth, said Dr. Parodi, has been implemented “in a huge way” throughout the Permanente system. “We have reduced primary care visits by 90% in the past week, and also subspecialty visits by 50%. … A large amount of the workforce can work from home. We turned off elective surgeries more than a week ago to reduce the number of patients who are requiring intensive care.” Making these changes means the organization is more prepared now for a surge they expect in the coming weeks.
Dr. Pittman voiced an opinion widely shared by those who are implementing large-scale telehealth efforts “We’re going to learn a lot. Many of the traditional doctor-patient visits can be done by telemedicine in the future.”
Knowledge about local trends in infection rates is key to preparedness. “We’ve ramped up testing, to understand what’s happening in the community,” said Dr. Parodi, noting that test turnaround time is currently running 8-24 hours. Tightening up this window can free up resources when an admitted patient’s test is negative.
Still, some national projections forecast a need for hospital beds at two to three times current capacity – or even more, said Dr. Parodi.
He noted that Permanente is “working hand in glove with state authorities throughout the country.” Efforts include establishing alternative sites for assessment and testing, as well as opening up closed hospitals and working with the National Guard and the Department of Defense to prepare mobile hospital units that can be deployed in areas with peak infection rates. “Having all of those options available to us is critically important,” he said.
To mitigate potential provider shortages, Dr. Pittman said, “All members of the care team could potentially do more” than their current licenses allow. Expanding the scope of practice for pharmacists, clinical laboratory staff, licensed practical nurses, and medical assistants can help with efficient care delivery.
Other measures include expedited licensing for near-graduates and nonpracticing foreign medical graduates, as well as relicensing for retired health care personnel and those who are not currently working directly with patients, she said.
Getting these things done “requires leadership on behalf of the licensing bodies,” as well as coordination with state regulatory authorities, Dr. Pittman pointed out.
Dr. Parodi called for state and federal governments to implement emergency declarations that suspend some existing health codes to achieve repurposing of staff. Getting these measures in place now will allow facilities “to be able to provide that in-time training now before the surge occurs. ... We are actively developing plans knowing that there’s going to be a need for more critical care.”
The game plan at Permanente, he said, is to repurpose critical care physicians to provide consultations to multiple hospitalists who are providing the bulk of frontline care. At the same time, they plan to repurpose other specialists to backfill the hospitalists, and to repurpose family medicine physicians to supplement staff in emergency departments and other frontline intake areas.
All the organizational measures being taken won’t be in vain if they increase preparedness for the long battle ahead, he said. “We need to double down on the work. ... We need to continue social distancing, and we’ve got to ramp up testing. Until we do that we have to hold the line on basic public health measures.”
Dr. Parodi is employed by Permanente. The panelists reported no disclosures relevant to the presentation, which was sponsored by the Alliance for Health Policy, the Commonwealth Fund, and the National Institute for Health Care Management Foundation.
REPORTING FROM AN ALLIANCE FOR HEALTH POLICY WEBINAR
Stage I mycosis fungoides is the general dermatologist’s bailiwick
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
LAHAINA, HAWAII – without bringing in a medical oncologist, Trilokraj Tejasvi, MBBS, said at the Hawaii Dermatology Seminar provided by Global Academy for Medical Education/Skin Disease Education Foundation.
This approach is in the best interest of patients with stage I mycosis fungoides, the skin-limited, patch/plaque form of the disease that generally responds well to skin-directed therapies without needing to resort to the medical oncologist’s arsenal of toxic treatments.
“For many medical oncologists, a lymphoma is a lymphoma. The first thing they give is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), and all the variants of CHOP,” cautioned Dr. Tejasvi, a dermatologist who is director of the cutaneous lymphoma program at the University of Michigan, Ann Arbor, and chief of the dermatology service at the Ann Arbor Veteran Affairs Hospital.
Stage IA mycosis fungoides is defined under the TNMB (tumor, node, metastasis, blood) classification as patches and/or plaques covering less than 10% of body surface area along with negative nodes, no metastases, and no or low burden of disease in the blood. Stage IB differs only in that it features 10% or greater body surface area involvement. The extent of body surface area involvement can be estimated by hands-on measurement in which the area of one of the patient’s hands – palm plus fingers – is considered equivalent to 1% of that individual’s total body surface area.
The first question patients newly diagnosed with a cutaneous T-cell lymphoma ask concerns their prognosis. For those with stage IA or IB mycosis fungoides, the news is very good, as highlighted in a retrospective study of nearly 1,400 patients with mycosis fungoides, 71% of whom presented with patch/plaque stage disease (J Clin Oncol. 2010 Nov 1;28[31]:4730-9).
The median overall survival was 35.5 years in patients with stage IA disease and 21.5 years in those with stage IB disease.
“I tell patients with stage IA disease that whether we treat it or not will not change the course of their life,” Dr. Tejasvri said.
His message to patients with stage IB disease is that, because of their 38% risk of disease progression, he wants to see them in follow-up annually for the rest of their life.
Stage IIA disease – that is, patches and/or plaques with lymph node involvement with no effacement – is a tipping point at which serious consideration should be given to possible referral to a specialized multidisciplinary lymphoma center, in his view. That’s because the 10-year overall survival rate is only 52%.
Topical therapies
Topical corticosteroids remain the time-honored first-line skin-directed treatment. The mechanism of benefit involves induction of apoptosis and inhibition of lymphocyte binding. In one prospective study, clobetasol propionate achieved a 94% overall response rate in patients with stage IA or B disease, with minimal toxicity.
Alternatives include topical 5% imiquimod (Aldara), with an overall response rate of 80% and complete response rate of 45% in a 20-patient study. A newer formulation of mechlorethamine gel (Valchlor), is reported to have a 59% overall response rate and a sustained response in 86% of initial responders. For refractory skin lesions, 1% bexarotene gel (Targretin) is an option, with overall response rates of 44%-63% reported in prospective trials.
“I like it if the patient’s insurance covers it. Otherwise, it’s like buying a Prius: it’s $30,000 for a 45-g tube, which is insane,” Dr. Tejasvi commented.
Narrow-band UVB phototherapy is an effective modality for thin plaques and patches, as is PUVA for thicker ones. Dr. Tejasvi typically treats with topical steroids and/or phototherapy for at least 3 months before tapering.
When to suspect mycosis fungoides
“Mycosis fungoides is a great masquerader,” the dermatologist observed. For that reason, it deserves to be included in the differential diagnosis of an atypical psoriasiform or eczematoid rash, any new-onset rash in an elderly patient, or a rash with fever, night sweats, and unintended weight loss in a patient of any age. Generalized erythema with severe itching is another red flag.
“This pruritus is so severe that the only other condition which in my clinical practice would match it is Norwegian scabies,” according to Dr. Tejasvi.
Polychromatic patches or plaques in skin of color warrant further investigation as possible mycosis fungoides, he added.
Dr. Tejasvi reported having no financial conflicts of interest regarding his presentation.
SDEF/Global Academy for Medical Education and this news organization are owned by the same parent company.
REPORTING FROM SDEF HAWAII DERMATOLOGY SEMINAR
Do we need another vital sign?
If you haven’t already found out that activity is a critical component in the physical and mental health of your patients, or if you’re trying to convince an influential person or group it deserves their attention and investment, I suggest you chase down this clinical report from the American Academy of Pediatrics. Representing the AAP’s Council on Sports Medicine and Fitness and Section on Obesity, the authors quite thoroughly make the case that anyone concerned about the health of this nation and its children should make promotion of physical activity a top priority.
I suspect that, like many of the position papers that come from the AAP, this clinical report is another example of preaching to the choir. However, I understand that the academy also hopes to convince a broader audience of nonphysician decision makers by laying out all of the evidence they can muster.
With their voluminous supporting evidence on the table, the authors move on to getting those of us in clinical practice to make our approach to this more systematic – including the addition of a Physical Activity Vital Sign (PAVS) in our patients’ health records. And here is where the authors begin to drift into the hazy dream world of unreality. They admit that “pediatricians will need efficient workflows to incorporate physical activity assessment, counseling and referral in the clinical visit.” Although there is no pediatrician more convinced of the importance of physical activity, I would find it very difficult to include a detailed assessment of my patients’ daily activity in their charts in the manner that the council members envision. Clunky EHRs, limited support staff, and a crowd of advocates already clamoring for my attention on their favorite health issue (nutrition, gun safety, parental depression, dental health to name just a few) all make creating an “efficient workflow” difficult on a good day and impossible on many days.
But, as I have said, I am a strong advocate of physical activity. So here’s a more nuanced suggestion based on a combination of my practical experience and the council’s recommendations.
If you provide good continuity of care to the families in your practice and have been asking good “getting to know you” questions at each visit, you probably already know which of your patients are sufficiently active. You don’t need to ask them how many hours a week they are doing something active. You should be able to just check a box that says “active.”
For patients that you haven’t seen before or suspect are too sedentary from looking at their biometrics and listening to their complaints you need only ask “What do you and your family like to do for fun?” The simple follow-up question of how many hours are spent watching TV, looking at smart phones or tablets, and playing video games in each day completes the survey. You don’t need to chart the depressing details because, as we know, relying on patient or parental recall is unlikely to provide the actual numbers. Just simply check the box that says “not active enough.” What you do with this crude assessment activity is another story and will be the topic for the next Letters from Maine.
This clinical report from the AAP is an excellent and exhaustive discussion of the importance of physical activity, but I hope that it doesn’t spark further cluttering of our already challenged EHR systems. Most of us don’t have the time to be data collectors and quantifiers. Let’s leave that to the clinical researchers. We already know activity is important and that most of our sedentary families aren’t going to be impressed by more science. Our challenge is to get them moving.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@mdedge.com.
If you haven’t already found out that activity is a critical component in the physical and mental health of your patients, or if you’re trying to convince an influential person or group it deserves their attention and investment, I suggest you chase down this clinical report from the American Academy of Pediatrics. Representing the AAP’s Council on Sports Medicine and Fitness and Section on Obesity, the authors quite thoroughly make the case that anyone concerned about the health of this nation and its children should make promotion of physical activity a top priority.
I suspect that, like many of the position papers that come from the AAP, this clinical report is another example of preaching to the choir. However, I understand that the academy also hopes to convince a broader audience of nonphysician decision makers by laying out all of the evidence they can muster.
With their voluminous supporting evidence on the table, the authors move on to getting those of us in clinical practice to make our approach to this more systematic – including the addition of a Physical Activity Vital Sign (PAVS) in our patients’ health records. And here is where the authors begin to drift into the hazy dream world of unreality. They admit that “pediatricians will need efficient workflows to incorporate physical activity assessment, counseling and referral in the clinical visit.” Although there is no pediatrician more convinced of the importance of physical activity, I would find it very difficult to include a detailed assessment of my patients’ daily activity in their charts in the manner that the council members envision. Clunky EHRs, limited support staff, and a crowd of advocates already clamoring for my attention on their favorite health issue (nutrition, gun safety, parental depression, dental health to name just a few) all make creating an “efficient workflow” difficult on a good day and impossible on many days.
