MDedge Rheumatology

Here are the stories our MDedge editors across specialties think you need to know about today:

Remdesivir trial data published

Weeks after topline remdesivir data appeared in the press, investigators published their full experience using the drug to treat COVID-19 patients. The study, published in the New England Journal of Medicine, showed the drug reduced recovery time from 15 to 11 days, compared with placebo. Patients receiving oxygen seemed to fare best from treatment with remdesivir. “There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.” READ MORE.

FDA approves contraceptive gel

The Food and Drug Administration approved Phexxi (lactic acid, citric acid, and potassium bitartrate) vaginal gel to prevent pregnancy in women of reproductive potential. It’s the first nonhormonal, on-demand, vaginal pH regulator contraceptive designed to maintain vaginal pH within the range of 3.5-4.5. READ MORE.

COVID-19 lessons from one cancer center

Physicians at Levine Cancer Institute in Charlotte, N.C., largely have been able to keep hematologic oncology patients on their treatment regimens and continue to care for inpatients during the early months of the COVID-19 pandemic. How have they kept the situation managable? Strict infection control, liberal testing, and a proactive plan to defer and temporarily replace infusion care when medically appropriate were all part of the strategy. “My impression is that the incidence has been low partly because our patients, especially those with hematologic malignancies including those on active chemotherapy, were already getting warned to be cautious, even before the coronavirus, using distancing, masking, and meticulous hand hygiene,” said Peter Voorhees, MD, professor of medicine and director of Medical Operations and Outreach Services in Levine Cancer Institute’s Department of Hematologic Oncology and Blood Disorders. READ MORE.

Convalescent plasma: Hope or hype?

There are currently more than two dozen trials of convalescent plasma in the United States and elsewhere but most are single-arm trials to determine if one infusion can decrease the need for intubation or help patients on a ventilator to improve. Others researchers are investigating whether convalescent plasma might be used before severe disease sets in. Meanwhile, about 2,200 hospitals are participating in an expanded access program being led by the Mayo Clinic nationwide. The National Institutes of Health recently said that “there are insufficient clinical data to recommend either for or against” its use for COVID-19. READ MORE.

New rosacea treatment guidelines

Patients with rosacea should receive treatments based on their phenotype and specific symptoms, rather than being assigned into distinct subtype categories, according to updated guidance published in the Journal of the American Academy of Dermatology. The update comes from the National Rosacea Society Expert Committee and is based on a review of the evidence. Patients “shouldn’t be classified as having a certain subtype of rosacea” since “many patients have features that overlap more than one subtype,” said Diane Thiboutot, MD, lead author of the update and a professor of dermatology and associate dean of clinical and translational research education at Penn State University, Hershey. READ MORE.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

Here are the stories our MDedge editors across specialties think you need to know about today:

Remdesivir trial data published

Weeks after topline remdesivir data appeared in the press, investigators published their full experience using the drug to treat COVID-19 patients. The study, published in the New England Journal of Medicine, showed the drug reduced recovery time from 15 to 11 days, compared with placebo. Patients receiving oxygen seemed to fare best from treatment with remdesivir. “There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.” READ MORE.

FDA approves contraceptive gel

The Food and Drug Administration approved Phexxi (lactic acid, citric acid, and potassium bitartrate) vaginal gel to prevent pregnancy in women of reproductive potential. It’s the first nonhormonal, on-demand, vaginal pH regulator contraceptive designed to maintain vaginal pH within the range of 3.5-4.5. READ MORE.

COVID-19 lessons from one cancer center

Physicians at Levine Cancer Institute in Charlotte, N.C., largely have been able to keep hematologic oncology patients on their treatment regimens and continue to care for inpatients during the early months of the COVID-19 pandemic. How have they kept the situation managable? Strict infection control, liberal testing, and a proactive plan to defer and temporarily replace infusion care when medically appropriate were all part of the strategy. “My impression is that the incidence has been low partly because our patients, especially those with hematologic malignancies including those on active chemotherapy, were already getting warned to be cautious, even before the coronavirus, using distancing, masking, and meticulous hand hygiene,” said Peter Voorhees, MD, professor of medicine and director of Medical Operations and Outreach Services in Levine Cancer Institute’s Department of Hematologic Oncology and Blood Disorders. READ MORE.

Convalescent plasma: Hope or hype?

There are currently more than two dozen trials of convalescent plasma in the United States and elsewhere but most are single-arm trials to determine if one infusion can decrease the need for intubation or help patients on a ventilator to improve. Others researchers are investigating whether convalescent plasma might be used before severe disease sets in. Meanwhile, about 2,200 hospitals are participating in an expanded access program being led by the Mayo Clinic nationwide. The National Institutes of Health recently said that “there are insufficient clinical data to recommend either for or against” its use for COVID-19. READ MORE.

New rosacea treatment guidelines

Patients with rosacea should receive treatments based on their phenotype and specific symptoms, rather than being assigned into distinct subtype categories, according to updated guidance published in the Journal of the American Academy of Dermatology. The update comes from the National Rosacea Society Expert Committee and is based on a review of the evidence. Patients “shouldn’t be classified as having a certain subtype of rosacea” since “many patients have features that overlap more than one subtype,” said Diane Thiboutot, MD, lead author of the update and a professor of dermatology and associate dean of clinical and translational research education at Penn State University, Hershey. READ MORE.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

Here are the stories our MDedge editors across specialties think you need to know about today:

Remdesivir trial data published

Weeks after topline remdesivir data appeared in the press, investigators published their full experience using the drug to treat COVID-19 patients. The study, published in the New England Journal of Medicine, showed the drug reduced recovery time from 15 to 11 days, compared with placebo. Patients receiving oxygen seemed to fare best from treatment with remdesivir. “There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.” READ MORE.

FDA approves contraceptive gel

The Food and Drug Administration approved Phexxi (lactic acid, citric acid, and potassium bitartrate) vaginal gel to prevent pregnancy in women of reproductive potential. It’s the first nonhormonal, on-demand, vaginal pH regulator contraceptive designed to maintain vaginal pH within the range of 3.5-4.5. READ MORE.

COVID-19 lessons from one cancer center

Physicians at Levine Cancer Institute in Charlotte, N.C., largely have been able to keep hematologic oncology patients on their treatment regimens and continue to care for inpatients during the early months of the COVID-19 pandemic. How have they kept the situation managable? Strict infection control, liberal testing, and a proactive plan to defer and temporarily replace infusion care when medically appropriate were all part of the strategy. “My impression is that the incidence has been low partly because our patients, especially those with hematologic malignancies including those on active chemotherapy, were already getting warned to be cautious, even before the coronavirus, using distancing, masking, and meticulous hand hygiene,” said Peter Voorhees, MD, professor of medicine and director of Medical Operations and Outreach Services in Levine Cancer Institute’s Department of Hematologic Oncology and Blood Disorders. READ MORE.

Convalescent plasma: Hope or hype?

There are currently more than two dozen trials of convalescent plasma in the United States and elsewhere but most are single-arm trials to determine if one infusion can decrease the need for intubation or help patients on a ventilator to improve. Others researchers are investigating whether convalescent plasma might be used before severe disease sets in. Meanwhile, about 2,200 hospitals are participating in an expanded access program being led by the Mayo Clinic nationwide. The National Institutes of Health recently said that “there are insufficient clinical data to recommend either for or against” its use for COVID-19. READ MORE.

New rosacea treatment guidelines

Patients with rosacea should receive treatments based on their phenotype and specific symptoms, rather than being assigned into distinct subtype categories, according to updated guidance published in the Journal of the American Academy of Dermatology. The update comes from the National Rosacea Society Expert Committee and is based on a review of the evidence. Patients “shouldn’t be classified as having a certain subtype of rosacea” since “many patients have features that overlap more than one subtype,” said Diane Thiboutot, MD, lead author of the update and a professor of dermatology and associate dean of clinical and translational research education at Penn State University, Hershey. READ MORE.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

Ignorance may be bliss for some. But as I sit here in my scenic social isolation on the Maine coast I find that, like most people, what I don’t know unsettles me. How is the COVID-19 virus spread? Does my wife’s wipe down of the doorknobs after I return from the grocery store really make us any less likely to contract the virus? Is wearing my homemade bandana face mask doing anything to protect me? I suspect not, but I wear it as a statement of courtesy and solidarity to my fellow community members.

zimmytws/Thinkstock

Does the 6-foot rule make any sense? I’ve read that it is based on a study dating back to the 1930s. I’ve seen images of the 25-foot droplet plume blasting out from a sneeze and understand that, as a bicyclist, I may be generating a shower of droplets in my wake. But, are those droplets a threat to anyone I pedal by if I am symptom free? What does being a carrier mean when we are talking about COVID-19?

What makes me more vulnerable to this particular virus as an apparently healthy septuagenarian? What collection of misfortunes have fallen on those younger victims of the pandemic? How often was it genetic?

Of course, none of us has the information yet that can provide us answers. This vacuum has attracted scores of “experts” bold enough or careless enough to venture an opinion. They may have also issued a caveat, but how often have the media failed to include it in the report or buried it in the fine print at the end of the story?

My discomfort with this information void has left me and you and everyone else to our imaginations to craft our own explanations. So, I try to piece together a construct based on what I can glean from what I read and see in the news because like most people I fortunately have no first-hand information about even a single case. The number of deaths is horrifying, but may not have hit close to home and given most of us a real personal sense of the illness and its character.

Maine is a small state with just over a million inhabitants, and most of us have some connection to one another. It may be that a person is the second cousin of someone who used to live 2 miles down the road. But, there is some feeling of familiarity. We have had deaths related to COVID-19, but very scanty information other than the county about where they occurred and whether the victim was a resident of an extended care facility. We are told very little if any details about exposure as officials invoke HIPAA regulations that leave us in the dark. Other than one vague reference to a “traveling salesman” who may have introduced the virus to several nursing homes, there has been very little information about how the virus may have been spread here in Maine. Even national reports of the deaths of high-profile entertainers and retired athletes are usually draped in the same haze of privacy.

Most of us don’t need to know the names and street addresses of the victims but a few anonymous narratives that include some general information on how epidemiologists believe clusters began and propagated would help us understand our risks with just a glimmer of clarity.

Of course the epidemiologists may not have the answers we are seeking because they too are struggling to untangle connections hampered by concerns of privacy. There is no question that privacy must remain an important part of the physician-patient relationship. But a pandemic has thrown us into a situation where common sense demands that HIPAA be interpreted with an emphasis on the greater good. Finding that balance between privacy and public knowledge will continue to be one of our greatest challenges.

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 [email protected].

Ignorance may be bliss for some. But as I sit here in my scenic social isolation on the Maine coast I find that, like most people, what I don’t know unsettles me. How is the COVID-19 virus spread? Does my wife’s wipe down of the doorknobs after I return from the grocery store really make us any less likely to contract the virus? Is wearing my homemade bandana face mask doing anything to protect me? I suspect not, but I wear it as a statement of courtesy and solidarity to my fellow community members.

zimmytws/Thinkstock

Does the 6-foot rule make any sense? I’ve read that it is based on a study dating back to the 1930s. I’ve seen images of the 25-foot droplet plume blasting out from a sneeze and understand that, as a bicyclist, I may be generating a shower of droplets in my wake. But, are those droplets a threat to anyone I pedal by if I am symptom free? What does being a carrier mean when we are talking about COVID-19?

What makes me more vulnerable to this particular virus as an apparently healthy septuagenarian? What collection of misfortunes have fallen on those younger victims of the pandemic? How often was it genetic?

Of course, none of us has the information yet that can provide us answers. This vacuum has attracted scores of “experts” bold enough or careless enough to venture an opinion. They may have also issued a caveat, but how often have the media failed to include it in the report or buried it in the fine print at the end of the story?

My discomfort with this information void has left me and you and everyone else to our imaginations to craft our own explanations. So, I try to piece together a construct based on what I can glean from what I read and see in the news because like most people I fortunately have no first-hand information about even a single case. The number of deaths is horrifying, but may not have hit close to home and given most of us a real personal sense of the illness and its character.

Maine is a small state with just over a million inhabitants, and most of us have some connection to one another. It may be that a person is the second cousin of someone who used to live 2 miles down the road. But, there is some feeling of familiarity. We have had deaths related to COVID-19, but very scanty information other than the county about where they occurred and whether the victim was a resident of an extended care facility. We are told very little if any details about exposure as officials invoke HIPAA regulations that leave us in the dark. Other than one vague reference to a “traveling salesman” who may have introduced the virus to several nursing homes, there has been very little information about how the virus may have been spread here in Maine. Even national reports of the deaths of high-profile entertainers and retired athletes are usually draped in the same haze of privacy.

Most of us don’t need to know the names and street addresses of the victims but a few anonymous narratives that include some general information on how epidemiologists believe clusters began and propagated would help us understand our risks with just a glimmer of clarity.

Of course the epidemiologists may not have the answers we are seeking because they too are struggling to untangle connections hampered by concerns of privacy. There is no question that privacy must remain an important part of the physician-patient relationship. But a pandemic has thrown us into a situation where common sense demands that HIPAA be interpreted with an emphasis on the greater good. Finding that balance between privacy and public knowledge will continue to be one of our greatest challenges.

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 [email protected].

Ignorance may be bliss for some. But as I sit here in my scenic social isolation on the Maine coast I find that, like most people, what I don’t know unsettles me. How is the COVID-19 virus spread? Does my wife’s wipe down of the doorknobs after I return from the grocery store really make us any less likely to contract the virus? Is wearing my homemade bandana face mask doing anything to protect me? I suspect not, but I wear it as a statement of courtesy and solidarity to my fellow community members.

zimmytws/Thinkstock

Does the 6-foot rule make any sense? I’ve read that it is based on a study dating back to the 1930s. I’ve seen images of the 25-foot droplet plume blasting out from a sneeze and understand that, as a bicyclist, I may be generating a shower of droplets in my wake. But, are those droplets a threat to anyone I pedal by if I am symptom free? What does being a carrier mean when we are talking about COVID-19?

What makes me more vulnerable to this particular virus as an apparently healthy septuagenarian? What collection of misfortunes have fallen on those younger victims of the pandemic? How often was it genetic?

Of course, none of us has the information yet that can provide us answers. This vacuum has attracted scores of “experts” bold enough or careless enough to venture an opinion. They may have also issued a caveat, but how often have the media failed to include it in the report or buried it in the fine print at the end of the story?

My discomfort with this information void has left me and you and everyone else to our imaginations to craft our own explanations. So, I try to piece together a construct based on what I can glean from what I read and see in the news because like most people I fortunately have no first-hand information about even a single case. The number of deaths is horrifying, but may not have hit close to home and given most of us a real personal sense of the illness and its character.

Maine is a small state with just over a million inhabitants, and most of us have some connection to one another. It may be that a person is the second cousin of someone who used to live 2 miles down the road. But, there is some feeling of familiarity. We have had deaths related to COVID-19, but very scanty information other than the county about where they occurred and whether the victim was a resident of an extended care facility. We are told very little if any details about exposure as officials invoke HIPAA regulations that leave us in the dark. Other than one vague reference to a “traveling salesman” who may have introduced the virus to several nursing homes, there has been very little information about how the virus may have been spread here in Maine. Even national reports of the deaths of high-profile entertainers and retired athletes are usually draped in the same haze of privacy.

Most of us don’t need to know the names and street addresses of the victims but a few anonymous narratives that include some general information on how epidemiologists believe clusters began and propagated would help us understand our risks with just a glimmer of clarity.

Of course the epidemiologists may not have the answers we are seeking because they too are struggling to untangle connections hampered by concerns of privacy. There is no question that privacy must remain an important part of the physician-patient relationship. But a pandemic has thrown us into a situation where common sense demands that HIPAA be interpreted with an emphasis on the greater good. Finding that balance between privacy and public knowledge will continue to be one of our greatest challenges.

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 [email protected].

On March 31, soon after the Food and Drug Administration authorized emergency use of antibody-packed plasma from recovered patients with COVID-19, Marisa Leuzzi became the first donor at an American Red Cross center. She hoped it could help her aunt, Renee Bannister, who was failing after 3 weeks on a ventilator at Virtua Hospital in Voorhees, N.J.

It may have worked; 11 days after receiving the plasma, Ms. Bannister was weaned off the ventilator and she is now awake and speaking, said Red Cross spokesperson Stephanie Rendon.

This kind of anecdote is fueling demand for the therapy, which can be provided through an expanded access program led by the Mayo Clinic, backed by the FDA, and the plasma paid for by the U.S. Department of Health & Human Services. But while this program is collecting safety and outcomes data, it’s not a randomized, controlled trial.

Others, however, are pursuing that data. At least a dozen researchers are investigating the potential of plasma – both as a treatment and whether it could act as a stand-in for a vaccine until one is developed.

“One of the things I don’t want this to be is the flavor of the month,” Shmuel Shoham, MD, associate professor of medicine at Johns Hopkins University, said in an interview.

Dr. Shoham, principal investigator for a study evaluating convalescent plasma to prevent the infection in high-risk individuals, said some clinicians, desperate for any treatment, have tried potential therapies such as hydroxychloroquine and remdesivir without evidence of safety or efficacy in COVID-19.

The National Institutes of Health recently said something similar for convalescent plasma, that “there are insufficient clinical data to recommend either for or against” its use for COVID-19.

But plasma has promise, according to a Johns Hopkins School of Medicine’s Bloomberg Distinguished Professor, Arturo Casadevall, MD, PhD, in Baltimore, and Liise-anne Pirofski, MD, a professor at Albert Einstein College of Medicine, New York. They lay out the case for convalescent plasma in an article published online March 13 in the Journal of Clinical Investigation. Passive antibody therapy, they wrote, has been used to stem polio, measles, mumps, and influenza, and more recently has shown some success against SARS-CoV-1 and Middle East respiratory syndrome (MERS).