But, as I have said, I am a strong advocate of physical activity. So here’s a more nuanced suggestion based on a combination of my practical experience and the council’s recommendations.
If you provide good continuity of care to the families in your practice and have been asking good “getting to know you” questions at each visit, you probably already know which of your patients are sufficiently active. You don’t need to ask them how many hours a week they are doing something active. You should be able to just check a box that says “active.”
For patients that you haven’t seen before or suspect are too sedentary from looking at their biometrics and listening to their complaints you need only ask “What do you and your family like to do for fun?” The simple follow-up question of how many hours are spent watching TV, looking at smart phones or tablets, and playing video games in each day completes the survey. You don’t need to chart the depressing details because, as we know, relying on patient or parental recall is unlikely to provide the actual numbers. Just simply check the box that says “not active enough.” What you do with this crude assessment activity is another story and will be the topic for the next Letters from Maine.
This clinical report from the AAP is an excellent and exhaustive discussion of the importance of physical activity, but I hope that it doesn’t spark further cluttering of our already challenged EHR systems. Most of us don’t have the time to be data collectors and quantifiers. Let’s leave that to the clinical researchers. We already know activity is important and that most of our sedentary families aren’t going to be impressed by more science. Our challenge is to get them moving.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@mdedge.com.
If you haven’t already found out that activity is a critical component in the physical and mental health of your patients, or if you’re trying to convince an influential person or group it deserves their attention and investment, I suggest you chase down this clinical report from the American Academy of Pediatrics. Representing the AAP’s Council on Sports Medicine and Fitness and Section on Obesity, the authors quite thoroughly make the case that anyone concerned about the health of this nation and its children should make promotion of physical activity a top priority.
I suspect that, like many of the position papers that come from the AAP, this clinical report is another example of preaching to the choir. However, I understand that the academy also hopes to convince a broader audience of nonphysician decision makers by laying out all of the evidence they can muster.
With their voluminous supporting evidence on the table, the authors move on to getting those of us in clinical practice to make our approach to this more systematic – including the addition of a Physical Activity Vital Sign (PAVS) in our patients’ health records. And here is where the authors begin to drift into the hazy dream world of unreality. They admit that “pediatricians will need efficient workflows to incorporate physical activity assessment, counseling and referral in the clinical visit.” Although there is no pediatrician more convinced of the importance of physical activity, I would find it very difficult to include a detailed assessment of my patients’ daily activity in their charts in the manner that the council members envision. Clunky EHRs, limited support staff, and a crowd of advocates already clamoring for my attention on their favorite health issue (nutrition, gun safety, parental depression, dental health to name just a few) all make creating an “efficient workflow” difficult on a good day and impossible on many days.
But, as I have said, I am a strong advocate of physical activity. So here’s a more nuanced suggestion based on a combination of my practical experience and the council’s recommendations.
If you provide good continuity of care to the families in your practice and have been asking good “getting to know you” questions at each visit, you probably already know which of your patients are sufficiently active. You don’t need to ask them how many hours a week they are doing something active. You should be able to just check a box that says “active.”
For patients that you haven’t seen before or suspect are too sedentary from looking at their biometrics and listening to their complaints you need only ask “What do you and your family like to do for fun?” The simple follow-up question of how many hours are spent watching TV, looking at smart phones or tablets, and playing video games in each day completes the survey. You don’t need to chart the depressing details because, as we know, relying on patient or parental recall is unlikely to provide the actual numbers. Just simply check the box that says “not active enough.” What you do with this crude assessment activity is another story and will be the topic for the next Letters from Maine.
This clinical report from the AAP is an excellent and exhaustive discussion of the importance of physical activity, but I hope that it doesn’t spark further cluttering of our already challenged EHR systems. Most of us don’t have the time to be data collectors and quantifiers. Let’s leave that to the clinical researchers. We already know activity is important and that most of our sedentary families aren’t going to be impressed by more science. Our challenge is to get them moving.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at pdnews@mdedge.com.
FDA okays emergency use of convalescent plasma for seriously ill COVID-19 patients
As the proportion of patients infected with COVID-19 continues to rise in the United States, the Food and Drug Administration is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections.
While clinical trials are underway to evaluate the safety and efficacy of administering convalescent plasma to patients with COVID-19, the FDA is granting clinicians permission for use of investigational convalescent plasma under single-patient emergency Investigational New Drug Applications (INDs), since no known cure exists and a vaccine is more than 1 year away from becoming available.
This allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization. This does not include the use of COVID-19 convalescent plasma for the prevention of infection, according to a statement issued by the agency on March 24.
“It is possible that convalescent plasma that contains antibodies to SARS-CoV-2 (the virus that causes COVID-19) might be effective against the infection,” the FDA statement reads. “Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic. Although promising, convalescent plasma has not been shown to be effective in every disease studied.”
“I think the FDA got caught initially a little flat-footed when it came to the development of COVID-19 tests, but they’re quickly catching up,” Peter J. Pitts, who was the FDA’s associate commissioner from 2002 to 2004, said in an interview. “I think that the attitude now is, ‘If it’s safe, let’s create a pathway to see how these things work in the real world.’ I think that’s going to be as true for treatments to lessen the symptoms and shorten the duration of the disease, as well as convalescent plasma as a potential alternative to a yet-to-be-developed vaccine.”
At the University of Washington School of Medicine, Seattle, Terry B. Gernsheimer, MD, and her colleagues are recruiting recovered COVID-19 patients to donate plasma for seriously ill patients affected with the virus. “The thought of using convalescent plasma makes total sense, because it’s immediately available, and it’s something that we can try to give people,” said Dr. Gernsheimer, a hematologist who is professor of medicine at the medical school. “It’s been used in China, and reports should be coming out shortly about their experience with this.”
In a case series that appeared in JAMA on March 27 (doi: 10.1001/jama.2020.4783), Chinese researchers led by Chenguang Shen, PhD, reported findings from five critically ill COVID-19 patients with acute respiratory distress syndrome who received a transfusion with convalescent plasma at Shenzhen Third People’s Hospital 10 and 22 days after hospital admission. The patients ranged in age from 36 to 73 years, three were men, and all were receiving mechanical ventilation at the time of treatment.
Dr. Shen and colleagues reported that viral loads decreased and became negative within 12 days following the transfusion. Three of the patients were discharged from the hospital after a length of stay that ranged from 51 to 55 days, and two remain in stable condition at 37 days after the transfusion. The researchers pointed out that all patients received antiviral agents, including interferon and lopinavir/ritonavir, during and following convalescent plasma treatment, “which also may have contributed to the viral clearance observed.”
Under the FDA policy on emergency IND use, COVID-19 convalescent plasma must only be collected from recovered individuals if they are eligible to donate blood, required testing must be performed, and the donation must be found suitable.
Potential donors “are going to be screened the way all blood donors are screened,” Dr. Gernsheimer said. “It’s not going to be any less safe than any unit of plasma that’s on the shelf that comes from our volunteer donors. There are always transfusion reactions that we have to worry about, [and] there are potentially unknown pathogens that we don’t yet know about that we are not yet testing for. It’s the regular risk we see with any unit of plasma.”
She added that COVID-19 survivors appear to start increasing their titer of the antibody around day 28. “We’ll be looking for recovered individuals who have had a documented infection, and whose symptoms started about 28 days before we collect,” she said.
The FDA advises clinicians to address several considerations for donor eligibility, including prior diagnosis of COVID-19 documented by a laboratory test; complete resolution of symptoms at least 14 days prior to donation; female donors negative for HLA antibodies or male donors, and negative results for COVID-19 either from one or more nasopharyngeal swab specimens or by a molecular diagnostic test from blood. [A partial list of available tests can be accessed on the FDA website.] The agency also advises that donors have defined SARS-CoV-2–neutralizing antibody titers, if testing can be conducted (optimally greater than 1:320).
Patients eligible to receive COVID-19 convalescent plasma must have a severe or immediately life-threatening infection with laboratory-confirmed COVID-19. The agency defines severe disease as dyspnea, respiratory frequency of 30 per minute or greater, blood oxygen saturation of 93% or less, partial pressure of arterial oxygen to fraction of inspired oxygen ratio of less than 300, and/or lung infiltrates of greater than 50% within 24-48 hours. Life-threatening disease is defined as respiratory failure, septic shock, and/or multiple organ dysfunction or failure. Patients must provide informed consent.
The potential risks of receiving COVID-19 convalescent plasma remain unknown, according to Dr. Gernsheimer. “What some people have thought about is, could there be such an inflammatory response with the virus that we would initially see these patients get worse?” she said. “My understanding is that has not occurred in China yet, but we don’t have all those data. But we always worry if we have something that’s going to cause inflammation around an infection, for example, that could initially make it more difficult to breathe if it’s a lung infection. So far, my understanding is that has not been seen.”
For COVID-19 convalescent plasma authorization requests that require a response within 4-8 hours, requesting clinicians may complete form 3296 and submit it by email to CBER_eIND_Covid-19@FDA.HHS.gov.
For COVID-19 convalescent plasma authorization requests that require a response in less than 4 hours, or if the clinician is unable to complete and submit form 3926 because of extenuating circumstances, verbal authorization can be sought by calling the FDA’s Office of Emergency Operations at 1-866-300-4374.
The FDA is working with the National Institutes of Health, the Centers for Disease Control and Prevention, and other government partners to develop protocols for use by multiple investigators in order to coordinate the collection and use of COVID-19 convalescent plasma.
“It’s crucial that data be captured for every patient so that we really understand what safety and effectiveness looks like on as close to a real-world level as we can, as quickly as we can,” said Mr. Pitts, who is president and cofounder of the Center for Medicine in the Public Interest, and who also does consulting work for the FDA. “I understand that health care professionals are overworked and overburdened right now. I applaud them for their heroic work. But that doesn’t mean that we can shirk off collecting the data. When I was at the FDA, I helped address the SARS epidemic. The agency attitude at that point was, ‘Let’s get things that just might work through the process, as long as the cure isn’t going to be worse than the disease.’ I think that’s the attitude that’s leading the charge today.”
As the proportion of patients infected with COVID-19 continues to rise in the United States, the Food and Drug Administration is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections.
While clinical trials are underway to evaluate the safety and efficacy of administering convalescent plasma to patients with COVID-19, the FDA is granting clinicians permission for use of investigational convalescent plasma under single-patient emergency Investigational New Drug Applications (INDs), since no known cure exists and a vaccine is more than 1 year away from becoming available.
This allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization. This does not include the use of COVID-19 convalescent plasma for the prevention of infection, according to a statement issued by the agency on March 24.
“It is possible that convalescent plasma that contains antibodies to SARS-CoV-2 (the virus that causes COVID-19) might be effective against the infection,” the FDA statement reads. “Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic. Although promising, convalescent plasma has not been shown to be effective in every disease studied.”
“I think the FDA got caught initially a little flat-footed when it came to the development of COVID-19 tests, but they’re quickly catching up,” Peter J. Pitts, who was the FDA’s associate commissioner from 2002 to 2004, said in an interview. “I think that the attitude now is, ‘If it’s safe, let’s create a pathway to see how these things work in the real world.’ I think that’s going to be as true for treatments to lessen the symptoms and shorten the duration of the disease, as well as convalescent plasma as a potential alternative to a yet-to-be-developed vaccine.”
At the University of Washington School of Medicine, Seattle, Terry B. Gernsheimer, MD, and her colleagues are recruiting recovered COVID-19 patients to donate plasma for seriously ill patients affected with the virus. “The thought of using convalescent plasma makes total sense, because it’s immediately available, and it’s something that we can try to give people,” said Dr. Gernsheimer, a hematologist who is professor of medicine at the medical school. “It’s been used in China, and reports should be coming out shortly about their experience with this.”
In a case series that appeared in JAMA on March 27 (doi: 10.1001/jama.2020.4783), Chinese researchers led by Chenguang Shen, PhD, reported findings from five critically ill COVID-19 patients with acute respiratory distress syndrome who received a transfusion with convalescent plasma at Shenzhen Third People’s Hospital 10 and 22 days after hospital admission. The patients ranged in age from 36 to 73 years, three were men, and all were receiving mechanical ventilation at the time of treatment.
Dr. Shen and colleagues reported that viral loads decreased and became negative within 12 days following the transfusion. Three of the patients were discharged from the hospital after a length of stay that ranged from 51 to 55 days, and two remain in stable condition at 37 days after the transfusion. The researchers pointed out that all patients received antiviral agents, including interferon and lopinavir/ritonavir, during and following convalescent plasma treatment, “which also may have contributed to the viral clearance observed.”
Under the FDA policy on emergency IND use, COVID-19 convalescent plasma must only be collected from recovered individuals if they are eligible to donate blood, required testing must be performed, and the donation must be found suitable.
Potential donors “are going to be screened the way all blood donors are screened,” Dr. Gernsheimer said. “It’s not going to be any less safe than any unit of plasma that’s on the shelf that comes from our volunteer donors. There are always transfusion reactions that we have to worry about, [and] there are potentially unknown pathogens that we don’t yet know about that we are not yet testing for. It’s the regular risk we see with any unit of plasma.”
She added that COVID-19 survivors appear to start increasing their titer of the antibody around day 28. “We’ll be looking for recovered individuals who have had a documented infection, and whose symptoms started about 28 days before we collect,” she said.
The FDA advises clinicians to address several considerations for donor eligibility, including prior diagnosis of COVID-19 documented by a laboratory test; complete resolution of symptoms at least 14 days prior to donation; female donors negative for HLA antibodies or male donors, and negative results for COVID-19 either from one or more nasopharyngeal swab specimens or by a molecular diagnostic test from blood. [A partial list of available tests can be accessed on the FDA website.] The agency also advises that donors have defined SARS-CoV-2–neutralizing antibody titers, if testing can be conducted (optimally greater than 1:320).
Patients eligible to receive COVID-19 convalescent plasma must have a severe or immediately life-threatening infection with laboratory-confirmed COVID-19. The agency defines severe disease as dyspnea, respiratory frequency of 30 per minute or greater, blood oxygen saturation of 93% or less, partial pressure of arterial oxygen to fraction of inspired oxygen ratio of less than 300, and/or lung infiltrates of greater than 50% within 24-48 hours. Life-threatening disease is defined as respiratory failure, septic shock, and/or multiple organ dysfunction or failure. Patients must provide informed consent.
The potential risks of receiving COVID-19 convalescent plasma remain unknown, according to Dr. Gernsheimer. “What some people have thought about is, could there be such an inflammatory response with the virus that we would initially see these patients get worse?” she said. “My understanding is that has not occurred in China yet, but we don’t have all those data. But we always worry if we have something that’s going to cause inflammation around an infection, for example, that could initially make it more difficult to breathe if it’s a lung infection. So far, my understanding is that has not been seen.”
For COVID-19 convalescent plasma authorization requests that require a response within 4-8 hours, requesting clinicians may complete form 3296 and submit it by email to CBER_eIND_Covid-19@FDA.HHS.gov.
For COVID-19 convalescent plasma authorization requests that require a response in less than 4 hours, or if the clinician is unable to complete and submit form 3926 because of extenuating circumstances, verbal authorization can be sought by calling the FDA’s Office of Emergency Operations at 1-866-300-4374.
The FDA is working with the National Institutes of Health, the Centers for Disease Control and Prevention, and other government partners to develop protocols for use by multiple investigators in order to coordinate the collection and use of COVID-19 convalescent plasma.
“It’s crucial that data be captured for every patient so that we really understand what safety and effectiveness looks like on as close to a real-world level as we can, as quickly as we can,” said Mr. Pitts, who is president and cofounder of the Center for Medicine in the Public Interest, and who also does consulting work for the FDA. “I understand that health care professionals are overworked and overburdened right now. I applaud them for their heroic work. But that doesn’t mean that we can shirk off collecting the data. When I was at the FDA, I helped address the SARS epidemic. The agency attitude at that point was, ‘Let’s get things that just might work through the process, as long as the cure isn’t going to be worse than the disease.’ I think that’s the attitude that’s leading the charge today.”
As the proportion of patients infected with COVID-19 continues to rise in the United States, the Food and Drug Administration is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections.
While clinical trials are underway to evaluate the safety and efficacy of administering convalescent plasma to patients with COVID-19, the FDA is granting clinicians permission for use of investigational convalescent plasma under single-patient emergency Investigational New Drug Applications (INDs), since no known cure exists and a vaccine is more than 1 year away from becoming available.
This allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization. This does not include the use of COVID-19 convalescent plasma for the prevention of infection, according to a statement issued by the agency on March 24.
“It is possible that convalescent plasma that contains antibodies to SARS-CoV-2 (the virus that causes COVID-19) might be effective against the infection,” the FDA statement reads. “Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic. Although promising, convalescent plasma has not been shown to be effective in every disease studied.”
“I think the FDA got caught initially a little flat-footed when it came to the development of COVID-19 tests, but they’re quickly catching up,” Peter J. Pitts, who was the FDA’s associate commissioner from 2002 to 2004, said in an interview. “I think that the attitude now is, ‘If it’s safe, let’s create a pathway to see how these things work in the real world.’ I think that’s going to be as true for treatments to lessen the symptoms and shorten the duration of the disease, as well as convalescent plasma as a potential alternative to a yet-to-be-developed vaccine.”
At the University of Washington School of Medicine, Seattle, Terry B. Gernsheimer, MD, and her colleagues are recruiting recovered COVID-19 patients to donate plasma for seriously ill patients affected with the virus. “The thought of using convalescent plasma makes total sense, because it’s immediately available, and it’s something that we can try to give people,” said Dr. Gernsheimer, a hematologist who is professor of medicine at the medical school. “It’s been used in China, and reports should be coming out shortly about their experience with this.”
In a case series that appeared in JAMA on March 27 (doi: 10.1001/jama.2020.4783), Chinese researchers led by Chenguang Shen, PhD, reported findings from five critically ill COVID-19 patients with acute respiratory distress syndrome who received a transfusion with convalescent plasma at Shenzhen Third People’s Hospital 10 and 22 days after hospital admission. The patients ranged in age from 36 to 73 years, three were men, and all were receiving mechanical ventilation at the time of treatment.
Dr. Shen and colleagues reported that viral loads decreased and became negative within 12 days following the transfusion. Three of the patients were discharged from the hospital after a length of stay that ranged from 51 to 55 days, and two remain in stable condition at 37 days after the transfusion. The researchers pointed out that all patients received antiviral agents, including interferon and lopinavir/ritonavir, during and following convalescent plasma treatment, “which also may have contributed to the viral clearance observed.”
Under the FDA policy on emergency IND use, COVID-19 convalescent plasma must only be collected from recovered individuals if they are eligible to donate blood, required testing must be performed, and the donation must be found suitable.
Potential donors “are going to be screened the way all blood donors are screened,” Dr. Gernsheimer said. “It’s not going to be any less safe than any unit of plasma that’s on the shelf that comes from our volunteer donors. There are always transfusion reactions that we have to worry about, [and] there are potentially unknown pathogens that we don’t yet know about that we are not yet testing for. It’s the regular risk we see with any unit of plasma.”
She added that COVID-19 survivors appear to start increasing their titer of the antibody around day 28. “We’ll be looking for recovered individuals who have had a documented infection, and whose symptoms started about 28 days before we collect,” she said.
The FDA advises clinicians to address several considerations for donor eligibility, including prior diagnosis of COVID-19 documented by a laboratory test; complete resolution of symptoms at least 14 days prior to donation; female donors negative for HLA antibodies or male donors, and negative results for COVID-19 either from one or more nasopharyngeal swab specimens or by a molecular diagnostic test from blood. [A partial list of available tests can be accessed on the FDA website.] The agency also advises that donors have defined SARS-CoV-2–neutralizing antibody titers, if testing can be conducted (optimally greater than 1:320).
Patients eligible to receive COVID-19 convalescent plasma must have a severe or immediately life-threatening infection with laboratory-confirmed COVID-19. The agency defines severe disease as dyspnea, respiratory frequency of 30 per minute or greater, blood oxygen saturation of 93% or less, partial pressure of arterial oxygen to fraction of inspired oxygen ratio of less than 300, and/or lung infiltrates of greater than 50% within 24-48 hours. Life-threatening disease is defined as respiratory failure, septic shock, and/or multiple organ dysfunction or failure. Patients must provide informed consent.
The potential risks of receiving COVID-19 convalescent plasma remain unknown, according to Dr. Gernsheimer. “What some people have thought about is, could there be such an inflammatory response with the virus that we would initially see these patients get worse?” she said. “My understanding is that has not occurred in China yet, but we don’t have all those data. But we always worry if we have something that’s going to cause inflammation around an infection, for example, that could initially make it more difficult to breathe if it’s a lung infection. So far, my understanding is that has not been seen.”
For COVID-19 convalescent plasma authorization requests that require a response within 4-8 hours, requesting clinicians may complete form 3296 and submit it by email to CBER_eIND_Covid-19@FDA.HHS.gov.
For COVID-19 convalescent plasma authorization requests that require a response in less than 4 hours, or if the clinician is unable to complete and submit form 3926 because of extenuating circumstances, verbal authorization can be sought by calling the FDA’s Office of Emergency Operations at 1-866-300-4374.