“The special attraction of this modality of treatment is that, unlike vaccines or newly developed drugs, it could, in principle, be made available very rapidly,” said researchers with the National COVID-19 Convalescent Plasma Project, which includes physicians and scientists from 57 institutions in 46 states. But where principle veers from reality is in availability of the plasma itself, and donors are in short supply.
 

Aiming to prevent infection

So far, the FDA has approved 12 plasma trials – including Dr. Shoham’s – and the NIH’s clinicaltrials.gov lists more than two dozen convalescent plasma studies in the United States and elsewhere.

Most are single-arm trials to determine if one infusion can decrease the need for intubation or help those on a ventilator improve. Two others, one at Johns Hopkins and one at Stanford (Calif.) Hospital are investigating whether convalescent plasma might be used before severe disease sets in.

“A general principle of passive antibody therapy is that it is more effective when used for prophylaxis than for treatment of disease,” Dr. Casadevall and Dr. Pirofski wrote.

Stanford’s randomized, double-blind study will evaluate regular versus convalescent plasma in ED patients who are not sick enough to require hospitalization.

The Johns Hopkins trial, which aims to protect against infection in the first place, will begin at Johns Hopkins, Baltimore, and at Hopkins-affiliated hospitals throughout Maryland, Dr. Shoham said. He hopes it will expand nationwide eventually, and said that they expect to enroll the first patients soon.

To start, the prevention study will enroll only 150 patients, each of whom must have had close contact with someone who has COVID-19 within the previous 120 hours and be asymptomatic. The number of subjects is small, compared with the trial size of other potential therapies, and an issue, Shoham said, “that keeps me up at night.” But finding thousands of enrollees for plasma studies is hard, in part because it’s so difficult to recruit donors.

Participants will receive normal plasma (which will act as a placebo) or convalescent plasma.

The primary endpoint is cumulative incidence of COVID-19, defined as symptoms and a polymerase chain reaction–positive test; participants will be tracked for 90 days. Hospitals and health care workers could then decide if they want to use the therapy, he said.

The study will not answer whether participants will continue to have antibodies beyond the 90 days. Convalescent plasma is given as a rapid response to an emergent pathogen – a short-term boost of immunity rather than a long-term therapeutic.
 

What can we learn from expanded access?

Meanwhile, some 2,200 hospitals are participating in the expanded access program being led by the Mayo Clinic nationwide; more than 9,000 patients had received infusions at press time.

One participant is Northwell Health, a 23-hospital system that sprawls across the U.S. COVID epicenter: four of the five boroughs of New York City and Long Island.

Convalescent plasma is an in-demand therapy, said Christina Brennan, MD, vice president of clinical research at Northwell. “We get patients, family members, they say my family member is at X hospital – if it’s not being offered there, can you have them transferred?” she said in an interview.

When Northwell – through the New York Blood Bank – opened up donor registration, 800 people signed up in the first 24 hours, Dr. Brennan said. As of mid-May, 527 patients had received a transfusion.
 

Who’s the best donor and when should donation occur?

The Red Cross, hospitals, and independent blood banks are all soliciting donors, who can sign up at the Red Cross website. The FDA recommends that donors have a history of COVID-19 as confirmed by molecular or antibody testing, be symptom free for 14 days, have a negative follow-up molecular test, and be virus free at the time of collection. The FDA also suggests measuring a donor’s SARS-CoV-2 neutralizing antibody titers, if available, with a recommendation of at least 1:160.

But questions remain, such as whether there is a theoretical risk for antibody-dependent enhancement (ADE) of infection with SARS-CoV-2. “Antibodies to one type of coronavirus could enhance infection to another viral strain,” of coronavirus, Dr. Casadevall wrote. ADE has been observed in both severe acute respiratory syndrome (SARS) and MERS.

The other risk is that donors may still be shedding active virus. While the FDA suggests that donors are unlikely to still be infectious 14 days after infection, that is as of yet unproven. Both COVID-19 diagnostics and antibody tests have high rates of false negatives, which raises the specter that infection could be spread via the plasma donation.

Daniele Focosi, MD, PhD, from Pisa (Italy) University Hospital and colleagues raise that concern in a preprint review on convalescent plasma in COVID-19. “Although the recipient is already infected, theoretically transmission of more infectious particles could worsen clinical conditions,” they wrote, noting that “such a concern can be somewhat reduced by treatment with modern pathogen inactivation techniques.”

No evidence exists that SARS-CoV-2 can be transmitted through blood, but “we don’t know for sure,” Dr. Shoham said in an interview. A reassuring point: Even those with severe infection do not have viral RNA in their blood, he said, adding, “We don’t think there’s going to be viral transmission of this particular virus with transfusion.”

For another highly infectious pathogen, the Ebola virus, the World Health Organization recommended in 2014 that potential plasma donors wait at least 28 days after infection.

It’s also not known how long SARS-CoV-2 antibodies persist in the blood; longer viability could mean a longer donation window. Dr. Focosi noted that a previous Chinese study had shown that SARS-specific antibodies in people infected with the first SARS virus, SARS-CoV-1, persisted for 2 years.

Dr. Casadevall and Dr. Pirofski have disclosed no relevant financial relationships. Shoham has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

On March 31, soon after the Food and Drug Administration authorized emergency use of antibody-packed plasma from recovered patients with COVID-19, Marisa Leuzzi became the first donor at an American Red Cross center. She hoped it could help her aunt, Renee Bannister, who was failing after 3 weeks on a ventilator at Virtua Hospital in Voorhees, N.J.

It may have worked; 11 days after receiving the plasma, Ms. Bannister was weaned off the ventilator and she is now awake and speaking, said Red Cross spokesperson Stephanie Rendon.

This kind of anecdote is fueling demand for the therapy, which can be provided through an expanded access program led by the Mayo Clinic, backed by the FDA, and the plasma paid for by the U.S. Department of Health & Human Services. But while this program is collecting safety and outcomes data, it’s not a randomized, controlled trial.

Others, however, are pursuing that data. At least a dozen researchers are investigating the potential of plasma – both as a treatment and whether it could act as a stand-in for a vaccine until one is developed.

“One of the things I don’t want this to be is the flavor of the month,” Shmuel Shoham, MD, associate professor of medicine at Johns Hopkins University, said in an interview.

Dr. Shoham, principal investigator for a study evaluating convalescent plasma to prevent the infection in high-risk individuals, said some clinicians, desperate for any treatment, have tried potential therapies such as hydroxychloroquine and remdesivir without evidence of safety or efficacy in COVID-19.

The National Institutes of Health recently said something similar for convalescent plasma, that “there are insufficient clinical data to recommend either for or against” its use for COVID-19.

But plasma has promise, according to a Johns Hopkins School of Medicine’s Bloomberg Distinguished Professor, Arturo Casadevall, MD, PhD, in Baltimore, and Liise-anne Pirofski, MD, a professor at Albert Einstein College of Medicine, New York. They lay out the case for convalescent plasma in an article published online March 13 in the Journal of Clinical Investigation. Passive antibody therapy, they wrote, has been used to stem polio, measles, mumps, and influenza, and more recently has shown some success against SARS-CoV-1 and Middle East respiratory syndrome (MERS).

“The special attraction of this modality of treatment is that, unlike vaccines or newly developed drugs, it could, in principle, be made available very rapidly,” said researchers with the National COVID-19 Convalescent Plasma Project, which includes physicians and scientists from 57 institutions in 46 states. But where principle veers from reality is in availability of the plasma itself, and donors are in short supply.
 

Aiming to prevent infection

So far, the FDA has approved 12 plasma trials – including Dr. Shoham’s – and the NIH’s clinicaltrials.gov lists more than two dozen convalescent plasma studies in the United States and elsewhere.

Most are single-arm trials to determine if one infusion can decrease the need for intubation or help those on a ventilator improve. Two others, one at Johns Hopkins and one at Stanford (Calif.) Hospital are investigating whether convalescent plasma might be used before severe disease sets in.

“A general principle of passive antibody therapy is that it is more effective when used for prophylaxis than for treatment of disease,” Dr. Casadevall and Dr. Pirofski wrote.

Stanford’s randomized, double-blind study will evaluate regular versus convalescent plasma in ED patients who are not sick enough to require hospitalization.

The Johns Hopkins trial, which aims to protect against infection in the first place, will begin at Johns Hopkins, Baltimore, and at Hopkins-affiliated hospitals throughout Maryland, Dr. Shoham said. He hopes it will expand nationwide eventually, and said that they expect to enroll the first patients soon.

To start, the prevention study will enroll only 150 patients, each of whom must have had close contact with someone who has COVID-19 within the previous 120 hours and be asymptomatic. The number of subjects is small, compared with the trial size of other potential therapies, and an issue, Shoham said, “that keeps me up at night.” But finding thousands of enrollees for plasma studies is hard, in part because it’s so difficult to recruit donors.

Participants will receive normal plasma (which will act as a placebo) or convalescent plasma.

The primary endpoint is cumulative incidence of COVID-19, defined as symptoms and a polymerase chain reaction–positive test; participants will be tracked for 90 days. Hospitals and health care workers could then decide if they want to use the therapy, he said.

The study will not answer whether participants will continue to have antibodies beyond the 90 days. Convalescent plasma is given as a rapid response to an emergent pathogen – a short-term boost of immunity rather than a long-term therapeutic.
 

What can we learn from expanded access?

Meanwhile, some 2,200 hospitals are participating in the expanded access program being led by the Mayo Clinic nationwide; more than 9,000 patients had received infusions at press time.

One participant is Northwell Health, a 23-hospital system that sprawls across the U.S. COVID epicenter: four of the five boroughs of New York City and Long Island.

Convalescent plasma is an in-demand therapy, said Christina Brennan, MD, vice president of clinical research at Northwell. “We get patients, family members, they say my family member is at X hospital – if it’s not being offered there, can you have them transferred?” she said in an interview.

When Northwell – through the New York Blood Bank – opened up donor registration, 800 people signed up in the first 24 hours, Dr. Brennan said. As of mid-May, 527 patients had received a transfusion.
 

Who’s the best donor and when should donation occur?

The Red Cross, hospitals, and independent blood banks are all soliciting donors, who can sign up at the Red Cross website. The FDA recommends that donors have a history of COVID-19 as confirmed by molecular or antibody testing, be symptom free for 14 days, have a negative follow-up molecular test, and be virus free at the time of collection. The FDA also suggests measuring a donor’s SARS-CoV-2 neutralizing antibody titers, if available, with a recommendation of at least 1:160.

But questions remain, such as whether there is a theoretical risk for antibody-dependent enhancement (ADE) of infection with SARS-CoV-2. “Antibodies to one type of coronavirus could enhance infection to another viral strain,” of coronavirus, Dr. Casadevall wrote. ADE has been observed in both severe acute respiratory syndrome (SARS) and MERS.

The other risk is that donors may still be shedding active virus. While the FDA suggests that donors are unlikely to still be infectious 14 days after infection, that is as of yet unproven. Both COVID-19 diagnostics and antibody tests have high rates of false negatives, which raises the specter that infection could be spread via the plasma donation.

Daniele Focosi, MD, PhD, from Pisa (Italy) University Hospital and colleagues raise that concern in a preprint review on convalescent plasma in COVID-19. “Although the recipient is already infected, theoretically transmission of more infectious particles could worsen clinical conditions,” they wrote, noting that “such a concern can be somewhat reduced by treatment with modern pathogen inactivation techniques.”

No evidence exists that SARS-CoV-2 can be transmitted through blood, but “we don’t know for sure,” Dr. Shoham said in an interview. A reassuring point: Even those with severe infection do not have viral RNA in their blood, he said, adding, “We don’t think there’s going to be viral transmission of this particular virus with transfusion.”

For another highly infectious pathogen, the Ebola virus, the World Health Organization recommended in 2014 that potential plasma donors wait at least 28 days after infection.

It’s also not known how long SARS-CoV-2 antibodies persist in the blood; longer viability could mean a longer donation window. Dr. Focosi noted that a previous Chinese study had shown that SARS-specific antibodies in people infected with the first SARS virus, SARS-CoV-1, persisted for 2 years.

Dr. Casadevall and Dr. Pirofski have disclosed no relevant financial relationships. Shoham has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

On March 31, soon after the Food and Drug Administration authorized emergency use of antibody-packed plasma from recovered patients with COVID-19, Marisa Leuzzi became the first donor at an American Red Cross center. She hoped it could help her aunt, Renee Bannister, who was failing after 3 weeks on a ventilator at Virtua Hospital in Voorhees, N.J.

It may have worked; 11 days after receiving the plasma, Ms. Bannister was weaned off the ventilator and she is now awake and speaking, said Red Cross spokesperson Stephanie Rendon.

This kind of anecdote is fueling demand for the therapy, which can be provided through an expanded access program led by the Mayo Clinic, backed by the FDA, and the plasma paid for by the U.S. Department of Health & Human Services. But while this program is collecting safety and outcomes data, it’s not a randomized, controlled trial.

Others, however, are pursuing that data. At least a dozen researchers are investigating the potential of plasma – both as a treatment and whether it could act as a stand-in for a vaccine until one is developed.

“One of the things I don’t want this to be is the flavor of the month,” Shmuel Shoham, MD, associate professor of medicine at Johns Hopkins University, said in an interview.

Dr. Shoham, principal investigator for a study evaluating convalescent plasma to prevent the infection in high-risk individuals, said some clinicians, desperate for any treatment, have tried potential therapies such as hydroxychloroquine and remdesivir without evidence of safety or efficacy in COVID-19.

The National Institutes of Health recently said something similar for convalescent plasma, that “there are insufficient clinical data to recommend either for or against” its use for COVID-19.

But plasma has promise, according to a Johns Hopkins School of Medicine’s Bloomberg Distinguished Professor, Arturo Casadevall, MD, PhD, in Baltimore, and Liise-anne Pirofski, MD, a professor at Albert Einstein College of Medicine, New York. They lay out the case for convalescent plasma in an article published online March 13 in the Journal of Clinical Investigation. Passive antibody therapy, they wrote, has been used to stem polio, measles, mumps, and influenza, and more recently has shown some success against SARS-CoV-1 and Middle East respiratory syndrome (MERS).

“The special attraction of this modality of treatment is that, unlike vaccines or newly developed drugs, it could, in principle, be made available very rapidly,” said researchers with the National COVID-19 Convalescent Plasma Project, which includes physicians and scientists from 57 institutions in 46 states. But where principle veers from reality is in availability of the plasma itself, and donors are in short supply.
 

Aiming to prevent infection

So far, the FDA has approved 12 plasma trials – including Dr. Shoham’s – and the NIH’s clinicaltrials.gov lists more than two dozen convalescent plasma studies in the United States and elsewhere.

Most are single-arm trials to determine if one infusion can decrease the need for intubation or help those on a ventilator improve. Two others, one at Johns Hopkins and one at Stanford (Calif.) Hospital are investigating whether convalescent plasma might be used before severe disease sets in.

“A general principle of passive antibody therapy is that it is more effective when used for prophylaxis than for treatment of disease,” Dr. Casadevall and Dr. Pirofski wrote.

Stanford’s randomized, double-blind study will evaluate regular versus convalescent plasma in ED patients who are not sick enough to require hospitalization.

The Johns Hopkins trial, which aims to protect against infection in the first place, will begin at Johns Hopkins, Baltimore, and at Hopkins-affiliated hospitals throughout Maryland, Dr. Shoham said. He hopes it will expand nationwide eventually, and said that they expect to enroll the first patients soon.

To start, the prevention study will enroll only 150 patients, each of whom must have had close contact with someone who has COVID-19 within the previous 120 hours and be asymptomatic. The number of subjects is small, compared with the trial size of other potential therapies, and an issue, Shoham said, “that keeps me up at night.” But finding thousands of enrollees for plasma studies is hard, in part because it’s so difficult to recruit donors.

Participants will receive normal plasma (which will act as a placebo) or convalescent plasma.

The primary endpoint is cumulative incidence of COVID-19, defined as symptoms and a polymerase chain reaction–positive test; participants will be tracked for 90 days. Hospitals and health care workers could then decide if they want to use the therapy, he said.

The study will not answer whether participants will continue to have antibodies beyond the 90 days. Convalescent plasma is given as a rapid response to an emergent pathogen – a short-term boost of immunity rather than a long-term therapeutic.
 

What can we learn from expanded access?

Meanwhile, some 2,200 hospitals are participating in the expanded access program being led by the Mayo Clinic nationwide; more than 9,000 patients had received infusions at press time.

One participant is Northwell Health, a 23-hospital system that sprawls across the U.S. COVID epicenter: four of the five boroughs of New York City and Long Island.

Convalescent plasma is an in-demand therapy, said Christina Brennan, MD, vice president of clinical research at Northwell. “We get patients, family members, they say my family member is at X hospital – if it’s not being offered there, can you have them transferred?” she said in an interview.

When Northwell – through the New York Blood Bank – opened up donor registration, 800 people signed up in the first 24 hours, Dr. Brennan said. As of mid-May, 527 patients had received a transfusion.
 

Who’s the best donor and when should donation occur?

The Red Cross, hospitals, and independent blood banks are all soliciting donors, who can sign up at the Red Cross website. The FDA recommends that donors have a history of COVID-19 as confirmed by molecular or antibody testing, be symptom free for 14 days, have a negative follow-up molecular test, and be virus free at the time of collection. The FDA also suggests measuring a donor’s SARS-CoV-2 neutralizing antibody titers, if available, with a recommendation of at least 1:160.

But questions remain, such as whether there is a theoretical risk for antibody-dependent enhancement (ADE) of infection with SARS-CoV-2. “Antibodies to one type of coronavirus could enhance infection to another viral strain,” of coronavirus, Dr. Casadevall wrote. ADE has been observed in both severe acute respiratory syndrome (SARS) and MERS.

The other risk is that donors may still be shedding active virus. While the FDA suggests that donors are unlikely to still be infectious 14 days after infection, that is as of yet unproven. Both COVID-19 diagnostics and antibody tests have high rates of false negatives, which raises the specter that infection could be spread via the plasma donation.

Daniele Focosi, MD, PhD, from Pisa (Italy) University Hospital and colleagues raise that concern in a preprint review on convalescent plasma in COVID-19. “Although the recipient is already infected, theoretically transmission of more infectious particles could worsen clinical conditions,” they wrote, noting that “such a concern can be somewhat reduced by treatment with modern pathogen inactivation techniques.”

No evidence exists that SARS-CoV-2 can be transmitted through blood, but “we don’t know for sure,” Dr. Shoham said in an interview. A reassuring point: Even those with severe infection do not have viral RNA in their blood, he said, adding, “We don’t think there’s going to be viral transmission of this particular virus with transfusion.”

For another highly infectious pathogen, the Ebola virus, the World Health Organization recommended in 2014 that potential plasma donors wait at least 28 days after infection.

It’s also not known how long SARS-CoV-2 antibodies persist in the blood; longer viability could mean a longer donation window. Dr. Focosi noted that a previous Chinese study had shown that SARS-specific antibodies in people infected with the first SARS virus, SARS-CoV-1, persisted for 2 years.

Dr. Casadevall and Dr. Pirofski have disclosed no relevant financial relationships. Shoham has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Much-anticipated results from the National Institute of Allergy and Infectious Diseases’ clinical trial of remdesivir in COVID-19 patients published in the New England Journal of Medicine suggest remdesivir shortens the disease course for hospitalized COVID-19 patients.

The agency reported initial promising results from the study earlier this month, which prompted the Food and Drug Administration to issue an emergency use authorization (EUA) for the drug, but the full data and results have not been widely available until now.

In the study of 1,063 patients, the researchers found patients who received a 10-day course of remdesivir had a reduced recovery time of 11 days, compared with 15 days to recovery in the group that received a placebo. The findings also suggest remdesivir should be started, if possible, before patients have such severe pulmonary disease that they require mechanical ventilation, according to the study authors.

The published results are “completely consistent” with the NIAID’s earlier announcement, H. Clifford Lane, MD, deputy director for clinical research and special projects at the NIAID, said in an interview. “The benefit appeared to be the greatest for the patients who are hospitalized with severe disease who require supplemental oxygen.”

Given the limited supply of remdesivir, physicians have been eager to see the full data to ensure they use the drug most effectively, Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said in an interview. Hospitals in states across the country, including New York, Michigan, and Washington, have received limited supplies of the drug in the last couple of weeks since the FDA’s authorization.

“I am losing my patience waiting for #remdesivir data. I was willing to give them a week to verify the numbers, triple proof the tables, cautiously frame conclusions. But it’s gone on too long. We are rationing with no rationale. We are floating on whisps [sic] of data, adrift,” Kate Stephenson, MD, an infectious diseases specialist at the Center for Virology and Vaccine Research at Harvard Medical School, Boston, wrote on Twitter May 18. After reading the paper, she tweeted Friday evening that she was “relieved to see convincing benefit – I was starting to worry!”

In the midst of a public health crisis, however, it is not unusual to make an announcement about trial results before the full dataset has been analyzed, said Dr. Lane. The NIAID followed a similar playbook for the PALM trial evaluating possible Ebola treatments in the Democratic Republic of Congo, with the independent monitoring board recommending the trial be terminated early in response to positive results from two of the four candidate drugs.

“When you have a result you think is of public health importance, you don’t wait for it to be published in a peer-reviewed journal,” said Dr. Lane, a coauthor of the study. The lag time from announcement to study publication was a result of the time it took to write up the paper for publication and go through peer review, Dr. Lane added. He also noted that the FDA had access to the data when the agency wrote its guidance for physicians administering the drug to patients under the EUA.

The authors opted not to publish the initial findings on a preprint server because they felt it was important to undergo peer review, said Dr. Lane. “The last thing you want for something this critical is for incomplete data to be out there, or you don’t have everything audited to the level that you want.”

 

Trial details

In the ACTT-1 randomized, placebo-controlled, double-blinded trial, researchers enrolled 1,063 patients from Feb. 21 to April 19, 2020, at 60 trial sites and 13 subsites worldwide (45 sites in the United States). The remdesivir group had 541 patients, and the placebo group had 522. A small number of patients (49 in the remdesivir group and 53 in the placebo group) discontinued treatment before day 10 because of an adverse event or withdrawn consent. When data collection for this preliminary analysis ended in late April, 301 patients had not recovered and had not completed their final follow-up visit.

Most of the patients had one (27%) or more (52.1%) preexisting conditions, including hypertension (49.6%), obesity (37%), and type 2 diabetes mellitus (29.7%). Mean patient age was 58.9 years, and the majority of patients were men (64.3%). The median number of days from symptom onset to randomization was 9, and 53.6% of the patients were white, 20.6% were black, 12.6% were Asian, 23.4% were Hispanic or Latino, and the ethnicity of 13.6% were not reported or reported as other.

Patients received one 200-mg loading dose on the first day of the trial, and then one 100-mg maintenance dose every day for days 2 through 10, or until discharge or death. Patients in the control group of the study received a matching placebo on the same schedule and volume. The clinical status of each patient was assessed every day, from day 1 through day 29 of his or her hospital stay, according to an eight-category ordinal scale.

Time to recovery was defined as the first day during the 28-day enrollment period that a patient’s clinical status met a 1 (not hospitalization, no activity limitations), 2 (not hospitalized, activity limitation, oxygen requirement or both), or 3 (hospitalized, not requiring supplemental oxygen or medical care if hospitalization was extended for infection-control reasons) on the eight-category scale. A score of 4 indicated a patient was hospitalized and needed ongoing medical care, but did not require supplemental oxygen; a score of 8 signified death.

The analysis found remdesivir patients had a median time to recovery of 11 days, compared with the median 15 days for patients on the placebo (rate ratio for recovery, 1.32; 95% confidence interval, 1.12-1.55; P < .001). Mortality was also lower in the remdesivir group (hazard ratio for death, 0.70; 95% CI, 0.47-1.04), but the result was not statistically significant. By 14 days, the Kaplan-Meier estimate of mortality was 7.1 % in the remdesivir group and 11.9% in the placebo group.

Patients receiving oxygen, but not yet requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation, seemed to fare best from treatment with remdesivir (these patients had a baseline ordinal score of 5). That may be a result of the larger sample size of these patients, the researchers note in the study. The study authors were unable to estimate the recovery time for the most severely ill patients (category 7), possibly because the follow-up time was too short to fully evaluate this subgroup.

“There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Dr. Kaul, who was not involved in the study, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.”

Dr. Kaul said there is still the possibility that remdesivir could benefit patients on mechanical ventilation, but “clinicians will have to determine if the evidence suggesting no benefit in those who are intubated is strong enough to justify using this currently scarce resource in that population versus limiting use to those requiring oxygen but not on mechanical ventilation.”

Site investigators estimated that just four serious adverse events (two in each group) in enrolled patients were related to remdesivir or placebo. No deaths were attributed to the treatments, although acute respiratory failure, hypotension, acute kidney injury, and viral pneumonia were slightly more common in patients receiving the placebo than those receiving remdesivir.

The researchers plan to publish a follow-up study in the coming weeks or months, after the full cohort has completed 28 days of follow-up, Dr. Lane said. In future studies, the agency will likely focus on comparing remdesivir with combinations of remdesivir with other treatments, like the anti-inflammatory baricitinib.

A version of this article originally appeared on Medscape.com.

Much-anticipated results from the National Institute of Allergy and Infectious Diseases’ clinical trial of remdesivir in COVID-19 patients published in the New England Journal of Medicine suggest remdesivir shortens the disease course for hospitalized COVID-19 patients.

The agency reported initial promising results from the study earlier this month, which prompted the Food and Drug Administration to issue an emergency use authorization (EUA) for the drug, but the full data and results have not been widely available until now.

In the study of 1,063 patients, the researchers found patients who received a 10-day course of remdesivir had a reduced recovery time of 11 days, compared with 15 days to recovery in the group that received a placebo. The findings also suggest remdesivir should be started, if possible, before patients have such severe pulmonary disease that they require mechanical ventilation, according to the study authors.

The published results are “completely consistent” with the NIAID’s earlier announcement, H. Clifford Lane, MD, deputy director for clinical research and special projects at the NIAID, said in an interview. “The benefit appeared to be the greatest for the patients who are hospitalized with severe disease who require supplemental oxygen.”

Given the limited supply of remdesivir, physicians have been eager to see the full data to ensure they use the drug most effectively, Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said in an interview. Hospitals in states across the country, including New York, Michigan, and Washington, have received limited supplies of the drug in the last couple of weeks since the FDA’s authorization.

“I am losing my patience waiting for #remdesivir data. I was willing to give them a week to verify the numbers, triple proof the tables, cautiously frame conclusions. But it’s gone on too long. We are rationing with no rationale. We are floating on whisps [sic] of data, adrift,” Kate Stephenson, MD, an infectious diseases specialist at the Center for Virology and Vaccine Research at Harvard Medical School, Boston, wrote on Twitter May 18. After reading the paper, she tweeted Friday evening that she was “relieved to see convincing benefit – I was starting to worry!”

In the midst of a public health crisis, however, it is not unusual to make an announcement about trial results before the full dataset has been analyzed, said Dr. Lane. The NIAID followed a similar playbook for the PALM trial evaluating possible Ebola treatments in the Democratic Republic of Congo, with the independent monitoring board recommending the trial be terminated early in response to positive results from two of the four candidate drugs.

“When you have a result you think is of public health importance, you don’t wait for it to be published in a peer-reviewed journal,” said Dr. Lane, a coauthor of the study. The lag time from announcement to study publication was a result of the time it took to write up the paper for publication and go through peer review, Dr. Lane added. He also noted that the FDA had access to the data when the agency wrote its guidance for physicians administering the drug to patients under the EUA.

The authors opted not to publish the initial findings on a preprint server because they felt it was important to undergo peer review, said Dr. Lane. “The last thing you want for something this critical is for incomplete data to be out there, or you don’t have everything audited to the level that you want.”

 

Trial details

In the ACTT-1 randomized, placebo-controlled, double-blinded trial, researchers enrolled 1,063 patients from Feb. 21 to April 19, 2020, at 60 trial sites and 13 subsites worldwide (45 sites in the United States). The remdesivir group had 541 patients, and the placebo group had 522. A small number of patients (49 in the remdesivir group and 53 in the placebo group) discontinued treatment before day 10 because of an adverse event or withdrawn consent. When data collection for this preliminary analysis ended in late April, 301 patients had not recovered and had not completed their final follow-up visit.

Most of the patients had one (27%) or more (52.1%) preexisting conditions, including hypertension (49.6%), obesity (37%), and type 2 diabetes mellitus (29.7%). Mean patient age was 58.9 years, and the majority of patients were men (64.3%). The median number of days from symptom onset to randomization was 9, and 53.6% of the patients were white, 20.6% were black, 12.6% were Asian, 23.4% were Hispanic or Latino, and the ethnicity of 13.6% were not reported or reported as other.

Patients received one 200-mg loading dose on the first day of the trial, and then one 100-mg maintenance dose every day for days 2 through 10, or until discharge or death. Patients in the control group of the study received a matching placebo on the same schedule and volume. The clinical status of each patient was assessed every day, from day 1 through day 29 of his or her hospital stay, according to an eight-category ordinal scale.

Time to recovery was defined as the first day during the 28-day enrollment period that a patient’s clinical status met a 1 (not hospitalization, no activity limitations), 2 (not hospitalized, activity limitation, oxygen requirement or both), or 3 (hospitalized, not requiring supplemental oxygen or medical care if hospitalization was extended for infection-control reasons) on the eight-category scale. A score of 4 indicated a patient was hospitalized and needed ongoing medical care, but did not require supplemental oxygen; a score of 8 signified death.

The analysis found remdesivir patients had a median time to recovery of 11 days, compared with the median 15 days for patients on the placebo (rate ratio for recovery, 1.32; 95% confidence interval, 1.12-1.55; P < .001). Mortality was also lower in the remdesivir group (hazard ratio for death, 0.70; 95% CI, 0.47-1.04), but the result was not statistically significant. By 14 days, the Kaplan-Meier estimate of mortality was 7.1 % in the remdesivir group and 11.9% in the placebo group.

Patients receiving oxygen, but not yet requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation, seemed to fare best from treatment with remdesivir (these patients had a baseline ordinal score of 5). That may be a result of the larger sample size of these patients, the researchers note in the study. The study authors were unable to estimate the recovery time for the most severely ill patients (category 7), possibly because the follow-up time was too short to fully evaluate this subgroup.

“There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Dr. Kaul, who was not involved in the study, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.”

Dr. Kaul said there is still the possibility that remdesivir could benefit patients on mechanical ventilation, but “clinicians will have to determine if the evidence suggesting no benefit in those who are intubated is strong enough to justify using this currently scarce resource in that population versus limiting use to those requiring oxygen but not on mechanical ventilation.”

Site investigators estimated that just four serious adverse events (two in each group) in enrolled patients were related to remdesivir or placebo. No deaths were attributed to the treatments, although acute respiratory failure, hypotension, acute kidney injury, and viral pneumonia were slightly more common in patients receiving the placebo than those receiving remdesivir.

The researchers plan to publish a follow-up study in the coming weeks or months, after the full cohort has completed 28 days of follow-up, Dr. Lane said. In future studies, the agency will likely focus on comparing remdesivir with combinations of remdesivir with other treatments, like the anti-inflammatory baricitinib.

A version of this article originally appeared on Medscape.com.

Much-anticipated results from the National Institute of Allergy and Infectious Diseases’ clinical trial of remdesivir in COVID-19 patients published in the New England Journal of Medicine suggest remdesivir shortens the disease course for hospitalized COVID-19 patients.

The agency reported initial promising results from the study earlier this month, which prompted the Food and Drug Administration to issue an emergency use authorization (EUA) for the drug, but the full data and results have not been widely available until now.

In the study of 1,063 patients, the researchers found patients who received a 10-day course of remdesivir had a reduced recovery time of 11 days, compared with 15 days to recovery in the group that received a placebo. The findings also suggest remdesivir should be started, if possible, before patients have such severe pulmonary disease that they require mechanical ventilation, according to the study authors.

The published results are “completely consistent” with the NIAID’s earlier announcement, H. Clifford Lane, MD, deputy director for clinical research and special projects at the NIAID, said in an interview. “The benefit appeared to be the greatest for the patients who are hospitalized with severe disease who require supplemental oxygen.”

Given the limited supply of remdesivir, physicians have been eager to see the full data to ensure they use the drug most effectively, Daniel Kaul, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, said in an interview. Hospitals in states across the country, including New York, Michigan, and Washington, have received limited supplies of the drug in the last couple of weeks since the FDA’s authorization.

“I am losing my patience waiting for #remdesivir data. I was willing to give them a week to verify the numbers, triple proof the tables, cautiously frame conclusions. But it’s gone on too long. We are rationing with no rationale. We are floating on whisps [sic] of data, adrift,” Kate Stephenson, MD, an infectious diseases specialist at the Center for Virology and Vaccine Research at Harvard Medical School, Boston, wrote on Twitter May 18. After reading the paper, she tweeted Friday evening that she was “relieved to see convincing benefit – I was starting to worry!”

In the midst of a public health crisis, however, it is not unusual to make an announcement about trial results before the full dataset has been analyzed, said Dr. Lane. The NIAID followed a similar playbook for the PALM trial evaluating possible Ebola treatments in the Democratic Republic of Congo, with the independent monitoring board recommending the trial be terminated early in response to positive results from two of the four candidate drugs.

“When you have a result you think is of public health importance, you don’t wait for it to be published in a peer-reviewed journal,” said Dr. Lane, a coauthor of the study. The lag time from announcement to study publication was a result of the time it took to write up the paper for publication and go through peer review, Dr. Lane added. He also noted that the FDA had access to the data when the agency wrote its guidance for physicians administering the drug to patients under the EUA.

The authors opted not to publish the initial findings on a preprint server because they felt it was important to undergo peer review, said Dr. Lane. “The last thing you want for something this critical is for incomplete data to be out there, or you don’t have everything audited to the level that you want.”

 

Trial details

In the ACTT-1 randomized, placebo-controlled, double-blinded trial, researchers enrolled 1,063 patients from Feb. 21 to April 19, 2020, at 60 trial sites and 13 subsites worldwide (45 sites in the United States). The remdesivir group had 541 patients, and the placebo group had 522. A small number of patients (49 in the remdesivir group and 53 in the placebo group) discontinued treatment before day 10 because of an adverse event or withdrawn consent. When data collection for this preliminary analysis ended in late April, 301 patients had not recovered and had not completed their final follow-up visit.

Most of the patients had one (27%) or more (52.1%) preexisting conditions, including hypertension (49.6%), obesity (37%), and type 2 diabetes mellitus (29.7%). Mean patient age was 58.9 years, and the majority of patients were men (64.3%). The median number of days from symptom onset to randomization was 9, and 53.6% of the patients were white, 20.6% were black, 12.6% were Asian, 23.4% were Hispanic or Latino, and the ethnicity of 13.6% were not reported or reported as other.