The FDA is working with the National Institutes of Health, the Centers for Disease Control and Prevention, and other government partners to develop protocols for use by multiple investigators in order to coordinate the collection and use of COVID-19 convalescent plasma.
“It’s crucial that data be captured for every patient so that we really understand what safety and effectiveness looks like on as close to a real-world level as we can, as quickly as we can,” said Mr. Pitts, who is president and cofounder of the Center for Medicine in the Public Interest, and who also does consulting work for the FDA. “I understand that health care professionals are overworked and overburdened right now. I applaud them for their heroic work. But that doesn’t mean that we can shirk off collecting the data. When I was at the FDA, I helped address the SARS epidemic. The agency attitude at that point was, ‘Let’s get things that just might work through the process, as long as the cure isn’t going to be worse than the disease.’ I think that’s the attitude that’s leading the charge today.”
SABR slashes progression of advanced prostate cancer
Patients with oligometastatic disease who received stereotactic ablative radiotherapy (SABR) had a significant threefold decrease in disease progression at 6 months compared with patients who were randomly assigned to observation alone.
“Local control for SABR-treated lesions was excellent, and the adverse effects associated with SABR were mild and did not appear to affect quality of life,” say the investigators, led by Ryan Phillips, MD, PhD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore.
“Although the approach is controversial, many men are interested in avoiding the unpleasant adverse effects and potential health risks of androgen deprivation therapy (ADT) for as long as is reasonable,” they write.
These results come from outcomes of the Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 trial and were published online March 26 in JAMA Oncology.
An intriguing finding from the study was evidence that SABR may evoke an immune response.
“We observed enhanced differential clonotype expansion, clusters of similar expanded T-cell receptors, and a clinical benefit to greater baseline clonality seen only in participants treated with SABR,” said senior author Phuoc T. Tran, MD, PhD, from the department of radiation oncology and molecular radiation sciences at Johns Hopkins.
“This the only data I’m aware of that really shows that radiation in isolation can cause a systemic immune response,” Tran told Medscape Medical News.
Previous studies suggesting an immune response with radiation have been confounded by coadministration of radiation and chemotherapy, he said.
Drive the Disease to ‘Near Extinction’
SABR appears to “alter the natural history of prostate oligometastatic disease by removing or greatly affecting signals that promote further development of micrometastatic disease,” write the authors of accompanying editorial.
This hypothesis is consistent with the oligometastatic paradigm, which postulates that this is a transient phase that offers “a window of opportunity for cancer cure if equilibrium-phase lesions are ablated before polymetastatic escape occurs,” write Carlo Greco, MD, and Zvi Fuks, MD, both from the Champalimaud Centre for the Unknown, Lisbon, Portugal; Fuks is also affiliated with Memorial Sloan Kettering Cancer Center, New York.
“Taken together, these observations support the hypothesis that all detectable oligometastatic lesions should be systematically ablated, if feasible, in an effort to maximize oligometastatic cancer cure,” Greco and Fuks comment.
However, there is no clear consensus on what constitutes oligometastatic disease, they point out, and they warn that “a numerical-based decision to withhold lesion ablation may represent a strategic error, potentially reducing the benefit of metastasis-directed therapy (MDT) in the treatment of oligometastatic cancer.”
“We speculate that, if clinically and technically feasible, there should be no restriction to MDT at first oligometastatic presentation and as sequential lesions appear, regardless of lesion numbers, because each lesion may potentially constitute a generator of evolving metastatogenic clonogens,” they add.
Multiple rounds of MDT theoretically could “drive the disease to near extinction” and prevent the development of polymetastatic disease, they contend.
Study Details
For their study, Phillips and colleagues enrolled 54 men with recurrent hormone-sensitive prostate cancer with one, two, or three metastases detectable on conventional imaging who had not received ADT within 6 months of enrollment, or for a total of 3 or more years.
The patients were randomly assigned in a 2:1 ratio to receive either SABR, with dose and fractionation based on the size and location of each lesion, or to observation. The median age in each group was 68 years.
Prostate-specific membrane antigen (PSMA)-targeted PET-CT, a relatively new technique that is more accurate than conventional imaging, was performed during treatment planning and at day 180 of follow-up for patients assigned to SABR, but the investigators were blinded to the results to prevent bias in target-lesion selection.
The primary endpoint of progression at 6 months was measured by prostate-specific antigen increase, radiographic evidence, symptomatic progression, ADT initiation for any reason, or death.
This primary endpoint occurred in 7 of 36 men (19%) who were treated with SABR, compared with 11 of 18 (61%) who underwent observation (P = .005).
Median progression-free survival (PFS) was not reached in the SABR group vs. 5.8 months in the observation group, translating into a hazard ratio of 0.30 (P = .002).
Of the 36 men treated with SABR, 16 had baseline PET-avid lesions that, because of investigator blinding, were not included in the treatment fields.
Among all SABR-treated patients, the rate of progression at 6 months among men for whom all lesions were treated was 5%, compared with 38% for men with any lesions outside the treatment field (P = .03). The median PFS for patients with no untreated lesions was not reached, vs. 11.8 months for men in whom PET-avid lesions were missed (HR, 0.26; P = .006).
Oligometastatic vs. Polymetastatic
In an interview with Medscape Medical News, Tran noted that using PSMA PET-CT for imaging appears to be very important for identifying those patients with numerous or disseminated (polymetastatic) lesions, compared with those patients with limited disease who are most likely to benefit from SABR. He emphasized, however, that the PSMA PET-CT findings were an exploratory endpoint that required further validation.
Another secondary, exploratory endpoint of the study was the use of a circulating tumor DNA (ctDNA) analysis by the CAPP-Seq (cancer personalized profiling by deep sequencing) method.
“We show, in a discovery fashion, that certain mutations in the circulation seem to distinguish patients who would benefit from SABR vs those who would not,” he said.
The study was supported by the Nesbitt-McMaster Foundation, Ronald Rose and Joan Lazar, the Movember Foundation and Prostate Cancer Foundation, and the National Cancer Institute. Phillips reported receiving consulting fees and honoraria from RefleXion Medical outside the submitted work. Tran holds a licensed patent related to ablative radiotherapy compounds and methods (Natsar Pharmaceuticals). Several other authors reported financial disclosures. The full list can be found with the original article. Editorialists Greco and Fuks reported serving as cofounders of and owning stock in Ceramedix Holding, LLC.
This article first appeared on Medscape.com.
Patients with oligometastatic disease who received stereotactic ablative radiotherapy (SABR) had a significant threefold decrease in disease progression at 6 months compared with patients who were randomly assigned to observation alone.
“Local control for SABR-treated lesions was excellent, and the adverse effects associated with SABR were mild and did not appear to affect quality of life,” say the investigators, led by Ryan Phillips, MD, PhD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore.
“Although the approach is controversial, many men are interested in avoiding the unpleasant adverse effects and potential health risks of androgen deprivation therapy (ADT) for as long as is reasonable,” they write.
These results come from outcomes of the Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 trial and were published online March 26 in JAMA Oncology.
An intriguing finding from the study was evidence that SABR may evoke an immune response.
“We observed enhanced differential clonotype expansion, clusters of similar expanded T-cell receptors, and a clinical benefit to greater baseline clonality seen only in participants treated with SABR,” said senior author Phuoc T. Tran, MD, PhD, from the department of radiation oncology and molecular radiation sciences at Johns Hopkins.
“This the only data I’m aware of that really shows that radiation in isolation can cause a systemic immune response,” Tran told Medscape Medical News.
Previous studies suggesting an immune response with radiation have been confounded by coadministration of radiation and chemotherapy, he said.
Drive the Disease to ‘Near Extinction’
SABR appears to “alter the natural history of prostate oligometastatic disease by removing or greatly affecting signals that promote further development of micrometastatic disease,” write the authors of accompanying editorial.
This hypothesis is consistent with the oligometastatic paradigm, which postulates that this is a transient phase that offers “a window of opportunity for cancer cure if equilibrium-phase lesions are ablated before polymetastatic escape occurs,” write Carlo Greco, MD, and Zvi Fuks, MD, both from the Champalimaud Centre for the Unknown, Lisbon, Portugal; Fuks is also affiliated with Memorial Sloan Kettering Cancer Center, New York.
“Taken together, these observations support the hypothesis that all detectable oligometastatic lesions should be systematically ablated, if feasible, in an effort to maximize oligometastatic cancer cure,” Greco and Fuks comment.
However, there is no clear consensus on what constitutes oligometastatic disease, they point out, and they warn that “a numerical-based decision to withhold lesion ablation may represent a strategic error, potentially reducing the benefit of metastasis-directed therapy (MDT) in the treatment of oligometastatic cancer.”
“We speculate that, if clinically and technically feasible, there should be no restriction to MDT at first oligometastatic presentation and as sequential lesions appear, regardless of lesion numbers, because each lesion may potentially constitute a generator of evolving metastatogenic clonogens,” they add.
Multiple rounds of MDT theoretically could “drive the disease to near extinction” and prevent the development of polymetastatic disease, they contend.
Study Details
For their study, Phillips and colleagues enrolled 54 men with recurrent hormone-sensitive prostate cancer with one, two, or three metastases detectable on conventional imaging who had not received ADT within 6 months of enrollment, or for a total of 3 or more years.
The patients were randomly assigned in a 2:1 ratio to receive either SABR, with dose and fractionation based on the size and location of each lesion, or to observation. The median age in each group was 68 years.
Prostate-specific membrane antigen (PSMA)-targeted PET-CT, a relatively new technique that is more accurate than conventional imaging, was performed during treatment planning and at day 180 of follow-up for patients assigned to SABR, but the investigators were blinded to the results to prevent bias in target-lesion selection.
The primary endpoint of progression at 6 months was measured by prostate-specific antigen increase, radiographic evidence, symptomatic progression, ADT initiation for any reason, or death.
This primary endpoint occurred in 7 of 36 men (19%) who were treated with SABR, compared with 11 of 18 (61%) who underwent observation (P = .005).
Median progression-free survival (PFS) was not reached in the SABR group vs. 5.8 months in the observation group, translating into a hazard ratio of 0.30 (P = .002).
Of the 36 men treated with SABR, 16 had baseline PET-avid lesions that, because of investigator blinding, were not included in the treatment fields.
Among all SABR-treated patients, the rate of progression at 6 months among men for whom all lesions were treated was 5%, compared with 38% for men with any lesions outside the treatment field (P = .03). The median PFS for patients with no untreated lesions was not reached, vs. 11.8 months for men in whom PET-avid lesions were missed (HR, 0.26; P = .006).
Oligometastatic vs. Polymetastatic
In an interview with Medscape Medical News, Tran noted that using PSMA PET-CT for imaging appears to be very important for identifying those patients with numerous or disseminated (polymetastatic) lesions, compared with those patients with limited disease who are most likely to benefit from SABR. He emphasized, however, that the PSMA PET-CT findings were an exploratory endpoint that required further validation.
Another secondary, exploratory endpoint of the study was the use of a circulating tumor DNA (ctDNA) analysis by the CAPP-Seq (cancer personalized profiling by deep sequencing) method.
“We show, in a discovery fashion, that certain mutations in the circulation seem to distinguish patients who would benefit from SABR vs those who would not,” he said.
The study was supported by the Nesbitt-McMaster Foundation, Ronald Rose and Joan Lazar, the Movember Foundation and Prostate Cancer Foundation, and the National Cancer Institute. Phillips reported receiving consulting fees and honoraria from RefleXion Medical outside the submitted work. Tran holds a licensed patent related to ablative radiotherapy compounds and methods (Natsar Pharmaceuticals). Several other authors reported financial disclosures. The full list can be found with the original article. Editorialists Greco and Fuks reported serving as cofounders of and owning stock in Ceramedix Holding, LLC.
This article first appeared on Medscape.com.
Patients with oligometastatic disease who received stereotactic ablative radiotherapy (SABR) had a significant threefold decrease in disease progression at 6 months compared with patients who were randomly assigned to observation alone.
“Local control for SABR-treated lesions was excellent, and the adverse effects associated with SABR were mild and did not appear to affect quality of life,” say the investigators, led by Ryan Phillips, MD, PhD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore.
“Although the approach is controversial, many men are interested in avoiding the unpleasant adverse effects and potential health risks of androgen deprivation therapy (ADT) for as long as is reasonable,” they write.
These results come from outcomes of the Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 trial and were published online March 26 in JAMA Oncology.
An intriguing finding from the study was evidence that SABR may evoke an immune response.
“We observed enhanced differential clonotype expansion, clusters of similar expanded T-cell receptors, and a clinical benefit to greater baseline clonality seen only in participants treated with SABR,” said senior author Phuoc T. Tran, MD, PhD, from the department of radiation oncology and molecular radiation sciences at Johns Hopkins.
“This the only data I’m aware of that really shows that radiation in isolation can cause a systemic immune response,” Tran told Medscape Medical News.
Previous studies suggesting an immune response with radiation have been confounded by coadministration of radiation and chemotherapy, he said.
Drive the Disease to ‘Near Extinction’
SABR appears to “alter the natural history of prostate oligometastatic disease by removing or greatly affecting signals that promote further development of micrometastatic disease,” write the authors of accompanying editorial.
This hypothesis is consistent with the oligometastatic paradigm, which postulates that this is a transient phase that offers “a window of opportunity for cancer cure if equilibrium-phase lesions are ablated before polymetastatic escape occurs,” write Carlo Greco, MD, and Zvi Fuks, MD, both from the Champalimaud Centre for the Unknown, Lisbon, Portugal; Fuks is also affiliated with Memorial Sloan Kettering Cancer Center, New York.
“Taken together, these observations support the hypothesis that all detectable oligometastatic lesions should be systematically ablated, if feasible, in an effort to maximize oligometastatic cancer cure,” Greco and Fuks comment.
However, there is no clear consensus on what constitutes oligometastatic disease, they point out, and they warn that “a numerical-based decision to withhold lesion ablation may represent a strategic error, potentially reducing the benefit of metastasis-directed therapy (MDT) in the treatment of oligometastatic cancer.”
“We speculate that, if clinically and technically feasible, there should be no restriction to MDT at first oligometastatic presentation and as sequential lesions appear, regardless of lesion numbers, because each lesion may potentially constitute a generator of evolving metastatogenic clonogens,” they add.
Multiple rounds of MDT theoretically could “drive the disease to near extinction” and prevent the development of polymetastatic disease, they contend.
Study Details
For their study, Phillips and colleagues enrolled 54 men with recurrent hormone-sensitive prostate cancer with one, two, or three metastases detectable on conventional imaging who had not received ADT within 6 months of enrollment, or for a total of 3 or more years.
The patients were randomly assigned in a 2:1 ratio to receive either SABR, with dose and fractionation based on the size and location of each lesion, or to observation. The median age in each group was 68 years.
Prostate-specific membrane antigen (PSMA)-targeted PET-CT, a relatively new technique that is more accurate than conventional imaging, was performed during treatment planning and at day 180 of follow-up for patients assigned to SABR, but the investigators were blinded to the results to prevent bias in target-lesion selection.
The primary endpoint of progression at 6 months was measured by prostate-specific antigen increase, radiographic evidence, symptomatic progression, ADT initiation for any reason, or death.
This primary endpoint occurred in 7 of 36 men (19%) who were treated with SABR, compared with 11 of 18 (61%) who underwent observation (P = .005).
Median progression-free survival (PFS) was not reached in the SABR group vs. 5.8 months in the observation group, translating into a hazard ratio of 0.30 (P = .002).
Of the 36 men treated with SABR, 16 had baseline PET-avid lesions that, because of investigator blinding, were not included in the treatment fields.
Among all SABR-treated patients, the rate of progression at 6 months among men for whom all lesions were treated was 5%, compared with 38% for men with any lesions outside the treatment field (P = .03). The median PFS for patients with no untreated lesions was not reached, vs. 11.8 months for men in whom PET-avid lesions were missed (HR, 0.26; P = .006).
Oligometastatic vs. Polymetastatic
In an interview with Medscape Medical News, Tran noted that using PSMA PET-CT for imaging appears to be very important for identifying those patients with numerous or disseminated (polymetastatic) lesions, compared with those patients with limited disease who are most likely to benefit from SABR. He emphasized, however, that the PSMA PET-CT findings were an exploratory endpoint that required further validation.
Another secondary, exploratory endpoint of the study was the use of a circulating tumor DNA (ctDNA) analysis by the CAPP-Seq (cancer personalized profiling by deep sequencing) method.
“We show, in a discovery fashion, that certain mutations in the circulation seem to distinguish patients who would benefit from SABR vs those who would not,” he said.
The study was supported by the Nesbitt-McMaster Foundation, Ronald Rose and Joan Lazar, the Movember Foundation and Prostate Cancer Foundation, and the National Cancer Institute. Phillips reported receiving consulting fees and honoraria from RefleXion Medical outside the submitted work. Tran holds a licensed patent related to ablative radiotherapy compounds and methods (Natsar Pharmaceuticals). Several other authors reported financial disclosures. The full list can be found with the original article. Editorialists Greco and Fuks reported serving as cofounders of and owning stock in Ceramedix Holding, LLC.
This article first appeared on Medscape.com.
‘Impressive’ SOLO3 results should influence practice
In this edition of “Applying research to practice,” I highlight a study suggesting olaparib is helpful in patients BRCA mutations experiencing multiple relapses of ovarian cancer.
SOLO3 was the first phase 3 trial comparing the oral PARP inhibitor olaparib (OLA; 300 mg twice daily) with physician’s choice of intravenous single-agent chemotherapy (TPC) in relapsed high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer (J Clin Oncol. 2020 Feb 19. doi: 10.1200/JCO.19.02745).
The trial involved 266 BRCA-mutated patients who had received two (approximately 50%) or more lines of platinum-based TPC. All patients were required to be completely platinum sensitive (progression beyond 12 months from last platinum exposure) or partially platinum sensitive (progression within 6-12 months).
Women were randomized to receive either OLA or nonplatinum TPC (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). After an amendment to the study in 2017, the primary endpoint was objective response rate, determined by blinded independent central review, with a variety of secondary endpoints.
Among 223 patients with measurable disease, the objective response rate was 72.2% with OLA and 51.4% with TPC (odds ratio, 2.53; P = .002). Across all patients, the median progression-free survival was significantly better with OLA (13.4 months) than with TPC (9.2 months; P = .013). Overall survival data were immature.
The superiority of OLA for the primary endpoint was maintained in multiple subgroups of patients, including those who had received only two prior lines of therapy (OR, 3.44) and those who had three or more prior lines (OR, 2.21). Time to first subsequent therapy (HR, 0.48) and time to treatment discontinuation or death (HR, 0.17) were significantly longer for OLA than for TPC.
Adverse events were consistent with the established safety profiles of OLA and chemotherapy. The most common grade 3 or higher adverse events were anemia (21.3%) with OLA and neutropenia (15.8%) and hand-foot syndrome (11.8%) with TPC.
However, median treatment durations were substantially and consistently longer for OLA than for TPC, and there were fewer treatment discontinuations because of toxicity for OLA than for TPC. At the time of data cutoff, 43 patients in the OLA group and 1 patient in the TPC cohort remained on treatment.
How these results influence practice
The results of the SOLO3 trial are clear: Treatment with OLA is a reasonable alternative to nonplatinum-containing chemotherapy for women with BRCA mutations and platinum-sensitive ovarian cancer. OLA is a “chemotherapy-free” option for these patients in the second- and later-line settings.
Less clear are the following:
- How many patients with BRCA mutations will not have already received a PARP inhibitor in the frontline maintenance setting in the future? SOLO3 required modification in the accrual target and endpoint because of challenges in patient recruitment from the entry of PARP inhibitors into routine clinical practice.
- Would OLA be superior to a carboplatin doublet rather than a nonplatinum single agent in patients with two prior relapses of platinum-sensitive ovarian cancer? Standard practice would be for patients in the second-line setting to receive a platinum doublet.
- Is extending the platinum-free interval a worthwhile objective, or would some patients prefer a finite interval of a platinum doublet over an indefinite period of treatment with OLA?
All phase 3 clinical trials have limitations since they require years to complete and the applicability of the results are challenged by intercurrent advances in treatment options and diagnostic tests.
However, overall, the results of SOLO3 are impressive and should influence clinical practice for the subset of relapsed ovarian cancer patients who would have qualified to participate in it. OLA represents an important treatment advance for a group of patients who are trying to string together remission after remission, with limited negative impact on quality of life.
Dr. Lyss was an oncologist and researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
In this edition of “Applying research to practice,” I highlight a study suggesting olaparib is helpful in patients BRCA mutations experiencing multiple relapses of ovarian cancer.
SOLO3 was the first phase 3 trial comparing the oral PARP inhibitor olaparib (OLA; 300 mg twice daily) with physician’s choice of intravenous single-agent chemotherapy (TPC) in relapsed high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer (J Clin Oncol. 2020 Feb 19. doi: 10.1200/JCO.19.02745).
The trial involved 266 BRCA-mutated patients who had received two (approximately 50%) or more lines of platinum-based TPC. All patients were required to be completely platinum sensitive (progression beyond 12 months from last platinum exposure) or partially platinum sensitive (progression within 6-12 months).