Patients received one 200-mg loading dose on the first day of the trial, and then one 100-mg maintenance dose every day for days 2 through 10, or until discharge or death. Patients in the control group of the study received a matching placebo on the same schedule and volume. The clinical status of each patient was assessed every day, from day 1 through day 29 of his or her hospital stay, according to an eight-category ordinal scale.

Time to recovery was defined as the first day during the 28-day enrollment period that a patient’s clinical status met a 1 (not hospitalization, no activity limitations), 2 (not hospitalized, activity limitation, oxygen requirement or both), or 3 (hospitalized, not requiring supplemental oxygen or medical care if hospitalization was extended for infection-control reasons) on the eight-category scale. A score of 4 indicated a patient was hospitalized and needed ongoing medical care, but did not require supplemental oxygen; a score of 8 signified death.

The analysis found remdesivir patients had a median time to recovery of 11 days, compared with the median 15 days for patients on the placebo (rate ratio for recovery, 1.32; 95% confidence interval, 1.12-1.55; P < .001). Mortality was also lower in the remdesivir group (hazard ratio for death, 0.70; 95% CI, 0.47-1.04), but the result was not statistically significant. By 14 days, the Kaplan-Meier estimate of mortality was 7.1 % in the remdesivir group and 11.9% in the placebo group.

Patients receiving oxygen, but not yet requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation, seemed to fare best from treatment with remdesivir (these patients had a baseline ordinal score of 5). That may be a result of the larger sample size of these patients, the researchers note in the study. The study authors were unable to estimate the recovery time for the most severely ill patients (category 7), possibly because the follow-up time was too short to fully evaluate this subgroup.

“There is clear and consistent evidence of clinically significant benefit for those hospitalized on oxygen but not yet requiring mechanical ventilation,” Dr. Kaul, who was not involved in the study, said after seeing the published results. “Surprisingly, early dosing as measured from time to onset of symptoms did not seem to make a difference.”

Dr. Kaul said there is still the possibility that remdesivir could benefit patients on mechanical ventilation, but “clinicians will have to determine if the evidence suggesting no benefit in those who are intubated is strong enough to justify using this currently scarce resource in that population versus limiting use to those requiring oxygen but not on mechanical ventilation.”

Site investigators estimated that just four serious adverse events (two in each group) in enrolled patients were related to remdesivir or placebo. No deaths were attributed to the treatments, although acute respiratory failure, hypotension, acute kidney injury, and viral pneumonia were slightly more common in patients receiving the placebo than those receiving remdesivir.

The researchers plan to publish a follow-up study in the coming weeks or months, after the full cohort has completed 28 days of follow-up, Dr. Lane said. In future studies, the agency will likely focus on comparing remdesivir with combinations of remdesivir with other treatments, like the anti-inflammatory baricitinib.

A version of this article originally appeared on Medscape.com.

Real epidemiologists are out knocking on doors, chasing down contacts, or hunched over their computers trying to make sense out of screens full of data and maps. A few are trying valiantly to talk some sense into our elected officials.

konradlew/Thinkstock

This leaves the rest of us with time on our hands to fabricate our own less-than-scientific explanations for the behavior of the SARS-CoV-2 virus. So I have decided to put on hold my current mental challenge of choosing which pasta shape to pair with the sauce I’ve prepared from an online recipe. Here is my educated guess based on what I can glean from media sources that may have been filtered through a variety politically biased lenses. Remember, I did go to medical school; however, when I was in college the DNA helix was still just theoretical.

From those halcyon days of mid-February when our attention was focused on the Diamond Princess quarantined in Yokohama Harbor, it didn’t take a board-certified epidemiologist to suspect that the virus was spreading through the ventilating system in the ship’s tight quarters. Subsequent outbreaks on U.S. and French military ships suggests a similar explanation.

While still not proven, it sounds like SARS-CoV-2 jumped to humans from bats. It should not surprise us that having evolved in a dense population of mammals it would thrive in other high-density populations such as New York and nursing homes. Because we have lacked a robust testing capability, it has been less obvious until recently that, while it is easily transmitted, the virus has infected many who are asymptomatic (“Antibody surveys suggesting vast undercount of coronavirus infections may be unreliable,” Gretchen Vogel, Science, April 21, 2020). Subsequent surveys seem to confirm this higher level carrier state; it suggests that the virus is far less deadly than was previously suggested. However, it seems to be a crafty little bug attacking just about any organ system it lands on.

I don’t think any of us are surprised that the elderly population with weakened immune systems, particularly those in congregate housing, has been much more vulnerable. However, many of the deaths among younger apparently healthy people have defied explanation. The anecdotal observations that physicians, particularly those who practice in-your-face medicine (e.g., ophthalmologists and otolaryngologists) may be more vulnerable raises the issue of viral load. It may be that, although it can be extremely contagious, the virus is not terribly dangerous for most people until the inoculum dose of the virus reaches a certain level. To my knowledge this dose is unknown.

A published survey of more than 300 outbreaks from 120 Chinese cities also may support my suspicion that viral load is of critical importance. The researchers found that all the “identified outbreaks of three or more cases occurred in an indoor environment, which confirms that sharing indoor space is a major SARS-CoV-2 infection risk” (Huan Qian et al. “Indoor transmission of SARS-CoV-2,” MedRxiv. 2020 Apr 7. doi: 10.1101/2020.04.04.20053058). Again, this data shouldn’t surprise us when we look back at what little we know about the outbreaks in the confined spaces on cruise ships and in nursing homes.

I’m not sure that we have any data that helps us determine whether wearing a mask in an outdoor space has any more than symbolic value when we are talking about this particular virus. We may read that the virus in a droplet can survive on the surface it lands on for 8 minutes, and we can see those slow motion videos of the impressive plume of snot spray released by a sneeze. It would seem obvious that even outside someone within 10 feet of the sneeze has a good chance of being infected. However, how much of a threat is the asymptomatic carrier who passes within three feet of you while you are out on lovely summer day stroll? This armchair epidemiologist suspects that, when we are talking about an outside space, the 6-foot guideline for small groups of a dozen or less is overly restrictive. But until we know, I’m staying put in my armchair ... outside on the porch overlooking Casco Bay.
 

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.” He has no disclosures. Email him at [email protected].

Real epidemiologists are out knocking on doors, chasing down contacts, or hunched over their computers trying to make sense out of screens full of data and maps. A few are trying valiantly to talk some sense into our elected officials.

konradlew/Thinkstock

This leaves the rest of us with time on our hands to fabricate our own less-than-scientific explanations for the behavior of the SARS-CoV-2 virus. So I have decided to put on hold my current mental challenge of choosing which pasta shape to pair with the sauce I’ve prepared from an online recipe. Here is my educated guess based on what I can glean from media sources that may have been filtered through a variety politically biased lenses. Remember, I did go to medical school; however, when I was in college the DNA helix was still just theoretical.

From those halcyon days of mid-February when our attention was focused on the Diamond Princess quarantined in Yokohama Harbor, it didn’t take a board-certified epidemiologist to suspect that the virus was spreading through the ventilating system in the ship’s tight quarters. Subsequent outbreaks on U.S. and French military ships suggests a similar explanation.

While still not proven, it sounds like SARS-CoV-2 jumped to humans from bats. It should not surprise us that having evolved in a dense population of mammals it would thrive in other high-density populations such as New York and nursing homes. Because we have lacked a robust testing capability, it has been less obvious until recently that, while it is easily transmitted, the virus has infected many who are asymptomatic (“Antibody surveys suggesting vast undercount of coronavirus infections may be unreliable,” Gretchen Vogel, Science, April 21, 2020). Subsequent surveys seem to confirm this higher level carrier state; it suggests that the virus is far less deadly than was previously suggested. However, it seems to be a crafty little bug attacking just about any organ system it lands on.

I don’t think any of us are surprised that the elderly population with weakened immune systems, particularly those in congregate housing, has been much more vulnerable. However, many of the deaths among younger apparently healthy people have defied explanation. The anecdotal observations that physicians, particularly those who practice in-your-face medicine (e.g., ophthalmologists and otolaryngologists) may be more vulnerable raises the issue of viral load. It may be that, although it can be extremely contagious, the virus is not terribly dangerous for most people until the inoculum dose of the virus reaches a certain level. To my knowledge this dose is unknown.

A published survey of more than 300 outbreaks from 120 Chinese cities also may support my suspicion that viral load is of critical importance. The researchers found that all the “identified outbreaks of three or more cases occurred in an indoor environment, which confirms that sharing indoor space is a major SARS-CoV-2 infection risk” (Huan Qian et al. “Indoor transmission of SARS-CoV-2,” MedRxiv. 2020 Apr 7. doi: 10.1101/2020.04.04.20053058). Again, this data shouldn’t surprise us when we look back at what little we know about the outbreaks in the confined spaces on cruise ships and in nursing homes.

I’m not sure that we have any data that helps us determine whether wearing a mask in an outdoor space has any more than symbolic value when we are talking about this particular virus. We may read that the virus in a droplet can survive on the surface it lands on for 8 minutes, and we can see those slow motion videos of the impressive plume of snot spray released by a sneeze. It would seem obvious that even outside someone within 10 feet of the sneeze has a good chance of being infected. However, how much of a threat is the asymptomatic carrier who passes within three feet of you while you are out on lovely summer day stroll? This armchair epidemiologist suspects that, when we are talking about an outside space, the 6-foot guideline for small groups of a dozen or less is overly restrictive. But until we know, I’m staying put in my armchair ... outside on the porch overlooking Casco Bay.
 

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.” He has no disclosures. Email him at [email protected].

Real epidemiologists are out knocking on doors, chasing down contacts, or hunched over their computers trying to make sense out of screens full of data and maps. A few are trying valiantly to talk some sense into our elected officials.

konradlew/Thinkstock

This leaves the rest of us with time on our hands to fabricate our own less-than-scientific explanations for the behavior of the SARS-CoV-2 virus. So I have decided to put on hold my current mental challenge of choosing which pasta shape to pair with the sauce I’ve prepared from an online recipe. Here is my educated guess based on what I can glean from media sources that may have been filtered through a variety politically biased lenses. Remember, I did go to medical school; however, when I was in college the DNA helix was still just theoretical.

From those halcyon days of mid-February when our attention was focused on the Diamond Princess quarantined in Yokohama Harbor, it didn’t take a board-certified epidemiologist to suspect that the virus was spreading through the ventilating system in the ship’s tight quarters. Subsequent outbreaks on U.S. and French military ships suggests a similar explanation.

While still not proven, it sounds like SARS-CoV-2 jumped to humans from bats. It should not surprise us that having evolved in a dense population of mammals it would thrive in other high-density populations such as New York and nursing homes. Because we have lacked a robust testing capability, it has been less obvious until recently that, while it is easily transmitted, the virus has infected many who are asymptomatic (“Antibody surveys suggesting vast undercount of coronavirus infections may be unreliable,” Gretchen Vogel, Science, April 21, 2020). Subsequent surveys seem to confirm this higher level carrier state; it suggests that the virus is far less deadly than was previously suggested. However, it seems to be a crafty little bug attacking just about any organ system it lands on.

I don’t think any of us are surprised that the elderly population with weakened immune systems, particularly those in congregate housing, has been much more vulnerable. However, many of the deaths among younger apparently healthy people have defied explanation. The anecdotal observations that physicians, particularly those who practice in-your-face medicine (e.g., ophthalmologists and otolaryngologists) may be more vulnerable raises the issue of viral load. It may be that, although it can be extremely contagious, the virus is not terribly dangerous for most people until the inoculum dose of the virus reaches a certain level. To my knowledge this dose is unknown.

A published survey of more than 300 outbreaks from 120 Chinese cities also may support my suspicion that viral load is of critical importance. The researchers found that all the “identified outbreaks of three or more cases occurred in an indoor environment, which confirms that sharing indoor space is a major SARS-CoV-2 infection risk” (Huan Qian et al. “Indoor transmission of SARS-CoV-2,” MedRxiv. 2020 Apr 7. doi: 10.1101/2020.04.04.20053058). Again, this data shouldn’t surprise us when we look back at what little we know about the outbreaks in the confined spaces on cruise ships and in nursing homes.

I’m not sure that we have any data that helps us determine whether wearing a mask in an outdoor space has any more than symbolic value when we are talking about this particular virus. We may read that the virus in a droplet can survive on the surface it lands on for 8 minutes, and we can see those slow motion videos of the impressive plume of snot spray released by a sneeze. It would seem obvious that even outside someone within 10 feet of the sneeze has a good chance of being infected. However, how much of a threat is the asymptomatic carrier who passes within three feet of you while you are out on lovely summer day stroll? This armchair epidemiologist suspects that, when we are talking about an outside space, the 6-foot guideline for small groups of a dozen or less is overly restrictive. But until we know, I’m staying put in my armchair ... outside on the porch overlooking Casco Bay.
 

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.” He has no disclosures. Email him at [email protected].

The direct oral anticoagulant (DOAC) drugs apixaban, dabigatran, and rivaroxaban are associated with a lower risk of osteoporotic fracture than is warfarin in patients with atrial fibrillation (AFib), according to a new retrospective analysis.

There was no difference in risk between individual DOAC medications.

The study drew from an EHR database of the Hong Kong Hospital Authority. It was led by Wallis C.Y. Lau, PhD, of the University of Hong Kong and appeared online May 19 in Annals of Internal Medicine.

Warfarin is suspected to contribute to osteoporotic fracturing in AFib patients, but previous studies returned mixed results. The more recently introduced DOACs were not tested for fracture risks, and it hasn’t been determined if individual DOACs have different risks. The question is even more important in AFib, in which patients are older and often have comorbidities that could predispose them to fractures.

The study included 23,515 patients with AFib who used anticoagulants. 3,241 used apixaban, 6,867 dabigatran, 3,866 rivaroxaban, and 9,541 used warfarin. The median follow-up was 423 days.

According to Cox proportional hazards model analyses, DOAC use was associated with fewer fractures than was warfarin (hazard ratio for apixaban vs. warfarin, 0.62; 95% confidence interval, 0.41-0.94; HR for dabigatran, 0.65; 95% CI, 0.49-0.86; HR for rivaroxaban, 0.52; 95% CI, 0.37-0.73). Subanalyses in men and women showed similar results (P for interaction >.05).

Head-to-head comparisons between individual DOACs yielded no statistically significant differences in osteoporotic fracture risk.

Although the findings couldn’t absolutely rule out a difference in osteoporotic fracture risk between different DOACs, the authors argue that any clinical significance would likely be small.

“Given the supportive evidence from experimental settings, findings from our study using clinical data, and the indirect evidence provided by the previous meta-analysis of randomized, controlled trials, there exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” the authors wrote.

The study is limited by the potential for residual confounding, the investigators noted.

The study was funded by the University of Hong Kong and University College London Strategic Partnership Fund.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 19. doi: 10.7326/M19-3671.

The direct oral anticoagulant (DOAC) drugs apixaban, dabigatran, and rivaroxaban are associated with a lower risk of osteoporotic fracture than is warfarin in patients with atrial fibrillation (AFib), according to a new retrospective analysis.

There was no difference in risk between individual DOAC medications.

The study drew from an EHR database of the Hong Kong Hospital Authority. It was led by Wallis C.Y. Lau, PhD, of the University of Hong Kong and appeared online May 19 in Annals of Internal Medicine.

Warfarin is suspected to contribute to osteoporotic fracturing in AFib patients, but previous studies returned mixed results. The more recently introduced DOACs were not tested for fracture risks, and it hasn’t been determined if individual DOACs have different risks. The question is even more important in AFib, in which patients are older and often have comorbidities that could predispose them to fractures.

The study included 23,515 patients with AFib who used anticoagulants. 3,241 used apixaban, 6,867 dabigatran, 3,866 rivaroxaban, and 9,541 used warfarin. The median follow-up was 423 days.

According to Cox proportional hazards model analyses, DOAC use was associated with fewer fractures than was warfarin (hazard ratio for apixaban vs. warfarin, 0.62; 95% confidence interval, 0.41-0.94; HR for dabigatran, 0.65; 95% CI, 0.49-0.86; HR for rivaroxaban, 0.52; 95% CI, 0.37-0.73). Subanalyses in men and women showed similar results (P for interaction >.05).

Head-to-head comparisons between individual DOACs yielded no statistically significant differences in osteoporotic fracture risk.

Although the findings couldn’t absolutely rule out a difference in osteoporotic fracture risk between different DOACs, the authors argue that any clinical significance would likely be small.

“Given the supportive evidence from experimental settings, findings from our study using clinical data, and the indirect evidence provided by the previous meta-analysis of randomized, controlled trials, there exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” the authors wrote.

The study is limited by the potential for residual confounding, the investigators noted.

The study was funded by the University of Hong Kong and University College London Strategic Partnership Fund.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 19. doi: 10.7326/M19-3671.

The direct oral anticoagulant (DOAC) drugs apixaban, dabigatran, and rivaroxaban are associated with a lower risk of osteoporotic fracture than is warfarin in patients with atrial fibrillation (AFib), according to a new retrospective analysis.

There was no difference in risk between individual DOAC medications.

The study drew from an EHR database of the Hong Kong Hospital Authority. It was led by Wallis C.Y. Lau, PhD, of the University of Hong Kong and appeared online May 19 in Annals of Internal Medicine.

Warfarin is suspected to contribute to osteoporotic fracturing in AFib patients, but previous studies returned mixed results. The more recently introduced DOACs were not tested for fracture risks, and it hasn’t been determined if individual DOACs have different risks. The question is even more important in AFib, in which patients are older and often have comorbidities that could predispose them to fractures.

The study included 23,515 patients with AFib who used anticoagulants. 3,241 used apixaban, 6,867 dabigatran, 3,866 rivaroxaban, and 9,541 used warfarin. The median follow-up was 423 days.