Women were randomized to receive either OLA or nonplatinum TPC (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). After an amendment to the study in 2017, the primary endpoint was objective response rate, determined by blinded independent central review, with a variety of secondary endpoints.
Among 223 patients with measurable disease, the objective response rate was 72.2% with OLA and 51.4% with TPC (odds ratio, 2.53; P = .002). Across all patients, the median progression-free survival was significantly better with OLA (13.4 months) than with TPC (9.2 months; P = .013). Overall survival data were immature.
The superiority of OLA for the primary endpoint was maintained in multiple subgroups of patients, including those who had received only two prior lines of therapy (OR, 3.44) and those who had three or more prior lines (OR, 2.21). Time to first subsequent therapy (HR, 0.48) and time to treatment discontinuation or death (HR, 0.17) were significantly longer for OLA than for TPC.
Adverse events were consistent with the established safety profiles of OLA and chemotherapy. The most common grade 3 or higher adverse events were anemia (21.3%) with OLA and neutropenia (15.8%) and hand-foot syndrome (11.8%) with TPC.
However, median treatment durations were substantially and consistently longer for OLA than for TPC, and there were fewer treatment discontinuations because of toxicity for OLA than for TPC. At the time of data cutoff, 43 patients in the OLA group and 1 patient in the TPC cohort remained on treatment.
How these results influence practice
The results of the SOLO3 trial are clear: Treatment with OLA is a reasonable alternative to nonplatinum-containing chemotherapy for women with BRCA mutations and platinum-sensitive ovarian cancer. OLA is a “chemotherapy-free” option for these patients in the second- and later-line settings.
Less clear are the following:
- How many patients with BRCA mutations will not have already received a PARP inhibitor in the frontline maintenance setting in the future? SOLO3 required modification in the accrual target and endpoint because of challenges in patient recruitment from the entry of PARP inhibitors into routine clinical practice.
- Would OLA be superior to a carboplatin doublet rather than a nonplatinum single agent in patients with two prior relapses of platinum-sensitive ovarian cancer? Standard practice would be for patients in the second-line setting to receive a platinum doublet.
- Is extending the platinum-free interval a worthwhile objective, or would some patients prefer a finite interval of a platinum doublet over an indefinite period of treatment with OLA?
All phase 3 clinical trials have limitations since they require years to complete and the applicability of the results are challenged by intercurrent advances in treatment options and diagnostic tests.
However, overall, the results of SOLO3 are impressive and should influence clinical practice for the subset of relapsed ovarian cancer patients who would have qualified to participate in it. OLA represents an important treatment advance for a group of patients who are trying to string together remission after remission, with limited negative impact on quality of life.
Dr. Lyss was an oncologist and researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
In this edition of “Applying research to practice,” I highlight a study suggesting olaparib is helpful in patients BRCA mutations experiencing multiple relapses of ovarian cancer.
SOLO3 was the first phase 3 trial comparing the oral PARP inhibitor olaparib (OLA; 300 mg twice daily) with physician’s choice of intravenous single-agent chemotherapy (TPC) in relapsed high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer (J Clin Oncol. 2020 Feb 19. doi: 10.1200/JCO.19.02745).
The trial involved 266 BRCA-mutated patients who had received two (approximately 50%) or more lines of platinum-based TPC. All patients were required to be completely platinum sensitive (progression beyond 12 months from last platinum exposure) or partially platinum sensitive (progression within 6-12 months).
Women were randomized to receive either OLA or nonplatinum TPC (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). After an amendment to the study in 2017, the primary endpoint was objective response rate, determined by blinded independent central review, with a variety of secondary endpoints.
Among 223 patients with measurable disease, the objective response rate was 72.2% with OLA and 51.4% with TPC (odds ratio, 2.53; P = .002). Across all patients, the median progression-free survival was significantly better with OLA (13.4 months) than with TPC (9.2 months; P = .013). Overall survival data were immature.
The superiority of OLA for the primary endpoint was maintained in multiple subgroups of patients, including those who had received only two prior lines of therapy (OR, 3.44) and those who had three or more prior lines (OR, 2.21). Time to first subsequent therapy (HR, 0.48) and time to treatment discontinuation or death (HR, 0.17) were significantly longer for OLA than for TPC.
Adverse events were consistent with the established safety profiles of OLA and chemotherapy. The most common grade 3 or higher adverse events were anemia (21.3%) with OLA and neutropenia (15.8%) and hand-foot syndrome (11.8%) with TPC.
However, median treatment durations were substantially and consistently longer for OLA than for TPC, and there were fewer treatment discontinuations because of toxicity for OLA than for TPC. At the time of data cutoff, 43 patients in the OLA group and 1 patient in the TPC cohort remained on treatment.
How these results influence practice
The results of the SOLO3 trial are clear: Treatment with OLA is a reasonable alternative to nonplatinum-containing chemotherapy for women with BRCA mutations and platinum-sensitive ovarian cancer. OLA is a “chemotherapy-free” option for these patients in the second- and later-line settings.
Less clear are the following:
- How many patients with BRCA mutations will not have already received a PARP inhibitor in the frontline maintenance setting in the future? SOLO3 required modification in the accrual target and endpoint because of challenges in patient recruitment from the entry of PARP inhibitors into routine clinical practice.
- Would OLA be superior to a carboplatin doublet rather than a nonplatinum single agent in patients with two prior relapses of platinum-sensitive ovarian cancer? Standard practice would be for patients in the second-line setting to receive a platinum doublet.
- Is extending the platinum-free interval a worthwhile objective, or would some patients prefer a finite interval of a platinum doublet over an indefinite period of treatment with OLA?
All phase 3 clinical trials have limitations since they require years to complete and the applicability of the results are challenged by intercurrent advances in treatment options and diagnostic tests.
However, overall, the results of SOLO3 are impressive and should influence clinical practice for the subset of relapsed ovarian cancer patients who would have qualified to participate in it. OLA represents an important treatment advance for a group of patients who are trying to string together remission after remission, with limited negative impact on quality of life.
Dr. Lyss was an oncologist and researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Wilkie and the VA vs COVID-19: Who’s Winning?
US Department of Veterans Affairs (VA) Secretary Robert Wilkie is finding out what it means to be on wartime footing against a virus. He is overseeing the VA’s internal response to COVID-19 while deciding how to fulfil the VA’s fourth mission: providing reinforcement for the nation’s healthcare system in a national emergency. Meanwhile, he’s facing hostilities on a third front: criticism of his efforts so far.
In late February, when lawmakers asked whether the VA needed more resources to fight COVID-19, Wilkie said no. He told NPR on March 19 that “we are poised for the onslaught.” But on March 13, 2020, the VA was being attacked for not releasing a comprehensive emergency response to the incipient pandemic. Wilkie countered, “Before there was a single confirmed case in the US,” he wrote in a recent op-ed piece for Military Times, “the VA was already conducting emergency preparedness exercises.”
In the NPR interview, Wilkie said the VA had undertaken “a very aggressive public health response at an early stage.” Now, the VA has added other measures. The VA, he said, was the first health system to stop people from entering its facilities without being questioned or tested, and the first to adopt the “hard decision” of a no-visitor rule for veterans in nursing homes. Every veteran who comes to a VA facility with flu-like symptoms is screened. Further, via tweets and blog posts, Wilkie is “inviting” retired medical personnel back to work to help deal with the pandemic.
The VA is also the “buttress force,” Wilkie says, for the Federal Emergency Management Agency and the US Department of Health and Human Services if they need medical professionals for crises. “We plan for that every day,” he says. “We are gaming out emergency preparedness scenarios and we stand ready when the President needs us to expand our mission.” But in The American Prospect, Suzanne Gordon and Jasper Craven, both fellows at the Veterans Healthcare Policy Institute, write that “one quiet action is ominous”—the VA website has deleted any mention of the department’s credo of caring for civilians in times of crisis.
According to Gordon and Craven, on Wednesday Wilkie “came out of the woodwork” to express the department’s readiness to help in the crisis. The VA has established 19 emergency operations centers across the country, Wilkie says, and has stopped elective surgeries to free up thousands of beds. He touts the agency’s flexibility, saying it’s prepared to move resources around the country as needed. “Some veterans hospitals have not been impacted [by the virus],” Wilkie said. “So, I’m not going to keep 500 respirators in the middle of a state that has one veteran with the infection, when I can use that in Seattle or New Orleans, or New York City.”
Wilkie says the VA has stockpiled equipment and its supply chain is stable. However, in the NPR interview, Mary Louise Kelly said the NPR VA correspondent had been hearing complaints about lack of gear, such as masks. When pressed on his claim that the VA had adequate protective supplies, Wilkie said those complaints “have not reached us.” In fact, he said, “I can tell you that the arrangements that we have made on both the masks side and also on the testing side—we’re in a very good place.”
Nonetheless, on March 16, the employee unions representing nearly 350,000 VA healthcare workers issued a joint statement that called on VHA management to “work with us to ensure the nation’s VA health facilities can safely handle COVID-19.” It’s time, said Everett Kelley, National President of the American Federation of Government Employees, “for the VA to invite our members to the table, instead of kicking them off the property, so we can finally work together on a solution….”
“Instead of relaxing standards and efforts,” the unions said, “like we have seen the CDC do [in allowing healthcare workers to reuse facemasks and rely on simple surgical facemasks], “we need to be stepping it up.”
It all takes money. After weeks of debate, the US Senate has just released details of the $2 trillion coronavirus aid package. The US Department of Defense (DoD) seems about to get $10.5 billion in emergency funding and the VA another $19.6 billion. The money includes funding for National Guard deployments to help state governments respond to emerging health needs, the expansion of military hospitals and mobile medical centers if needed, and help with production of medical supplies. Nearly $16 billion will be used for direct care specifically in response to veterans’ health needs, covering treatment for COVID-19 in VA hospitals, community urgent care clinics and emergency departments; overtime for clinical staff; and purchase of protective equipment, tests, and other supplies.
Despite having one of the best telehealth systems in the US, the VA has also come under fire for its telehealth preparations to meet the current pandemic-related demand. Former VA Under Secretary of Health Kenneth Kizer wrote in an op-ed for Military Times, “Regrettably, so far, there is no coordinated strategy for ramping up and optimizing the use of telehealth to combat the growing epidemic in the US.” The relief package proposes $3 billion for new telemedicine efforts, including staffing and equipping mobile treatment sites.
In mid-March, the VA had 3,000 coronavirus test kits but still had not used roughly 90%, an article in Mother Jones charged. At a White house press conference around that time, Wilkie was asked how many veterans of those who needed to be tested had been. “We believe we’ve caught most of them,” he replied.
But that was in the early days of the crisis.
With results from the 322 tests administered by Mar. 18, the VA had confirmed five positive cases, was tracking 33 presumptive cases, and acknowledged the first veteran death linked to COVID-19. As of Mar. 26, the VA had administered roughly 7,500 COVID-19 tests nationwide.