According to Cox proportional hazards model analyses, DOAC use was associated with fewer fractures than was warfarin (hazard ratio for apixaban vs. warfarin, 0.62; 95% confidence interval, 0.41-0.94; HR for dabigatran, 0.65; 95% CI, 0.49-0.86; HR for rivaroxaban, 0.52; 95% CI, 0.37-0.73). Subanalyses in men and women showed similar results (P for interaction >.05).

Head-to-head comparisons between individual DOACs yielded no statistically significant differences in osteoporotic fracture risk.

Although the findings couldn’t absolutely rule out a difference in osteoporotic fracture risk between different DOACs, the authors argue that any clinical significance would likely be small.

“Given the supportive evidence from experimental settings, findings from our study using clinical data, and the indirect evidence provided by the previous meta-analysis of randomized, controlled trials, there exists a compelling case for evaluating whether the risk for osteoporotic fractures should be considered at the point of prescribing an oral anticoagulant to minimize fracture risk,” the authors wrote.

The study is limited by the potential for residual confounding, the investigators noted.

The study was funded by the University of Hong Kong and University College London Strategic Partnership Fund.

SOURCE: Lau WCY et al. Ann Intern Med. 2020 May 19. doi: 10.7326/M19-3671.

Keeping hematologic oncology patients on their treatment regimens and caring for inpatients with hematologic malignancies remained “manageable” during the first 2 months of the COVID-19 pandemic at Levine Cancer Institute in Charlotte, N.C.

That level of manageability has partly been because a surge in cases so far hasn’t arrived at Levine or in most of the surrounding North Carolina and South Carolina communities it serves. As of May 15, 2020, the total number of confirmed and reported COVID-19 cases had reached about 19,000 in North Carolina, and just under 9,000 in South Carolina, out of a total population in the two states of close to 16 million. What’s happened instead at Levine Cancer Institute (LCI) has been a steady but low drumbeat of cases that, by mid-May 2020, totaled fewer than 10 patients with hematologic malignancies diagnosed with COVID-19.

“For a large system with multiple sites throughout North and South Carolina that saw 17,200 new patients in 2019 – including solid tumor, benign hematology, and malignant hematology patients – with 198,000 total patient visits, it is safe to say that we are off to a good start. However, we remain in the early throes of the pandemic and we will need to remain vigilant going forward,” said Peter Voorhees, MD, professor of medicine and director of Medical Operations and Outreach Services in LCI’s Department of Hematologic Oncology and Blood Disorders.

The limited effects to date of COVID-19 at LCI has been thanks to a regimen of great caution for preventing infections that’s been consistently conveyed to LCI patients from before the pandemic’s onset, liberal testing that started early, a proactive plan to defer and temporarily replace infusion care when medically appropriate, a novel staffing approach designed to minimize and contain potential staff outbreaks, and an early pivot to virtual patient contact when feasible.

COVID-19 has had limited penetration into the LCI case load because patients have, in general, “been very careful,” said Dr. Voorhees.

“My impression is that the incidence has been low partly because our patients, especially those with hematologic malignancies including those on active chemotherapy, were already getting warned to be cautious even before the coronavirus using distancing, masking, and meticulous hand hygiene,” he said in an interview that reviewed the steps LCI took starting in March to confront and manage the effects of the then-nascent pandemic. “Since we started screening asymptomatic patients in the inpatient and outpatient settings we have identified only one patient with COVID-19 infection, which supports the low rate of infection in our patient population thus far.”

Another key step was the launch of “robust” testing for the COVID-19 virus starting on March 9, using an in-house assay from LCI’s parent health system, Atrium Health, that delivered results within 24 hours. Testing became available at LCI “earlier than at many other health systems.” At first, testing was limited to patients or staff presenting with symptoms, but in the following weeks, it expanded to more patients, including those without symptoms who were scheduled for treatment at the apheresis center, cell donors and cell recipients, patients arriving for inpatient chemotherapy or cellular therapy, patients arriving from a skilled nursing facility or similar environments, and more recently, outpatient chemotherapy patients. “We’re now doing a lot of screening,” Dr. Voorhees said. “In general, screening has been well received because patients recognize that it’s for their own safety.”

Another piece of COVID-19 preparedness was a move toward technology as an alternative to face-to-face encounters between patients and staff. “We adopted virtual technology early.” When medically appropriate, they provided either video consultations with more tech-savvy patients or telephone-based virtual visits for patients who preferred a more familiar interface. As LCI starts the process of reentry for patients whose face-to-face encounters were deferred, virtual visits will remain an important facet of maintaining care while limiting exposure for appropriate patients and facilitating adequate space for social distancing in the clinics and infusion centers.

Atrium Health also launched a “virtual hospital” geared to intensified remote management of COVID-19 patients who aren’t sick enough for hospitalization. “People who test positive automatically enter the virtual hospital and have regular interactions with their team of providers,” with LCI providing additional support for their patients who get infected. Patients receive an equipment kit that lets them monitor and transmit their vital signs. The virtual hospital program also helps expedite personal needs like delivery of prescriptions and food. “It helps patients manage at home, and has been incredibly useful,” said Dr. Voorhees.

Perhaps the most challenging step LCI clinicians took to preclude a potential COVID-19 case surge was to review all patients receiving infusional therapy or planned cellular therapy and triage those who could potentially tolerate a temporary change to either an oral, at-home regimen or to a brief hold on their treatment. Some patients on maintenance, outpatient infusion-therapy regimens “expressed concern about coming to the clinic. We looked at the patients scheduled to come for infusions and decided which visits were essential and which were deferrable without disrupting care by briefly using a noninfusional approach,” said Dr. Voorhees. The number of patients who had their regimens modified or held was “relatively small,” and with the recent recognition that a surge of infections has not occurred, “we’re now rolling out cautious reentry of those patients back to their originally prescribed chemotherapy.”

In addition to concerns of exposure at infusion clinics, there are concerns about the heightened susceptibility of immunosuppressed hematologic oncology patients to COVID-19 and their risk for more severe infection. “Our view is that, if patients tested positive, continuing immunosuppressive treatment would likely be detrimental,” so when possible treatment is temporarily suspended and then resumed when the infection has cleared. “When patients test positive for a prolonged period, a decision to resume treatment must be in the best interests of the patient and weigh the benefits of resuming therapy against the risks of incurring a more severe infection by restarting potentially immunosuppressive therapy,” Dr. Voorhees said.

The enhanced risk that cancer patients face if they develop COVID-19 was documented in a recent review of 218 cancer patients hospitalized for COVID-19 during parts of March and April in a large New York health system. The results showed an overall mortality rate of 28%, including a 37% rate among 54 patients with hematologic malignancies and a 25% rate among 164 patients with solid tumors. The mortality rate “may not be quite as high as they reported because that depends on how many patients you test, but there is no question that patients with more comorbidities are at higher risk. Patients with active cancer on chemotherapy are a particularly vulnerable population, and many have expressed concerns about their vulnerability,” he observed.

For the few LCI patients who developed COVID-19 infection, the medical staff has had several therapeutic options they could match to each patient’s needs, with help from the Atrium Health infectious disease team. LCI and Atrium Health are participating in several COVID-19 clinical treatment trials, including an investigational convalescent plasma protocol spearheaded by the Mayo Clinic. They have also opened a randomized, phase 2 trial evaluating the safety and efficacy of selinexor (Xpovio), an oral drug that’s Food and Drug Administration approved for patients with multiple myeloma, for treatment of moderate or severe COVID-19 infection. Additional studies evaluating blockade of granulocyte-macrophage colony-stimulating factor, as well as inhaled antiviral therapy, have recently launched, and several additional studies are poised to open in the coming weeks.

The LCI and Atrium Health team also has a supply of the antiviral agent remdesivir as part of the FDA’s expanded access protocol and emergency use authorization. They also have a supply of and experience administering the interleukin-6 receptor inhibitor tocilizumab (Actemra), which showed some suggestion of efficacy in limited experience treating patients with severe or critical COVID-19 infections (Proc Natl Acad Sci. 2020 Apr 29; doi: 10.1073/pnas.2005615117). Clinicians at LCI have not used the investigational and unproven agents hydroxychloroquine, chloroquine, and azithromycin to either prevent or treat COVID-19.

LCI also instituted measures to try to minimize the risk that staff members could become infected and transmit the virus while asymptomatic. Following conversations held early on with COVID-19–experienced health authorities in China and Italy, the patient-facing LCI staff split into two teams starting on March 23 that alternated responsibility for direct patient interactions every 2 weeks. When one of these teams was off from direct patient contact they continued to care for patients remotely through virtual technologies. The concept was that, if a staffer became infected while remaining asymptomatic during their contact with patients, their status would either become diagnosable or resolve during their 2 weeks away from seeing any patients. Perhaps in part because of this approach infections among staff members “have not been a big issue. We’ve had an incredibly low infection rate among the LCI staff,” Dr. Voorhees noted.

By mid-May, with the imminent threat of a sudden CODIV-19 surge moderated, heme-onc operations at LCI began to cautiously revert to more normal operations. “We’re continuing patient screening for signs and symptoms of COVID-19 infection, testing for asymptomatic infections, and requiring masking and social distancing in the clinics and hospitals, but we’re starting to slowly restore the number of patients at our clinics [virtual and face to face[ and infusion centers,” and the staff’s division into two teams ended. “The idea was to get past a surge and make sure our system was not overwhelmed. We anticipated a local surge in late April, but then it kept getting pushed back. Current projections are for the infection rate among LCI patients to remain low provided that community spread remains stable or, ideally, decreases.” The LCI infectious disease staff is closely monitoring infection rates for early recognition of an outbreak, with plans to follow any new cases with contact tracing. So far, the COVID-19 pandemic at LCI “has been very manageable,” Dr. Voorhees concluded.

“We’re now better positioned to deal with a case surge if it were to happen. We could resume the two-team approach, hospital-wide plans are now in place for a future surge, and we are now up and running with robust testing and inpatient and outpatient virtual technology. The first time, we were all learning on the fly.”

The LCI biostatistics team has been prospectively collecting the Institutes’s COVID-19 patient data, with plans to report their findings.

Dr. Voorhees has had financial relationships with Bristol-Myers Squibb/Celgene, Janssen, Novartis, and Oncopeptides, none of which are relevant to this article.

[email protected]

Keeping hematologic oncology patients on their treatment regimens and caring for inpatients with hematologic malignancies remained “manageable” during the first 2 months of the COVID-19 pandemic at Levine Cancer Institute in Charlotte, N.C.

That level of manageability has partly been because a surge in cases so far hasn’t arrived at Levine or in most of the surrounding North Carolina and South Carolina communities it serves. As of May 15, 2020, the total number of confirmed and reported COVID-19 cases had reached about 19,000 in North Carolina, and just under 9,000 in South Carolina, out of a total population in the two states of close to 16 million. What’s happened instead at Levine Cancer Institute (LCI) has been a steady but low drumbeat of cases that, by mid-May 2020, totaled fewer than 10 patients with hematologic malignancies diagnosed with COVID-19.

“For a large system with multiple sites throughout North and South Carolina that saw 17,200 new patients in 2019 – including solid tumor, benign hematology, and malignant hematology patients – with 198,000 total patient visits, it is safe to say that we are off to a good start. However, we remain in the early throes of the pandemic and we will need to remain vigilant going forward,” said Peter Voorhees, MD, professor of medicine and director of Medical Operations and Outreach Services in LCI’s Department of Hematologic Oncology and Blood Disorders.

The limited effects to date of COVID-19 at LCI has been thanks to a regimen of great caution for preventing infections that’s been consistently conveyed to LCI patients from before the pandemic’s onset, liberal testing that started early, a proactive plan to defer and temporarily replace infusion care when medically appropriate, a novel staffing approach designed to minimize and contain potential staff outbreaks, and an early pivot to virtual patient contact when feasible.

COVID-19 has had limited penetration into the LCI case load because patients have, in general, “been very careful,” said Dr. Voorhees.

“My impression is that the incidence has been low partly because our patients, especially those with hematologic malignancies including those on active chemotherapy, were already getting warned to be cautious even before the coronavirus using distancing, masking, and meticulous hand hygiene,” he said in an interview that reviewed the steps LCI took starting in March to confront and manage the effects of the then-nascent pandemic. “Since we started screening asymptomatic patients in the inpatient and outpatient settings we have identified only one patient with COVID-19 infection, which supports the low rate of infection in our patient population thus far.”

Another key step was the launch of “robust” testing for the COVID-19 virus starting on March 9, using an in-house assay from LCI’s parent health system, Atrium Health, that delivered results within 24 hours. Testing became available at LCI “earlier than at many other health systems.” At first, testing was limited to patients or staff presenting with symptoms, but in the following weeks, it expanded to more patients, including those without symptoms who were scheduled for treatment at the apheresis center, cell donors and cell recipients, patients arriving for inpatient chemotherapy or cellular therapy, patients arriving from a skilled nursing facility or similar environments, and more recently, outpatient chemotherapy patients. “We’re now doing a lot of screening,” Dr. Voorhees said. “In general, screening has been well received because patients recognize that it’s for their own safety.”

Another piece of COVID-19 preparedness was a move toward technology as an alternative to face-to-face encounters between patients and staff. “We adopted virtual technology early.” When medically appropriate, they provided either video consultations with more tech-savvy patients or telephone-based virtual visits for patients who preferred a more familiar interface. As LCI starts the process of reentry for patients whose face-to-face encounters were deferred, virtual visits will remain an important facet of maintaining care while limiting exposure for appropriate patients and facilitating adequate space for social distancing in the clinics and infusion centers.

Atrium Health also launched a “virtual hospital” geared to intensified remote management of COVID-19 patients who aren’t sick enough for hospitalization. “People who test positive automatically enter the virtual hospital and have regular interactions with their team of providers,” with LCI providing additional support for their patients who get infected. Patients receive an equipment kit that lets them monitor and transmit their vital signs. The virtual hospital program also helps expedite personal needs like delivery of prescriptions and food. “It helps patients manage at home, and has been incredibly useful,” said Dr. Voorhees.

Perhaps the most challenging step LCI clinicians took to preclude a potential COVID-19 case surge was to review all patients receiving infusional therapy or planned cellular therapy and triage those who could potentially tolerate a temporary change to either an oral, at-home regimen or to a brief hold on their treatment. Some patients on maintenance, outpatient infusion-therapy regimens “expressed concern about coming to the clinic. We looked at the patients scheduled to come for infusions and decided which visits were essential and which were deferrable without disrupting care by briefly using a noninfusional approach,” said Dr. Voorhees. The number of patients who had their regimens modified or held was “relatively small,” and with the recent recognition that a surge of infections has not occurred, “we’re now rolling out cautious reentry of those patients back to their originally prescribed chemotherapy.”

In addition to concerns of exposure at infusion clinics, there are concerns about the heightened susceptibility of immunosuppressed hematologic oncology patients to COVID-19 and their risk for more severe infection. “Our view is that, if patients tested positive, continuing immunosuppressive treatment would likely be detrimental,” so when possible treatment is temporarily suspended and then resumed when the infection has cleared. “When patients test positive for a prolonged period, a decision to resume treatment must be in the best interests of the patient and weigh the benefits of resuming therapy against the risks of incurring a more severe infection by restarting potentially immunosuppressive therapy,” Dr. Voorhees said.

The enhanced risk that cancer patients face if they develop COVID-19 was documented in a recent review of 218 cancer patients hospitalized for COVID-19 during parts of March and April in a large New York health system. The results showed an overall mortality rate of 28%, including a 37% rate among 54 patients with hematologic malignancies and a 25% rate among 164 patients with solid tumors. The mortality rate “may not be quite as high as they reported because that depends on how many patients you test, but there is no question that patients with more comorbidities are at higher risk. Patients with active cancer on chemotherapy are a particularly vulnerable population, and many have expressed concerns about their vulnerability,” he observed.

For the few LCI patients who developed COVID-19 infection, the medical staff has had several therapeutic options they could match to each patient’s needs, with help from the Atrium Health infectious disease team. LCI and Atrium Health are participating in several COVID-19 clinical treatment trials, including an investigational convalescent plasma protocol spearheaded by the Mayo Clinic. They have also opened a randomized, phase 2 trial evaluating the safety and efficacy of selinexor (Xpovio), an oral drug that’s Food and Drug Administration approved for patients with multiple myeloma, for treatment of moderate or severe COVID-19 infection. Additional studies evaluating blockade of granulocyte-macrophage colony-stimulating factor, as well as inhaled antiviral therapy, have recently launched, and several additional studies are poised to open in the coming weeks.

The LCI and Atrium Health team also has a supply of the antiviral agent remdesivir as part of the FDA’s expanded access protocol and emergency use authorization. They also have a supply of and experience administering the interleukin-6 receptor inhibitor tocilizumab (Actemra), which showed some suggestion of efficacy in limited experience treating patients with severe or critical COVID-19 infections (Proc Natl Acad Sci. 2020 Apr 29; doi: 10.1073/pnas.2005615117). Clinicians at LCI have not used the investigational and unproven agents hydroxychloroquine, chloroquine, and azithromycin to either prevent or treat COVID-19.

LCI also instituted measures to try to minimize the risk that staff members could become infected and transmit the virus while asymptomatic. Following conversations held early on with COVID-19–experienced health authorities in China and Italy, the patient-facing LCI staff split into two teams starting on March 23 that alternated responsibility for direct patient interactions every 2 weeks. When one of these teams was off from direct patient contact they continued to care for patients remotely through virtual technologies. The concept was that, if a staffer became infected while remaining asymptomatic during their contact with patients, their status would either become diagnosable or resolve during their 2 weeks away from seeing any patients. Perhaps in part because of this approach infections among staff members “have not been a big issue. We’ve had an incredibly low infection rate among the LCI staff,” Dr. Voorhees noted.

By mid-May, with the imminent threat of a sudden CODIV-19 surge moderated, heme-onc operations at LCI began to cautiously revert to more normal operations. “We’re continuing patient screening for signs and symptoms of COVID-19 infection, testing for asymptomatic infections, and requiring masking and social distancing in the clinics and hospitals, but we’re starting to slowly restore the number of patients at our clinics [virtual and face to face[ and infusion centers,” and the staff’s division into two teams ended. “The idea was to get past a surge and make sure our system was not overwhelmed. We anticipated a local surge in late April, but then it kept getting pushed back. Current projections are for the infection rate among LCI patients to remain low provided that community spread remains stable or, ideally, decreases.” The LCI infectious disease staff is closely monitoring infection rates for early recognition of an outbreak, with plans to follow any new cases with contact tracing. So far, the COVID-19 pandemic at LCI “has been very manageable,” Dr. Voorhees concluded.

“We’re now better positioned to deal with a case surge if it were to happen. We could resume the two-team approach, hospital-wide plans are now in place for a future surge, and we are now up and running with robust testing and inpatient and outpatient virtual technology. The first time, we were all learning on the fly.”

The LCI biostatistics team has been prospectively collecting the Institutes’s COVID-19 patient data, with plans to report their findings.

Dr. Voorhees has had financial relationships with Bristol-Myers Squibb/Celgene, Janssen, Novartis, and Oncopeptides, none of which are relevant to this article.

[email protected]

Keeping hematologic oncology patients on their treatment regimens and caring for inpatients with hematologic malignancies remained “manageable” during the first 2 months of the COVID-19 pandemic at Levine Cancer Institute in Charlotte, N.C.

That level of manageability has partly been because a surge in cases so far hasn’t arrived at Levine or in most of the surrounding North Carolina and South Carolina communities it serves. As of May 15, 2020, the total number of confirmed and reported COVID-19 cases had reached about 19,000 in North Carolina, and just under 9,000 in South Carolina, out of a total population in the two states of close to 16 million. What’s happened instead at Levine Cancer Institute (LCI) has been a steady but low drumbeat of cases that, by mid-May 2020, totaled fewer than 10 patients with hematologic malignancies diagnosed with COVID-19.

“For a large system with multiple sites throughout North and South Carolina that saw 17,200 new patients in 2019 – including solid tumor, benign hematology, and malignant hematology patients – with 198,000 total patient visits, it is safe to say that we are off to a good start. However, we remain in the early throes of the pandemic and we will need to remain vigilant going forward,” said Peter Voorhees, MD, professor of medicine and director of Medical Operations and Outreach Services in LCI’s Department of Hematologic Oncology and Blood Disorders.

The limited effects to date of COVID-19 at LCI has been thanks to a regimen of great caution for preventing infections that’s been consistently conveyed to LCI patients from before the pandemic’s onset, liberal testing that started early, a proactive plan to defer and temporarily replace infusion care when medically appropriate, a novel staffing approach designed to minimize and contain potential staff outbreaks, and an early pivot to virtual patient contact when feasible.

COVID-19 has had limited penetration into the LCI case load because patients have, in general, “been very careful,” said Dr. Voorhees.

“My impression is that the incidence has been low partly because our patients, especially those with hematologic malignancies including those on active chemotherapy, were already getting warned to be cautious even before the coronavirus using distancing, masking, and meticulous hand hygiene,” he said in an interview that reviewed the steps LCI took starting in March to confront and manage the effects of the then-nascent pandemic. “Since we started screening asymptomatic patients in the inpatient and outpatient settings we have identified only one patient with COVID-19 infection, which supports the low rate of infection in our patient population thus far.”

Another key step was the launch of “robust” testing for the COVID-19 virus starting on March 9, using an in-house assay from LCI’s parent health system, Atrium Health, that delivered results within 24 hours. Testing became available at LCI “earlier than at many other health systems.” At first, testing was limited to patients or staff presenting with symptoms, but in the following weeks, it expanded to more patients, including those without symptoms who were scheduled for treatment at the apheresis center, cell donors and cell recipients, patients arriving for inpatient chemotherapy or cellular therapy, patients arriving from a skilled nursing facility or similar environments, and more recently, outpatient chemotherapy patients. “We’re now doing a lot of screening,” Dr. Voorhees said. “In general, screening has been well received because patients recognize that it’s for their own safety.”

Another piece of COVID-19 preparedness was a move toward technology as an alternative to face-to-face encounters between patients and staff. “We adopted virtual technology early.” When medically appropriate, they provided either video consultations with more tech-savvy patients or telephone-based virtual visits for patients who preferred a more familiar interface. As LCI starts the process of reentry for patients whose face-to-face encounters were deferred, virtual visits will remain an important facet of maintaining care while limiting exposure for appropriate patients and facilitating adequate space for social distancing in the clinics and infusion centers.

Atrium Health also launched a “virtual hospital” geared to intensified remote management of COVID-19 patients who aren’t sick enough for hospitalization. “People who test positive automatically enter the virtual hospital and have regular interactions with their team of providers,” with LCI providing additional support for their patients who get infected. Patients receive an equipment kit that lets them monitor and transmit their vital signs. The virtual hospital program also helps expedite personal needs like delivery of prescriptions and food. “It helps patients manage at home, and has been incredibly useful,” said Dr. Voorhees.

Perhaps the most challenging step LCI clinicians took to preclude a potential COVID-19 case surge was to review all patients receiving infusional therapy or planned cellular therapy and triage those who could potentially tolerate a temporary change to either an oral, at-home regimen or to a brief hold on their treatment. Some patients on maintenance, outpatient infusion-therapy regimens “expressed concern about coming to the clinic. We looked at the patients scheduled to come for infusions and decided which visits were essential and which were deferrable without disrupting care by briefly using a noninfusional approach,” said Dr. Voorhees. The number of patients who had their regimens modified or held was “relatively small,” and with the recent recognition that a surge of infections has not occurred, “we’re now rolling out cautious reentry of those patients back to their originally prescribed chemotherapy.”

In addition to concerns of exposure at infusion clinics, there are concerns about the heightened susceptibility of immunosuppressed hematologic oncology patients to COVID-19 and their risk for more severe infection. “Our view is that, if patients tested positive, continuing immunosuppressive treatment would likely be detrimental,” so when possible treatment is temporarily suspended and then resumed when the infection has cleared. “When patients test positive for a prolonged period, a decision to resume treatment must be in the best interests of the patient and weigh the benefits of resuming therapy against the risks of incurring a more severe infection by restarting potentially immunosuppressive therapy,” Dr. Voorhees said.

The enhanced risk that cancer patients face if they develop COVID-19 was documented in a recent review of 218 cancer patients hospitalized for COVID-19 during parts of March and April in a large New York health system. The results showed an overall mortality rate of 28%, including a 37% rate among 54 patients with hematologic malignancies and a 25% rate among 164 patients with solid tumors. The mortality rate “may not be quite as high as they reported because that depends on how many patients you test, but there is no question that patients with more comorbidities are at higher risk. Patients with active cancer on chemotherapy are a particularly vulnerable population, and many have expressed concerns about their vulnerability,” he observed.

For the few LCI patients who developed COVID-19 infection, the medical staff has had several therapeutic options they could match to each patient’s needs, with help from the Atrium Health infectious disease team. LCI and Atrium Health are participating in several COVID-19 clinical treatment trials, including an investigational convalescent plasma protocol spearheaded by the Mayo Clinic. They have also opened a randomized, phase 2 trial evaluating the safety and efficacy of selinexor (Xpovio), an oral drug that’s Food and Drug Administration approved for patients with multiple myeloma, for treatment of moderate or severe COVID-19 infection. Additional studies evaluating blockade of granulocyte-macrophage colony-stimulating factor, as well as inhaled antiviral therapy, have recently launched, and several additional studies are poised to open in the coming weeks.

The LCI and Atrium Health team also has a supply of the antiviral agent remdesivir as part of the FDA’s expanded access protocol and emergency use authorization. They also have a supply of and experience administering the interleukin-6 receptor inhibitor tocilizumab (Actemra), which showed some suggestion of efficacy in limited experience treating patients with severe or critical COVID-19 infections (Proc Natl Acad Sci. 2020 Apr 29; doi: 10.1073/pnas.2005615117). Clinicians at LCI have not used the investigational and unproven agents hydroxychloroquine, chloroquine, and azithromycin to either prevent or treat COVID-19.

LCI also instituted measures to try to minimize the risk that staff members could become infected and transmit the virus while asymptomatic. Following conversations held early on with COVID-19–experienced health authorities in China and Italy, the patient-facing LCI staff split into two teams starting on March 23 that alternated responsibility for direct patient interactions every 2 weeks. When one of these teams was off from direct patient contact they continued to care for patients remotely through virtual technologies. The concept was that, if a staffer became infected while remaining asymptomatic during their contact with patients, their status would either become diagnosable or resolve during their 2 weeks away from seeing any patients. Perhaps in part because of this approach infections among staff members “have not been a big issue. We’ve had an incredibly low infection rate among the LCI staff,” Dr. Voorhees noted.

By mid-May, with the imminent threat of a sudden CODIV-19 surge moderated, heme-onc operations at LCI began to cautiously revert to more normal operations. “We’re continuing patient screening for signs and symptoms of COVID-19 infection, testing for asymptomatic infections, and requiring masking and social distancing in the clinics and hospitals, but we’re starting to slowly restore the number of patients at our clinics [virtual and face to face[ and infusion centers,” and the staff’s division into two teams ended. “The idea was to get past a surge and make sure our system was not overwhelmed. We anticipated a local surge in late April, but then it kept getting pushed back. Current projections are for the infection rate among LCI patients to remain low provided that community spread remains stable or, ideally, decreases.” The LCI infectious disease staff is closely monitoring infection rates for early recognition of an outbreak, with plans to follow any new cases with contact tracing. So far, the COVID-19 pandemic at LCI “has been very manageable,” Dr. Voorhees concluded.

“We’re now better positioned to deal with a case surge if it were to happen. We could resume the two-team approach, hospital-wide plans are now in place for a future surge, and we are now up and running with robust testing and inpatient and outpatient virtual technology. The first time, we were all learning on the fly.”

The LCI biostatistics team has been prospectively collecting the Institutes’s COVID-19 patient data, with plans to report their findings.

Dr. Voorhees has had financial relationships with Bristol-Myers Squibb/Celgene, Janssen, Novartis, and Oncopeptides, none of which are relevant to this article.

[email protected]

We are months into the COVID-19 crisis, and mental health issues are proving to be rampant. In every crisis, there is opportunity, and this one is no different. The opportunity is clear. For Mental Health Awareness Month and beyond, we must convey a powerful message that mental health is key to our well-being and must be actively addressed. Because almost everyone has felt excess anxiety these last months, we have a unique chance to engage a wider audience.

To address the urgent need, the Mental Health Coalition was formed with the understanding that the mental health crisis is fueled by a pervasive and devastating stigma, preventing millions of individuals from being able to seek the critical treatment they need. Spearheaded by social activist and fashion designer, Kenneth Cole, it is a coalition of leading mental health organizations, brands, celebrities, and advocates who have joined forces to end the stigma surrounding mental health and to change the way people talk about, and care for, mental illness. The group’s mission listed on its website states: “We must increase the conversation around mental health. We must act to end silence, reduce stigma, and engage our community to inspire hope at this essential moment.”

As most of the United States has been under stay-at-home orders, our traditional relationships have been radically disrupted. New types of relationships are forming as we are relying even more on technology to connect us. Social media seems to be on the only “social” we can now safely engage in.

The coalition’s campaign, “#howareyoureally?” is harnessing the power of social media and creating a storytelling platform to allow users to more genuinely share their feelings in these unprecedented times. Celebrities include Whoopi Goldberg, Kendall Jenner, Chris Cuomo, Deepak Chopra, Kesha, and many more have already shared their stories.

“How Are You, Really?” challenges people to answer this question using social media in an open and honest fashion while still providing hope.

The second component of the initiative is to increase access to care, and they have a long list of collaborators, including leading mental health organizations such as the American Foundation for Suicide Prevention, Anxiety and Depression Association of America, Child Mind Institute, Depression and Bipolar Support Alliance, Didi Hirsch Mental Health Services, National Alliance on Mental Illness, and many more.

We have a unique opportunity this Mental Health Awareness Month, and I hope we will see more and more people sharing their stories and reaching out for help. As a community, we must be prepared to meet the escalating needs of our population.
 

Dr. Ritvo, a psychiatrist with more than 25 years’ experience, practices in Miami Beach, Fla. She is the author of “Bekindr – The Transformative Power of Kindness” (Hellertown, Pa.: Momosa Publishing, 2018) and is the founder of the Bekindr Global Initiative, a movement aimed at cultivating kindness in the world. Dr. Ritvo also is the cofounder of the Bold Beauty Project, a nonprofit group that pairs women with disabilities with photographers who create art exhibitions to raise awareness.

We are months into the COVID-19 crisis, and mental health issues are proving to be rampant. In every crisis, there is opportunity, and this one is no different. The opportunity is clear. For Mental Health Awareness Month and beyond, we must convey a powerful message that mental health is key to our well-being and must be actively addressed. Because almost everyone has felt excess anxiety these last months, we have a unique chance to engage a wider audience.

To address the urgent need, the Mental Health Coalition was formed with the understanding that the mental health crisis is fueled by a pervasive and devastating stigma, preventing millions of individuals from being able to seek the critical treatment they need. Spearheaded by social activist and fashion designer, Kenneth Cole, it is a coalition of leading mental health organizations, brands, celebrities, and advocates who have joined forces to end the stigma surrounding mental health and to change the way people talk about, and care for, mental illness. The group’s mission listed on its website states: “We must increase the conversation around mental health. We must act to end silence, reduce stigma, and engage our community to inspire hope at this essential moment.”

As most of the United States has been under stay-at-home orders, our traditional relationships have been radically disrupted. New types of relationships are forming as we are relying even more on technology to connect us. Social media seems to be on the only “social” we can now safely engage in.

The coalition’s campaign, “#howareyoureally?” is harnessing the power of social media and creating a storytelling platform to allow users to more genuinely share their feelings in these unprecedented times. Celebrities include Whoopi Goldberg, Kendall Jenner, Chris Cuomo, Deepak Chopra, Kesha, and many more have already shared their stories.

“How Are You, Really?” challenges people to answer this question using social media in an open and honest fashion while still providing hope.

The second component of the initiative is to increase access to care, and they have a long list of collaborators, including leading mental health organizations such as the American Foundation for Suicide Prevention, Anxiety and Depression Association of America, Child Mind Institute, Depression and Bipolar Support Alliance, Didi Hirsch Mental Health Services, National Alliance on Mental Illness, and many more.

We have a unique opportunity this Mental Health Awareness Month, and I hope we will see more and more people sharing their stories and reaching out for help. As a community, we must be prepared to meet the escalating needs of our population.
 

Dr. Ritvo, a psychiatrist with more than 25 years’ experience, practices in Miami Beach, Fla. She is the author of “Bekindr – The Transformative Power of Kindness” (Hellertown, Pa.: Momosa Publishing, 2018) and is the founder of the Bekindr Global Initiative, a movement aimed at cultivating kindness in the world. Dr. Ritvo also is the cofounder of the Bold Beauty Project, a nonprofit group that pairs women with disabilities with photographers who create art exhibitions to raise awareness.

We are months into the COVID-19 crisis, and mental health issues are proving to be rampant. In every crisis, there is opportunity, and this one is no different. The opportunity is clear. For Mental Health Awareness Month and beyond, we must convey a powerful message that mental health is key to our well-being and must be actively addressed. Because almost everyone has felt excess anxiety these last months, we have a unique chance to engage a wider audience.

To address the urgent need, the Mental Health Coalition was formed with the understanding that the mental health crisis is fueled by a pervasive and devastating stigma, preventing millions of individuals from being able to seek the critical treatment they need. Spearheaded by social activist and fashion designer, Kenneth Cole, it is a coalition of leading mental health organizations, brands, celebrities, and advocates who have joined forces to end the stigma surrounding mental health and to change the way people talk about, and care for, mental illness. The group’s mission listed on its website states: “We must increase the conversation around mental health. We must act to end silence, reduce stigma, and engage our community to inspire hope at this essential moment.”

As most of the United States has been under stay-at-home orders, our traditional relationships have been radically disrupted. New types of relationships are forming as we are relying even more on technology to connect us. Social media seems to be on the only “social” we can now safely engage in.

The coalition’s campaign, “#howareyoureally?” is harnessing the power of social media and creating a storytelling platform to allow users to more genuinely share their feelings in these unprecedented times. Celebrities include Whoopi Goldberg, Kendall Jenner, Chris Cuomo, Deepak Chopra, Kesha, and many more have already shared their stories.

“How Are You, Really?” challenges people to answer this question using social media in an open and honest fashion while still providing hope.

The second component of the initiative is to increase access to care, and they have a long list of collaborators, including leading mental health organizations such as the American Foundation for Suicide Prevention, Anxiety and Depression Association of America, Child Mind Institute, Depression and Bipolar Support Alliance, Didi Hirsch Mental Health Services, National Alliance on Mental Illness, and many more.

We have a unique opportunity this Mental Health Awareness Month, and I hope we will see more and more people sharing their stories and reaching out for help. As a community, we must be prepared to meet the escalating needs of our population.
 

Dr. Ritvo, a psychiatrist with more than 25 years’ experience, practices in Miami Beach, Fla. She is the author of “Bekindr – The Transformative Power of Kindness” (Hellertown, Pa.: Momosa Publishing, 2018) and is the founder of the Bekindr Global Initiative, a movement aimed at cultivating kindness in the world. Dr. Ritvo also is the cofounder of the Bold Beauty Project, a nonprofit group that pairs women with disabilities with photographers who create art exhibitions to raise awareness.