Secretary Wilkie has promised that the department’s first focus will always be caring for veterans. In an interview with Military Times, he said, “We don’t release any beds if veterans are needing them. The veterans still are primary. We are a [health] bridge for the larger community, but that’s only after veterans are taken care of.”
US Department of Veterans Affairs (VA) Secretary Robert Wilkie is finding out what it means to be on wartime footing against a virus. He is overseeing the VA’s internal response to COVID-19 while deciding how to fulfil the VA’s fourth mission: providing reinforcement for the nation’s healthcare system in a national emergency. Meanwhile, he’s facing hostilities on a third front: criticism of his efforts so far.
In late February, when lawmakers asked whether the VA needed more resources to fight COVID-19, Wilkie said no. He told NPR on March 19 that “we are poised for the onslaught.” But on March 13, 2020, the VA was being attacked for not releasing a comprehensive emergency response to the incipient pandemic. Wilkie countered, “Before there was a single confirmed case in the US,” he wrote in a recent op-ed piece for Military Times, “the VA was already conducting emergency preparedness exercises.”
In the NPR interview, Wilkie said the VA had undertaken “a very aggressive public health response at an early stage.” Now, the VA has added other measures. The VA, he said, was the first health system to stop people from entering its facilities without being questioned or tested, and the first to adopt the “hard decision” of a no-visitor rule for veterans in nursing homes. Every veteran who comes to a VA facility with flu-like symptoms is screened. Further, via tweets and blog posts, Wilkie is “inviting” retired medical personnel back to work to help deal with the pandemic.
The VA is also the “buttress force,” Wilkie says, for the Federal Emergency Management Agency and the US Department of Health and Human Services if they need medical professionals for crises. “We plan for that every day,” he says. “We are gaming out emergency preparedness scenarios and we stand ready when the President needs us to expand our mission.” But in The American Prospect, Suzanne Gordon and Jasper Craven, both fellows at the Veterans Healthcare Policy Institute, write that “one quiet action is ominous”—the VA website has deleted any mention of the department’s credo of caring for civilians in times of crisis.
According to Gordon and Craven, on Wednesday Wilkie “came out of the woodwork” to express the department’s readiness to help in the crisis. The VA has established 19 emergency operations centers across the country, Wilkie says, and has stopped elective surgeries to free up thousands of beds. He touts the agency’s flexibility, saying it’s prepared to move resources around the country as needed. “Some veterans hospitals have not been impacted [by the virus],” Wilkie said. “So, I’m not going to keep 500 respirators in the middle of a state that has one veteran with the infection, when I can use that in Seattle or New Orleans, or New York City.”
Wilkie says the VA has stockpiled equipment and its supply chain is stable. However, in the NPR interview, Mary Louise Kelly said the NPR VA correspondent had been hearing complaints about lack of gear, such as masks. When pressed on his claim that the VA had adequate protective supplies, Wilkie said those complaints “have not reached us.” In fact, he said, “I can tell you that the arrangements that we have made on both the masks side and also on the testing side—we’re in a very good place.”
Nonetheless, on March 16, the employee unions representing nearly 350,000 VA healthcare workers issued a joint statement that called on VHA management to “work with us to ensure the nation’s VA health facilities can safely handle COVID-19.” It’s time, said Everett Kelley, National President of the American Federation of Government Employees, “for the VA to invite our members to the table, instead of kicking them off the property, so we can finally work together on a solution….”
“Instead of relaxing standards and efforts,” the unions said, “like we have seen the CDC do [in allowing healthcare workers to reuse facemasks and rely on simple surgical facemasks], “we need to be stepping it up.”
It all takes money. After weeks of debate, the US Senate has just released details of the $2 trillion coronavirus aid package. The US Department of Defense (DoD) seems about to get $10.5 billion in emergency funding and the VA another $19.6 billion. The money includes funding for National Guard deployments to help state governments respond to emerging health needs, the expansion of military hospitals and mobile medical centers if needed, and help with production of medical supplies. Nearly $16 billion will be used for direct care specifically in response to veterans’ health needs, covering treatment for COVID-19 in VA hospitals, community urgent care clinics and emergency departments; overtime for clinical staff; and purchase of protective equipment, tests, and other supplies.
Despite having one of the best telehealth systems in the US, the VA has also come under fire for its telehealth preparations to meet the current pandemic-related demand. Former VA Under Secretary of Health Kenneth Kizer wrote in an op-ed for Military Times, “Regrettably, so far, there is no coordinated strategy for ramping up and optimizing the use of telehealth to combat the growing epidemic in the US.” The relief package proposes $3 billion for new telemedicine efforts, including staffing and equipping mobile treatment sites.
In mid-March, the VA had 3,000 coronavirus test kits but still had not used roughly 90%, an article in Mother Jones charged. At a White house press conference around that time, Wilkie was asked how many veterans of those who needed to be tested had been. “We believe we’ve caught most of them,” he replied.
But that was in the early days of the crisis.
With results from the 322 tests administered by Mar. 18, the VA had confirmed five positive cases, was tracking 33 presumptive cases, and acknowledged the first veteran death linked to COVID-19. As of Mar. 26, the VA had administered roughly 7,500 COVID-19 tests nationwide.
Secretary Wilkie has promised that the department’s first focus will always be caring for veterans. In an interview with Military Times, he said, “We don’t release any beds if veterans are needing them. The veterans still are primary. We are a [health] bridge for the larger community, but that’s only after veterans are taken care of.”
US Department of Veterans Affairs (VA) Secretary Robert Wilkie is finding out what it means to be on wartime footing against a virus. He is overseeing the VA’s internal response to COVID-19 while deciding how to fulfil the VA’s fourth mission: providing reinforcement for the nation’s healthcare system in a national emergency. Meanwhile, he’s facing hostilities on a third front: criticism of his efforts so far.
In late February, when lawmakers asked whether the VA needed more resources to fight COVID-19, Wilkie said no. He told NPR on March 19 that “we are poised for the onslaught.” But on March 13, 2020, the VA was being attacked for not releasing a comprehensive emergency response to the incipient pandemic. Wilkie countered, “Before there was a single confirmed case in the US,” he wrote in a recent op-ed piece for Military Times, “the VA was already conducting emergency preparedness exercises.”
In the NPR interview, Wilkie said the VA had undertaken “a very aggressive public health response at an early stage.” Now, the VA has added other measures. The VA, he said, was the first health system to stop people from entering its facilities without being questioned or tested, and the first to adopt the “hard decision” of a no-visitor rule for veterans in nursing homes. Every veteran who comes to a VA facility with flu-like symptoms is screened. Further, via tweets and blog posts, Wilkie is “inviting” retired medical personnel back to work to help deal with the pandemic.
The VA is also the “buttress force,” Wilkie says, for the Federal Emergency Management Agency and the US Department of Health and Human Services if they need medical professionals for crises. “We plan for that every day,” he says. “We are gaming out emergency preparedness scenarios and we stand ready when the President needs us to expand our mission.” But in The American Prospect, Suzanne Gordon and Jasper Craven, both fellows at the Veterans Healthcare Policy Institute, write that “one quiet action is ominous”—the VA website has deleted any mention of the department’s credo of caring for civilians in times of crisis.
According to Gordon and Craven, on Wednesday Wilkie “came out of the woodwork” to express the department’s readiness to help in the crisis. The VA has established 19 emergency operations centers across the country, Wilkie says, and has stopped elective surgeries to free up thousands of beds. He touts the agency’s flexibility, saying it’s prepared to move resources around the country as needed. “Some veterans hospitals have not been impacted [by the virus],” Wilkie said. “So, I’m not going to keep 500 respirators in the middle of a state that has one veteran with the infection, when I can use that in Seattle or New Orleans, or New York City.”
Wilkie says the VA has stockpiled equipment and its supply chain is stable. However, in the NPR interview, Mary Louise Kelly said the NPR VA correspondent had been hearing complaints about lack of gear, such as masks. When pressed on his claim that the VA had adequate protective supplies, Wilkie said those complaints “have not reached us.” In fact, he said, “I can tell you that the arrangements that we have made on both the masks side and also on the testing side—we’re in a very good place.”
Nonetheless, on March 16, the employee unions representing nearly 350,000 VA healthcare workers issued a joint statement that called on VHA management to “work with us to ensure the nation’s VA health facilities can safely handle COVID-19.” It’s time, said Everett Kelley, National President of the American Federation of Government Employees, “for the VA to invite our members to the table, instead of kicking them off the property, so we can finally work together on a solution….”
“Instead of relaxing standards and efforts,” the unions said, “like we have seen the CDC do [in allowing healthcare workers to reuse facemasks and rely on simple surgical facemasks], “we need to be stepping it up.”
It all takes money. After weeks of debate, the US Senate has just released details of the $2 trillion coronavirus aid package. The US Department of Defense (DoD) seems about to get $10.5 billion in emergency funding and the VA another $19.6 billion. The money includes funding for National Guard deployments to help state governments respond to emerging health needs, the expansion of military hospitals and mobile medical centers if needed, and help with production of medical supplies. Nearly $16 billion will be used for direct care specifically in response to veterans’ health needs, covering treatment for COVID-19 in VA hospitals, community urgent care clinics and emergency departments; overtime for clinical staff; and purchase of protective equipment, tests, and other supplies.
Despite having one of the best telehealth systems in the US, the VA has also come under fire for its telehealth preparations to meet the current pandemic-related demand. Former VA Under Secretary of Health Kenneth Kizer wrote in an op-ed for Military Times, “Regrettably, so far, there is no coordinated strategy for ramping up and optimizing the use of telehealth to combat the growing epidemic in the US.” The relief package proposes $3 billion for new telemedicine efforts, including staffing and equipping mobile treatment sites.
In mid-March, the VA had 3,000 coronavirus test kits but still had not used roughly 90%, an article in Mother Jones charged. At a White house press conference around that time, Wilkie was asked how many veterans of those who needed to be tested had been. “We believe we’ve caught most of them,” he replied.
But that was in the early days of the crisis.
With results from the 322 tests administered by Mar. 18, the VA had confirmed five positive cases, was tracking 33 presumptive cases, and acknowledged the first veteran death linked to COVID-19. As of Mar. 26, the VA had administered roughly 7,500 COVID-19 tests nationwide.
Secretary Wilkie has promised that the department’s first focus will always be caring for veterans. In an interview with Military Times, he said, “We don’t release any beds if veterans are needing them. The veterans still are primary. We are a [health] bridge for the larger community, but that’s only after veterans are taken care of.”
Reports suggest possible in utero transmission of novel coronavirus 2019
Reports of three neonates with elevated IgM antibody concentrations whose mothers had COVID-19 in two articles raise questions about whether the infants may have been infected with the virus in utero.