A new nationwide U.S. observational study suggests that ACE inhibitors may protect against severe illness in older people with COVID-19, prompting the start of a randomized clinical trial to test the strategy.

In addition, a new meta-analysis of all the available data on the use of ACE inhibitors and angiotensin-receptor blockers (ARBs) in COVID-19–infected patients has concluded that these drugs are not associated with more severe disease and do not increase susceptibility to infection.

The observational study, which was published on the MedRxiv preprint server on May 19 and has not yet been peer reviewed, was conducted by the health insurance company United Heath Group and by Yale University, New Haven, Conn.

The investigators analyzed data from 10,000 patients from across the United States who had tested positive for COVID-19, who were enrolled in Medicare Advantage insurance plans or were commercially insured, and who had received a prescription for one or more antihypertensive medications.

Results showed that the use of ACE inhibitors was associated with an almost 40% lower risk for COVID-19 hospitalization for older people enrolled in Medicare Advantage plans. No such benefit was seen in the younger commercially insured patients or in either group with ARBs.

Courtesy Yale University

At a telephone media briefing on the study, senior investigator Harlan M. Krumholz, MD, said: “We don’t believe this is enough info to change practice, but we do think this is an interesting and intriguing result.

“These findings merit a clinical trial to formally test whether ACE inhibitors – which are cheap, widely available, and well-tolerated drugs – can reduce hospitalization of patients infected with COVID-19,” added Dr. Krumholz, professor of medicine at Yale and director of the Yale New Haven Hospital Center for Outcomes Research.

A pragmatic clinical trial is now being planned. In this trial, 10,000 older people who test positive for COVID-19 will be randomly assigned to receive either a low dose of an ACE inhibitor or placebo. It is hoped that recruitment for the trial will begin in June of 2020. It is open to all eligible Americans who are older than 50 years, who test negative for COVID-19, and who are not taking medications for hypertension. Prospective patients can sign up at a dedicated website.

The randomized trial, also conducted by United Health Group and Yale, is said to be “one of the first virtual COVID-19 clinical trials to be launched at scale.”

For the observational study, the researchers identified 2,263 people who were receiving medication for hypertension and who tested positive for COVID-19. Of these, approximately two-thirds were older, Medicare Advantage enrollees; one-third were younger, commercially insured individuals.

In a propensity score–matched analysis, the investigators matched 441 patients who were taking ACE inhibitors to 441 patients who were taking other antihypertensive agents; and 412 patients who were receiving an ARB to 412 patients who were receiving other antihypertensive agents.

Results showed that during a median of 30 days after testing positive, 12.7% of the cohort were hospitalized for COVID-19. In propensity score–matched analyses, neither ACE inhibitors (hazard ratio [HR], 0.77; P = .18) nor ARBs (HR, 0.88; P =.48) were significantly associated with risk for hospitalization.

However, in analyses stratified by the insurance group, ACE inhibitors (but not ARBs) were associated with a significant lower risk for hospitalization among the Medicare group (HR, 0.61; P = .02) but not among the commercially insured group (HR, 2.14; P = .12).

A second study examined outcomes of 7,933 individuals with hypertension who were hospitalized with COVID-19 (92% of these patients were Medicare Advantage enrollees). Of these, 14.2% died, 59.5% survived to discharge, and 26.3% underwent ongoing hospitalization. In propensity score–matched analyses, use of neither an ACE inhibitor (HR, 0.97; P = .74) nor an ARB (HR, 1.15; P = .15) was associated with risk of in-hospital mortality.

The researchers said their findings are consistent with prior evidence from randomized clinical trials suggesting a reduced risk for pneumonia with ACE inhibitors that is not observed with ARBs.

They also cited some preclinical evidence that they said suggests a possible protective role for ACE inhibitors in COVID-19: that ACE inhibitors, but not ARBs, are associated with the upregulation of ACE2 receptors, which modulate the local interactions of the renin-angiotensin-aldosterone system in the lung tissue.

“The presence of ACE2 receptors, therefore, exerts a protective effect against the development of acute lung injury in infections with SARS coronaviruses, which lead to dysregulation of these mechanisms and endothelial damage,” they added. “Further, our observations do not support theoretical concerns of adverse outcomes due to enhanced virulence of SARS coronaviruses due to overexpression of ACE2 receptors in cell cultures – an indirect binding site for these viruses.”

The authors also noted that their findings have “important implications” for four ongoing randomized trials of ACE inhibitors/ARBs in COVID-19, “as none of them align with the observations of our study.”

They pointed out that of the four ongoing trials, three are testing the use of ACE inhibitors or ARBs in the treatment of hospitalized COVID-19 patients, and one is testing the use of a 10-day course of ARBs after a positive SARS-CoV-2 test to prevent hospitalization.
 

Experts cautious

However, two cardiovascular experts who were asked to comment on this latest study were not overly optimistic about the data.

Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, said: “This report adds to the growing number of observational studies that show varying effects of ACE inhibitors and ARBs in increasing or decreasing hospitalizations for COVID-19 and the likelihood of in-hospital mortality. Overall, this new report differs from others in the remarkable effects of insurance coverage: In particular, for ACE inhibitors, there was a 40% reduction in fatal events in Medicare patients but a twofold increase in patients using commercial insurance – albeit the test for heterogeneity when comparing the two groups did not quite reach statistical significance.

“In essence, these authors are saying that ACE inhibitors are highly protective in patients aged 65 or older but bordering on harmful in patients aged below 65. I agree that it’s worthwhile to check this finding in a prospective trial ... but this hypothesis does seem to be a reach.”

Dr. Weber noted that both ACE inhibitors and ARBs increase the level of the ACE2 enzyme to which the COVID-19 virus binds in the lungs.

“The ACE inhibitors do so by inhibiting the enzyme’s action and thus stimulate further enzyme production; the ARBs block the effects of angiotensin II, which results in high angiotensin II levels that also upregulate ACE2 production,” he said. “Perhaps the ACE inhibitors, by binding to the ACE enzyme, can in some way interfere with the enzyme’s uptake of the COVID virus and thus provide some measure of clinical protection. This is possible, but why would this effect be apparent only in older people?”

Catherine Hackett/MDedge News

John McMurray, MD, professor of medical cardiology at the University of Glasgow, Scotland, added: “This looks like a subgroup of a subgroup type analysis based on small numbers of events – I think there were only 77 hospitalizations among the 722 patients treated with an ACE inhibitor, and the Medicare Advantage subgroup was only 581 of those 722 patients.

“The hazard ratio had wide 95% CI [confidence interval] and a modest P value,” Dr. McMurray added. “So yes, interesting and hypothesis-generating, but not definitive.”
 

New meta-analysis

The new meta-analysis of all data so far available on ACE inhibitor and ARB use for patients with COVID-19 was published online in Annals of Internal Medicine on May 15.

The analysis is a living, systematic review with ongoing literature surveillance and critical appraisal, which will be updated as new data become available. It included 14 observational studies.

The authors, led by Katherine M. Mackey, MD, VA Portland Health Care System, Oregon, concluded: “High-certainty evidence suggests that ACE-inhibitor or ARB use is not associated with more severe COVID-19 disease, and moderate certainty evidence suggested no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain.”

In an accompanying editorial, William G. Kussmaul III, MD, Drexel University, Philadelphia, said that initial fears that these drugs may be harmful for patients with COVID-19 now seem to have been unfounded.

“We now have reasonable reassurance that drugs that alter the renin-angiotensin system do not pose substantial threats as either COVID-19 risk factors or severity multipliers,” he wrote.
 

A version of this article originally appeared on Medscape.com.

A new nationwide U.S. observational study suggests that ACE inhibitors may protect against severe illness in older people with COVID-19, prompting the start of a randomized clinical trial to test the strategy.

In addition, a new meta-analysis of all the available data on the use of ACE inhibitors and angiotensin-receptor blockers (ARBs) in COVID-19–infected patients has concluded that these drugs are not associated with more severe disease and do not increase susceptibility to infection.

The observational study, which was published on the MedRxiv preprint server on May 19 and has not yet been peer reviewed, was conducted by the health insurance company United Heath Group and by Yale University, New Haven, Conn.

The investigators analyzed data from 10,000 patients from across the United States who had tested positive for COVID-19, who were enrolled in Medicare Advantage insurance plans or were commercially insured, and who had received a prescription for one or more antihypertensive medications.

Results showed that the use of ACE inhibitors was associated with an almost 40% lower risk for COVID-19 hospitalization for older people enrolled in Medicare Advantage plans. No such benefit was seen in the younger commercially insured patients or in either group with ARBs.

Courtesy Yale University

At a telephone media briefing on the study, senior investigator Harlan M. Krumholz, MD, said: “We don’t believe this is enough info to change practice, but we do think this is an interesting and intriguing result.

“These findings merit a clinical trial to formally test whether ACE inhibitors – which are cheap, widely available, and well-tolerated drugs – can reduce hospitalization of patients infected with COVID-19,” added Dr. Krumholz, professor of medicine at Yale and director of the Yale New Haven Hospital Center for Outcomes Research.

A pragmatic clinical trial is now being planned. In this trial, 10,000 older people who test positive for COVID-19 will be randomly assigned to receive either a low dose of an ACE inhibitor or placebo. It is hoped that recruitment for the trial will begin in June of 2020. It is open to all eligible Americans who are older than 50 years, who test negative for COVID-19, and who are not taking medications for hypertension. Prospective patients can sign up at a dedicated website.

The randomized trial, also conducted by United Health Group and Yale, is said to be “one of the first virtual COVID-19 clinical trials to be launched at scale.”

For the observational study, the researchers identified 2,263 people who were receiving medication for hypertension and who tested positive for COVID-19. Of these, approximately two-thirds were older, Medicare Advantage enrollees; one-third were younger, commercially insured individuals.

In a propensity score–matched analysis, the investigators matched 441 patients who were taking ACE inhibitors to 441 patients who were taking other antihypertensive agents; and 412 patients who were receiving an ARB to 412 patients who were receiving other antihypertensive agents.

Results showed that during a median of 30 days after testing positive, 12.7% of the cohort were hospitalized for COVID-19. In propensity score–matched analyses, neither ACE inhibitors (hazard ratio [HR], 0.77; P = .18) nor ARBs (HR, 0.88; P =.48) were significantly associated with risk for hospitalization.

However, in analyses stratified by the insurance group, ACE inhibitors (but not ARBs) were associated with a significant lower risk for hospitalization among the Medicare group (HR, 0.61; P = .02) but not among the commercially insured group (HR, 2.14; P = .12).

A second study examined outcomes of 7,933 individuals with hypertension who were hospitalized with COVID-19 (92% of these patients were Medicare Advantage enrollees). Of these, 14.2% died, 59.5% survived to discharge, and 26.3% underwent ongoing hospitalization. In propensity score–matched analyses, use of neither an ACE inhibitor (HR, 0.97; P = .74) nor an ARB (HR, 1.15; P = .15) was associated with risk of in-hospital mortality.

The researchers said their findings are consistent with prior evidence from randomized clinical trials suggesting a reduced risk for pneumonia with ACE inhibitors that is not observed with ARBs.

They also cited some preclinical evidence that they said suggests a possible protective role for ACE inhibitors in COVID-19: that ACE inhibitors, but not ARBs, are associated with the upregulation of ACE2 receptors, which modulate the local interactions of the renin-angiotensin-aldosterone system in the lung tissue.

“The presence of ACE2 receptors, therefore, exerts a protective effect against the development of acute lung injury in infections with SARS coronaviruses, which lead to dysregulation of these mechanisms and endothelial damage,” they added. “Further, our observations do not support theoretical concerns of adverse outcomes due to enhanced virulence of SARS coronaviruses due to overexpression of ACE2 receptors in cell cultures – an indirect binding site for these viruses.”

The authors also noted that their findings have “important implications” for four ongoing randomized trials of ACE inhibitors/ARBs in COVID-19, “as none of them align with the observations of our study.”

They pointed out that of the four ongoing trials, three are testing the use of ACE inhibitors or ARBs in the treatment of hospitalized COVID-19 patients, and one is testing the use of a 10-day course of ARBs after a positive SARS-CoV-2 test to prevent hospitalization.
 

Experts cautious

However, two cardiovascular experts who were asked to comment on this latest study were not overly optimistic about the data.

Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, said: “This report adds to the growing number of observational studies that show varying effects of ACE inhibitors and ARBs in increasing or decreasing hospitalizations for COVID-19 and the likelihood of in-hospital mortality. Overall, this new report differs from others in the remarkable effects of insurance coverage: In particular, for ACE inhibitors, there was a 40% reduction in fatal events in Medicare patients but a twofold increase in patients using commercial insurance – albeit the test for heterogeneity when comparing the two groups did not quite reach statistical significance.

“In essence, these authors are saying that ACE inhibitors are highly protective in patients aged 65 or older but bordering on harmful in patients aged below 65. I agree that it’s worthwhile to check this finding in a prospective trial ... but this hypothesis does seem to be a reach.”

Dr. Weber noted that both ACE inhibitors and ARBs increase the level of the ACE2 enzyme to which the COVID-19 virus binds in the lungs.

“The ACE inhibitors do so by inhibiting the enzyme’s action and thus stimulate further enzyme production; the ARBs block the effects of angiotensin II, which results in high angiotensin II levels that also upregulate ACE2 production,” he said. “Perhaps the ACE inhibitors, by binding to the ACE enzyme, can in some way interfere with the enzyme’s uptake of the COVID virus and thus provide some measure of clinical protection. This is possible, but why would this effect be apparent only in older people?”

Catherine Hackett/MDedge News

John McMurray, MD, professor of medical cardiology at the University of Glasgow, Scotland, added: “This looks like a subgroup of a subgroup type analysis based on small numbers of events – I think there were only 77 hospitalizations among the 722 patients treated with an ACE inhibitor, and the Medicare Advantage subgroup was only 581 of those 722 patients.

“The hazard ratio had wide 95% CI [confidence interval] and a modest P value,” Dr. McMurray added. “So yes, interesting and hypothesis-generating, but not definitive.”
 

New meta-analysis

The new meta-analysis of all data so far available on ACE inhibitor and ARB use for patients with COVID-19 was published online in Annals of Internal Medicine on May 15.

The analysis is a living, systematic review with ongoing literature surveillance and critical appraisal, which will be updated as new data become available. It included 14 observational studies.

The authors, led by Katherine M. Mackey, MD, VA Portland Health Care System, Oregon, concluded: “High-certainty evidence suggests that ACE-inhibitor or ARB use is not associated with more severe COVID-19 disease, and moderate certainty evidence suggested no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain.”

In an accompanying editorial, William G. Kussmaul III, MD, Drexel University, Philadelphia, said that initial fears that these drugs may be harmful for patients with COVID-19 now seem to have been unfounded.

“We now have reasonable reassurance that drugs that alter the renin-angiotensin system do not pose substantial threats as either COVID-19 risk factors or severity multipliers,” he wrote.
 

A version of this article originally appeared on Medscape.com.

A new nationwide U.S. observational study suggests that ACE inhibitors may protect against severe illness in older people with COVID-19, prompting the start of a randomized clinical trial to test the strategy.

In addition, a new meta-analysis of all the available data on the use of ACE inhibitors and angiotensin-receptor blockers (ARBs) in COVID-19–infected patients has concluded that these drugs are not associated with more severe disease and do not increase susceptibility to infection.

The observational study, which was published on the MedRxiv preprint server on May 19 and has not yet been peer reviewed, was conducted by the health insurance company United Heath Group and by Yale University, New Haven, Conn.

The investigators analyzed data from 10,000 patients from across the United States who had tested positive for COVID-19, who were enrolled in Medicare Advantage insurance plans or were commercially insured, and who had received a prescription for one or more antihypertensive medications.

Results showed that the use of ACE inhibitors was associated with an almost 40% lower risk for COVID-19 hospitalization for older people enrolled in Medicare Advantage plans. No such benefit was seen in the younger commercially insured patients or in either group with ARBs.

Courtesy Yale University

At a telephone media briefing on the study, senior investigator Harlan M. Krumholz, MD, said: “We don’t believe this is enough info to change practice, but we do think this is an interesting and intriguing result.

“These findings merit a clinical trial to formally test whether ACE inhibitors – which are cheap, widely available, and well-tolerated drugs – can reduce hospitalization of patients infected with COVID-19,” added Dr. Krumholz, professor of medicine at Yale and director of the Yale New Haven Hospital Center for Outcomes Research.

A pragmatic clinical trial is now being planned. In this trial, 10,000 older people who test positive for COVID-19 will be randomly assigned to receive either a low dose of an ACE inhibitor or placebo. It is hoped that recruitment for the trial will begin in June of 2020. It is open to all eligible Americans who are older than 50 years, who test negative for COVID-19, and who are not taking medications for hypertension. Prospective patients can sign up at a dedicated website.

The randomized trial, also conducted by United Health Group and Yale, is said to be “one of the first virtual COVID-19 clinical trials to be launched at scale.”

For the observational study, the researchers identified 2,263 people who were receiving medication for hypertension and who tested positive for COVID-19. Of these, approximately two-thirds were older, Medicare Advantage enrollees; one-third were younger, commercially insured individuals.

In a propensity score–matched analysis, the investigators matched 441 patients who were taking ACE inhibitors to 441 patients who were taking other antihypertensive agents; and 412 patients who were receiving an ARB to 412 patients who were receiving other antihypertensive agents.