The data, while provocative, “are not conclusive and do not prove in utero transmission” of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), editorialists cautioned.
“The suggestion of in utero transmission rests on IgM detection in these 3 neonates, and IgM is a challenging way to diagnose many congenital infections,” David W. Kimberlin, MD, and Sergio Stagno, MD, of the division of pediatric infectious diseases at University of Alabama at Birmingham, wrote in their editorial. “IgM antibodies are too large to cross the placenta and so detection in a newborn reasonably could be assumed to reflect fetal production following in utero infection. However, most congenital infections are not diagnosed based on IgM detection because IgM assays can be prone to false-positive and false-negative results, along with cross-reactivity and testing challenges.”
None of the three infants had a positive reverse transcriptase–polymerase chain reaction (RT-PCR) test result, “so there is not virologic evidence for congenital infection in these cases to support the serologic suggestion of in utero transmission,” the editorialists noted.
Examining the possibility of vertical transmission
A prior case series of nine pregnant women found no transmission of the virus from mother to child, but the question of in utero transmission is not settled, said Lan Dong, MD, of the department of obstetrics and gynecology at Renmin Hospital of Wuhan University in China and colleagues. In their research letter, the investigators described a newborn with elevated IgM antibodies to novel coronavirus 2019 born to a mother with COVID-19. The infant was delivered by cesarean section February 22, 2020, at Renmin Hospital in a negative-pressure isolation room.
“The mother wore an N95 mask and did not hold the infant,” the researchers said. “The neonate had no symptoms and was immediately quarantined in the neonatal intensive care unit. At 2 hours of age, the SARS-CoV-2 IgG level was 140.32 AU/mL and the IgM level was 45.83 AU/mL.” Although the infant may have been infected at delivery, IgM antibodies usually take days to appear, Dr. Dong and colleagues wrote. “The infant’s repeatedly negative RT-PCR test results on nasopharyngeal swabs are difficult to explain, although these tests are not always positive with infection. ... Additional examination of maternal and newborn samples should be done to confirm this preliminary observation.”
A review of infants’ serologic characteristics
Hui Zeng, MD, of the department of laboratory medicine at Zhongnan Hospital of Wuhan University in China and colleagues retrospectively reviewed clinical records and laboratory results for six pregnant women with COVID-19, according to a study in JAMA. The women had mild clinical manifestations and were admitted to Zhongnan Hospital between February 16 and March 6. “All had cesarean deliveries in their third trimester in negative pressure isolation rooms,” the investigators said. “All mothers wore masks, and all medical staff wore protective suits and double masks. The infants were isolated from their mothers immediately after delivery.”
Two of the infants had elevated IgG and IgM concentrations. IgM “is not usually transferred from mother to fetus because of its larger macromolecular structure. ... Whether the placentas of women in this study were damaged and abnormal is unknown,” Dr. Zeng and colleagues said. “Alternatively, IgM could have been produced by the infant if the virus crossed the placenta.”
“Although these 2 studies deserve careful evaluation, more definitive evidence is needed” before physicians can “counsel pregnant women that their fetuses are at risk from congenital infection with SARS-CoV-2,” Dr. Kimberlin and Dr. Stagno concluded.
Dr. Dong and associates had no conflicts of interest. Their work was supported by the National Key Research and Development Project and others. Dr. Zeng and colleagues had no relevant financial disclosures. Their study was supported by grants from the National Natural Science Foundation of China and Zhongnan Hospital. Dr. Kimberlin and Dr. Stagno had no conflicts of interest.
SOURCE: Dong L et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4621; Zeng H et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4861.
Reports of three neonates with elevated IgM antibody concentrations whose mothers had COVID-19 in two articles raise questions about whether the infants may have been infected with the virus in utero.
The data, while provocative, “are not conclusive and do not prove in utero transmission” of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), editorialists cautioned.
“The suggestion of in utero transmission rests on IgM detection in these 3 neonates, and IgM is a challenging way to diagnose many congenital infections,” David W. Kimberlin, MD, and Sergio Stagno, MD, of the division of pediatric infectious diseases at University of Alabama at Birmingham, wrote in their editorial. “IgM antibodies are too large to cross the placenta and so detection in a newborn reasonably could be assumed to reflect fetal production following in utero infection. However, most congenital infections are not diagnosed based on IgM detection because IgM assays can be prone to false-positive and false-negative results, along with cross-reactivity and testing challenges.”
None of the three infants had a positive reverse transcriptase–polymerase chain reaction (RT-PCR) test result, “so there is not virologic evidence for congenital infection in these cases to support the serologic suggestion of in utero transmission,” the editorialists noted.
Examining the possibility of vertical transmission
A prior case series of nine pregnant women found no transmission of the virus from mother to child, but the question of in utero transmission is not settled, said Lan Dong, MD, of the department of obstetrics and gynecology at Renmin Hospital of Wuhan University in China and colleagues. In their research letter, the investigators described a newborn with elevated IgM antibodies to novel coronavirus 2019 born to a mother with COVID-19. The infant was delivered by cesarean section February 22, 2020, at Renmin Hospital in a negative-pressure isolation room.
“The mother wore an N95 mask and did not hold the infant,” the researchers said. “The neonate had no symptoms and was immediately quarantined in the neonatal intensive care unit. At 2 hours of age, the SARS-CoV-2 IgG level was 140.32 AU/mL and the IgM level was 45.83 AU/mL.” Although the infant may have been infected at delivery, IgM antibodies usually take days to appear, Dr. Dong and colleagues wrote. “The infant’s repeatedly negative RT-PCR test results on nasopharyngeal swabs are difficult to explain, although these tests are not always positive with infection. ... Additional examination of maternal and newborn samples should be done to confirm this preliminary observation.”
A review of infants’ serologic characteristics
Hui Zeng, MD, of the department of laboratory medicine at Zhongnan Hospital of Wuhan University in China and colleagues retrospectively reviewed clinical records and laboratory results for six pregnant women with COVID-19, according to a study in JAMA. The women had mild clinical manifestations and were admitted to Zhongnan Hospital between February 16 and March 6. “All had cesarean deliveries in their third trimester in negative pressure isolation rooms,” the investigators said. “All mothers wore masks, and all medical staff wore protective suits and double masks. The infants were isolated from their mothers immediately after delivery.”
Two of the infants had elevated IgG and IgM concentrations. IgM “is not usually transferred from mother to fetus because of its larger macromolecular structure. ... Whether the placentas of women in this study were damaged and abnormal is unknown,” Dr. Zeng and colleagues said. “Alternatively, IgM could have been produced by the infant if the virus crossed the placenta.”
“Although these 2 studies deserve careful evaluation, more definitive evidence is needed” before physicians can “counsel pregnant women that their fetuses are at risk from congenital infection with SARS-CoV-2,” Dr. Kimberlin and Dr. Stagno concluded.
Dr. Dong and associates had no conflicts of interest. Their work was supported by the National Key Research and Development Project and others. Dr. Zeng and colleagues had no relevant financial disclosures. Their study was supported by grants from the National Natural Science Foundation of China and Zhongnan Hospital. Dr. Kimberlin and Dr. Stagno had no conflicts of interest.
SOURCE: Dong L et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4621; Zeng H et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4861.
Reports of three neonates with elevated IgM antibody concentrations whose mothers had COVID-19 in two articles raise questions about whether the infants may have been infected with the virus in utero.
The data, while provocative, “are not conclusive and do not prove in utero transmission” of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), editorialists cautioned.
“The suggestion of in utero transmission rests on IgM detection in these 3 neonates, and IgM is a challenging way to diagnose many congenital infections,” David W. Kimberlin, MD, and Sergio Stagno, MD, of the division of pediatric infectious diseases at University of Alabama at Birmingham, wrote in their editorial. “IgM antibodies are too large to cross the placenta and so detection in a newborn reasonably could be assumed to reflect fetal production following in utero infection. However, most congenital infections are not diagnosed based on IgM detection because IgM assays can be prone to false-positive and false-negative results, along with cross-reactivity and testing challenges.”
None of the three infants had a positive reverse transcriptase–polymerase chain reaction (RT-PCR) test result, “so there is not virologic evidence for congenital infection in these cases to support the serologic suggestion of in utero transmission,” the editorialists noted.
Examining the possibility of vertical transmission
A prior case series of nine pregnant women found no transmission of the virus from mother to child, but the question of in utero transmission is not settled, said Lan Dong, MD, of the department of obstetrics and gynecology at Renmin Hospital of Wuhan University in China and colleagues. In their research letter, the investigators described a newborn with elevated IgM antibodies to novel coronavirus 2019 born to a mother with COVID-19. The infant was delivered by cesarean section February 22, 2020, at Renmin Hospital in a negative-pressure isolation room.
“The mother wore an N95 mask and did not hold the infant,” the researchers said. “The neonate had no symptoms and was immediately quarantined in the neonatal intensive care unit. At 2 hours of age, the SARS-CoV-2 IgG level was 140.32 AU/mL and the IgM level was 45.83 AU/mL.” Although the infant may have been infected at delivery, IgM antibodies usually take days to appear, Dr. Dong and colleagues wrote. “The infant’s repeatedly negative RT-PCR test results on nasopharyngeal swabs are difficult to explain, although these tests are not always positive with infection. ... Additional examination of maternal and newborn samples should be done to confirm this preliminary observation.”
A review of infants’ serologic characteristics
Hui Zeng, MD, of the department of laboratory medicine at Zhongnan Hospital of Wuhan University in China and colleagues retrospectively reviewed clinical records and laboratory results for six pregnant women with COVID-19, according to a study in JAMA. The women had mild clinical manifestations and were admitted to Zhongnan Hospital between February 16 and March 6. “All had cesarean deliveries in their third trimester in negative pressure isolation rooms,” the investigators said. “All mothers wore masks, and all medical staff wore protective suits and double masks. The infants were isolated from their mothers immediately after delivery.”
Two of the infants had elevated IgG and IgM concentrations. IgM “is not usually transferred from mother to fetus because of its larger macromolecular structure. ... Whether the placentas of women in this study were damaged and abnormal is unknown,” Dr. Zeng and colleagues said. “Alternatively, IgM could have been produced by the infant if the virus crossed the placenta.”
“Although these 2 studies deserve careful evaluation, more definitive evidence is needed” before physicians can “counsel pregnant women that their fetuses are at risk from congenital infection with SARS-CoV-2,” Dr. Kimberlin and Dr. Stagno concluded.
Dr. Dong and associates had no conflicts of interest. Their work was supported by the National Key Research and Development Project and others. Dr. Zeng and colleagues had no relevant financial disclosures. Their study was supported by grants from the National Natural Science Foundation of China and Zhongnan Hospital. Dr. Kimberlin and Dr. Stagno had no conflicts of interest.
SOURCE: Dong L et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4621; Zeng H et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4861.
FROM JAMA