Results showed that during a median of 30 days after testing positive, 12.7% of the cohort were hospitalized for COVID-19. In propensity score–matched analyses, neither ACE inhibitors (hazard ratio [HR], 0.77; P = .18) nor ARBs (HR, 0.88; P =.48) were significantly associated with risk for hospitalization.

However, in analyses stratified by the insurance group, ACE inhibitors (but not ARBs) were associated with a significant lower risk for hospitalization among the Medicare group (HR, 0.61; P = .02) but not among the commercially insured group (HR, 2.14; P = .12).

A second study examined outcomes of 7,933 individuals with hypertension who were hospitalized with COVID-19 (92% of these patients were Medicare Advantage enrollees). Of these, 14.2% died, 59.5% survived to discharge, and 26.3% underwent ongoing hospitalization. In propensity score–matched analyses, use of neither an ACE inhibitor (HR, 0.97; P = .74) nor an ARB (HR, 1.15; P = .15) was associated with risk of in-hospital mortality.

The researchers said their findings are consistent with prior evidence from randomized clinical trials suggesting a reduced risk for pneumonia with ACE inhibitors that is not observed with ARBs.

They also cited some preclinical evidence that they said suggests a possible protective role for ACE inhibitors in COVID-19: that ACE inhibitors, but not ARBs, are associated with the upregulation of ACE2 receptors, which modulate the local interactions of the renin-angiotensin-aldosterone system in the lung tissue.

“The presence of ACE2 receptors, therefore, exerts a protective effect against the development of acute lung injury in infections with SARS coronaviruses, which lead to dysregulation of these mechanisms and endothelial damage,” they added. “Further, our observations do not support theoretical concerns of adverse outcomes due to enhanced virulence of SARS coronaviruses due to overexpression of ACE2 receptors in cell cultures – an indirect binding site for these viruses.”

The authors also noted that their findings have “important implications” for four ongoing randomized trials of ACE inhibitors/ARBs in COVID-19, “as none of them align with the observations of our study.”

They pointed out that of the four ongoing trials, three are testing the use of ACE inhibitors or ARBs in the treatment of hospitalized COVID-19 patients, and one is testing the use of a 10-day course of ARBs after a positive SARS-CoV-2 test to prevent hospitalization.
 

Experts cautious

However, two cardiovascular experts who were asked to comment on this latest study were not overly optimistic about the data.

Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, said: “This report adds to the growing number of observational studies that show varying effects of ACE inhibitors and ARBs in increasing or decreasing hospitalizations for COVID-19 and the likelihood of in-hospital mortality. Overall, this new report differs from others in the remarkable effects of insurance coverage: In particular, for ACE inhibitors, there was a 40% reduction in fatal events in Medicare patients but a twofold increase in patients using commercial insurance – albeit the test for heterogeneity when comparing the two groups did not quite reach statistical significance.

“In essence, these authors are saying that ACE inhibitors are highly protective in patients aged 65 or older but bordering on harmful in patients aged below 65. I agree that it’s worthwhile to check this finding in a prospective trial ... but this hypothesis does seem to be a reach.”

Dr. Weber noted that both ACE inhibitors and ARBs increase the level of the ACE2 enzyme to which the COVID-19 virus binds in the lungs.

“The ACE inhibitors do so by inhibiting the enzyme’s action and thus stimulate further enzyme production; the ARBs block the effects of angiotensin II, which results in high angiotensin II levels that also upregulate ACE2 production,” he said. “Perhaps the ACE inhibitors, by binding to the ACE enzyme, can in some way interfere with the enzyme’s uptake of the COVID virus and thus provide some measure of clinical protection. This is possible, but why would this effect be apparent only in older people?”

Catherine Hackett/MDedge News

John McMurray, MD, professor of medical cardiology at the University of Glasgow, Scotland, added: “This looks like a subgroup of a subgroup type analysis based on small numbers of events – I think there were only 77 hospitalizations among the 722 patients treated with an ACE inhibitor, and the Medicare Advantage subgroup was only 581 of those 722 patients.

“The hazard ratio had wide 95% CI [confidence interval] and a modest P value,” Dr. McMurray added. “So yes, interesting and hypothesis-generating, but not definitive.”
 

New meta-analysis

The new meta-analysis of all data so far available on ACE inhibitor and ARB use for patients with COVID-19 was published online in Annals of Internal Medicine on May 15.

The analysis is a living, systematic review with ongoing literature surveillance and critical appraisal, which will be updated as new data become available. It included 14 observational studies.

The authors, led by Katherine M. Mackey, MD, VA Portland Health Care System, Oregon, concluded: “High-certainty evidence suggests that ACE-inhibitor or ARB use is not associated with more severe COVID-19 disease, and moderate certainty evidence suggested no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain.”

In an accompanying editorial, William G. Kussmaul III, MD, Drexel University, Philadelphia, said that initial fears that these drugs may be harmful for patients with COVID-19 now seem to have been unfounded.

“We now have reasonable reassurance that drugs that alter the renin-angiotensin system do not pose substantial threats as either COVID-19 risk factors or severity multipliers,” he wrote.
 

A version of this article originally appeared on Medscape.com.

The drastic drop in admissions for acute myocardial infarctions (AMI) during the COVID-19 pandemic in Italy has seen a parallel rise in MI fatality rates in those who do present to hospitals, according to a new report. This gives credence to suggestions that people have avoided hospitals during the pandemic despite life-threatening emergencies.

Salvatore De Rosa, MD, PhD, and colleagues reported their results in the European Heart Journal.

“These data return a frightening picture of about half of AMI patients not reaching out to the hospital at all, which will probably significantly increase mortality for AMI and bring with it a number of patients with post-MI heart failure, despite the fact that acute coronary syndrome management protocols were promptly implemented,” Dr. De Rosa, of Magna Graecia University in Catanzaro, Italy, and associates wrote.
 

Hospitalizations down

The study counted AMIs at 54 hospital coronary care units nationwide for the week of March 12-19, 2020, at the height of the coronavirus outbreak in northern Italy, and compared that with an equivalent week in 2019. The researchers reported 319 AMIs during the week in 2020, compared with 618 in the equivalent 2019 week, a 48% reduction (P < .001). Although the outbreak was worst in northern Italy, the decline in admissions occurred throughout the country.

An analysis of subtype determined the decline in the incidence of ST-segment elevation MI lagged significantly behind that of non-STEMI. STEMI declined from 268 in 2019 to 197 in 2020, a 27% reduction, while hospitalizations for non-STEMI went from 350 to 122, a 65% reduction.

The researchers also found substantial reductions in hospitalizations for heart failure, by 47%, and atrial fibrillation, by 53%. Incidentally, the mean age of atrial fibrillation patients was considerably younger in 2020: 64.6 vs. 70 years.
 

Death, complications up

AMI patients who managed to get to the hospital during the pandemic also had worse outcomes. Mortality for STEMI cases more than tripled, to 14% during the outbreak, compared with 4% in 2019 (P < .001) and complication rates increased by 80% to 19% (P = .025). Twenty-one STEMI patients were positive for COVID-19 and more than a quarter (29%) died, which was more than two and a half times the 12% death rate in non–COVID-19 STEMI patients.

Analysis of the STEMI group also found that the care gap for women with heart disease worsened significantly during the pandemic, as they comprised 20.3% of cases this year, compared with 25.4% before the pandemic. Also, the reduction in admissions for STEMI during the pandemic was statistically significant at 41% for women, but not for men at 18%.

Non-STEMI patients fared better overall than STEMI patients, but their outcomes also worsened during the pandemic. Non-STEMI patients were significantly less likely to have percutaneous coronary intervention during the pandemic than previously; the rate declined by 13%, from 77% to 66%. The non-STEMI mortality rate nearly doubled, although not statistically significantly, from 1.7% to 3.3%, whereas complication rates actually more than doubled, from 5.1% to 10.7%, a significant difference. Twelve (9.8%) of the non-STEMI patients were COVID-19 positive, but none died.
 

Trend extends beyond borders

Dr. De Rosa and colleagues noted that their findings are in line with studies that reported similar declines for STEMI interventions in the United States and Spain during the pandemic (J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.04.011; REC Interv Cardiol. 2020. doi: 10.24875/RECIC.M20000120).

Additionally, a group at Kaiser Permanente in Northern California also reported a 50% decline in the incidence of AMI hospitalizations during the pandemic (N Engl J Med. 2020 May 19. doi: 10.1056/NEJMc2015630). Likewise, a study of aortic dissections in New York reported a sharp decline in procedures during the pandemic in the city, from 13 to 3 a month (J Am Coll Cardiol. 2020 May 15. doi: 10.1016/j.jacc.2020.05.022)

The researchers in Italy didn’t aim to determine the reasons for the decline in AMI hospitalizations, but Dr. De Rosa and colleagues speculated on the following explanations: Fear of contagion in response to media reports, concentration of resources to address COVID-19 may have engendered a sense to defer less urgent care among patients and health care systems, and a true reduction in acute cardiovascular disease because people under stay-at-home orders had low physical stress.

“The concern is fewer MIs most likely means people are dying at home or presenting later as this study suggests,” said Martha Gulati, MD, chief of cardiology at the University of Arizona, Phoenix, in interpreting the results of the Italian study.

That could be a result of a mixed message from the media about accessing health care during the pandemic. “What it suggests to a lot of us is that the media has transmitted this notion that hospitals are busy taking care of COVID-19 patients, but we never said don’t come to hospital if you’re having a heart attack,” Dr. Gulati said. “I think we created some sort of fear that patients if they didn’t have COVID-19 they didn’t want to bother physicians.”

Dr. Gulati, whose practice focuses on women with CVD, said the study’s findings that interventions in women dropped more precipitously than men were concerning. “We know already that women don’t do as well after a heart attack, compared to men, and now we see it worsen it even further when women aren’t presenting,” she said. “We’re worried that this is going to increase the gap.”

Dr. DeRosa and colleagues have no relevant financial relationships to disclose.

SOURCE: De Rosa S et al. Euro Heart J. 2020 May 15. doi: 10.1093/eurheartj/ehaa409.

The drastic drop in admissions for acute myocardial infarctions (AMI) during the COVID-19 pandemic in Italy has seen a parallel rise in MI fatality rates in those who do present to hospitals, according to a new report. This gives credence to suggestions that people have avoided hospitals during the pandemic despite life-threatening emergencies.

Salvatore De Rosa, MD, PhD, and colleagues reported their results in the European Heart Journal.

“These data return a frightening picture of about half of AMI patients not reaching out to the hospital at all, which will probably significantly increase mortality for AMI and bring with it a number of patients with post-MI heart failure, despite the fact that acute coronary syndrome management protocols were promptly implemented,” Dr. De Rosa, of Magna Graecia University in Catanzaro, Italy, and associates wrote.
 

Hospitalizations down

The study counted AMIs at 54 hospital coronary care units nationwide for the week of March 12-19, 2020, at the height of the coronavirus outbreak in northern Italy, and compared that with an equivalent week in 2019. The researchers reported 319 AMIs during the week in 2020, compared with 618 in the equivalent 2019 week, a 48% reduction (P < .001). Although the outbreak was worst in northern Italy, the decline in admissions occurred throughout the country.

An analysis of subtype determined the decline in the incidence of ST-segment elevation MI lagged significantly behind that of non-STEMI. STEMI declined from 268 in 2019 to 197 in 2020, a 27% reduction, while hospitalizations for non-STEMI went from 350 to 122, a 65% reduction.

The researchers also found substantial reductions in hospitalizations for heart failure, by 47%, and atrial fibrillation, by 53%. Incidentally, the mean age of atrial fibrillation patients was considerably younger in 2020: 64.6 vs. 70 years.
 

Death, complications up

AMI patients who managed to get to the hospital during the pandemic also had worse outcomes. Mortality for STEMI cases more than tripled, to 14% during the outbreak, compared with 4% in 2019 (P < .001) and complication rates increased by 80% to 19% (P = .025). Twenty-one STEMI patients were positive for COVID-19 and more than a quarter (29%) died, which was more than two and a half times the 12% death rate in non–COVID-19 STEMI patients.

Analysis of the STEMI group also found that the care gap for women with heart disease worsened significantly during the pandemic, as they comprised 20.3% of cases this year, compared with 25.4% before the pandemic. Also, the reduction in admissions for STEMI during the pandemic was statistically significant at 41% for women, but not for men at 18%.

Non-STEMI patients fared better overall than STEMI patients, but their outcomes also worsened during the pandemic. Non-STEMI patients were significantly less likely to have percutaneous coronary intervention during the pandemic than previously; the rate declined by 13%, from 77% to 66%. The non-STEMI mortality rate nearly doubled, although not statistically significantly, from 1.7% to 3.3%, whereas complication rates actually more than doubled, from 5.1% to 10.7%, a significant difference. Twelve (9.8%) of the non-STEMI patients were COVID-19 positive, but none died.
 

Trend extends beyond borders

Dr. De Rosa and colleagues noted that their findings are in line with studies that reported similar declines for STEMI interventions in the United States and Spain during the pandemic (J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.04.011; REC Interv Cardiol. 2020. doi: 10.24875/RECIC.M20000120).

Additionally, a group at Kaiser Permanente in Northern California also reported a 50% decline in the incidence of AMI hospitalizations during the pandemic (N Engl J Med. 2020 May 19. doi: 10.1056/NEJMc2015630). Likewise, a study of aortic dissections in New York reported a sharp decline in procedures during the pandemic in the city, from 13 to 3 a month (J Am Coll Cardiol. 2020 May 15. doi: 10.1016/j.jacc.2020.05.022)

The researchers in Italy didn’t aim to determine the reasons for the decline in AMI hospitalizations, but Dr. De Rosa and colleagues speculated on the following explanations: Fear of contagion in response to media reports, concentration of resources to address COVID-19 may have engendered a sense to defer less urgent care among patients and health care systems, and a true reduction in acute cardiovascular disease because people under stay-at-home orders had low physical stress.

“The concern is fewer MIs most likely means people are dying at home or presenting later as this study suggests,” said Martha Gulati, MD, chief of cardiology at the University of Arizona, Phoenix, in interpreting the results of the Italian study.

That could be a result of a mixed message from the media about accessing health care during the pandemic. “What it suggests to a lot of us is that the media has transmitted this notion that hospitals are busy taking care of COVID-19 patients, but we never said don’t come to hospital if you’re having a heart attack,” Dr. Gulati said. “I think we created some sort of fear that patients if they didn’t have COVID-19 they didn’t want to bother physicians.”

Dr. Gulati, whose practice focuses on women with CVD, said the study’s findings that interventions in women dropped more precipitously than men were concerning. “We know already that women don’t do as well after a heart attack, compared to men, and now we see it worsen it even further when women aren’t presenting,” she said. “We’re worried that this is going to increase the gap.”

Dr. DeRosa and colleagues have no relevant financial relationships to disclose.

SOURCE: De Rosa S et al. Euro Heart J. 2020 May 15. doi: 10.1093/eurheartj/ehaa409.

The drastic drop in admissions for acute myocardial infarctions (AMI) during the COVID-19 pandemic in Italy has seen a parallel rise in MI fatality rates in those who do present to hospitals, according to a new report. This gives credence to suggestions that people have avoided hospitals during the pandemic despite life-threatening emergencies.

Salvatore De Rosa, MD, PhD, and colleagues reported their results in the European Heart Journal.

“These data return a frightening picture of about half of AMI patients not reaching out to the hospital at all, which will probably significantly increase mortality for AMI and bring with it a number of patients with post-MI heart failure, despite the fact that acute coronary syndrome management protocols were promptly implemented,” Dr. De Rosa, of Magna Graecia University in Catanzaro, Italy, and associates wrote.
 

Hospitalizations down

The study counted AMIs at 54 hospital coronary care units nationwide for the week of March 12-19, 2020, at the height of the coronavirus outbreak in northern Italy, and compared that with an equivalent week in 2019. The researchers reported 319 AMIs during the week in 2020, compared with 618 in the equivalent 2019 week, a 48% reduction (P < .001). Although the outbreak was worst in northern Italy, the decline in admissions occurred throughout the country.

An analysis of subtype determined the decline in the incidence of ST-segment elevation MI lagged significantly behind that of non-STEMI. STEMI declined from 268 in 2019 to 197 in 2020, a 27% reduction, while hospitalizations for non-STEMI went from 350 to 122, a 65% reduction.

The researchers also found substantial reductions in hospitalizations for heart failure, by 47%, and atrial fibrillation, by 53%. Incidentally, the mean age of atrial fibrillation patients was considerably younger in 2020: 64.6 vs. 70 years.
 

Death, complications up

AMI patients who managed to get to the hospital during the pandemic also had worse outcomes. Mortality for STEMI cases more than tripled, to 14% during the outbreak, compared with 4% in 2019 (P < .001) and complication rates increased by 80% to 19% (P = .025). Twenty-one STEMI patients were positive for COVID-19 and more than a quarter (29%) died, which was more than two and a half times the 12% death rate in non–COVID-19 STEMI patients.

Analysis of the STEMI group also found that the care gap for women with heart disease worsened significantly during the pandemic, as they comprised 20.3% of cases this year, compared with 25.4% before the pandemic. Also, the reduction in admissions for STEMI during the pandemic was statistically significant at 41% for women, but not for men at 18%.

Non-STEMI patients fared better overall than STEMI patients, but their outcomes also worsened during the pandemic. Non-STEMI patients were significantly less likely to have percutaneous coronary intervention during the pandemic than previously; the rate declined by 13%, from 77% to 66%. The non-STEMI mortality rate nearly doubled, although not statistically significantly, from 1.7% to 3.3%, whereas complication rates actually more than doubled, from 5.1% to 10.7%, a significant difference. Twelve (9.8%) of the non-STEMI patients were COVID-19 positive, but none died.
 

Trend extends beyond borders

Dr. De Rosa and colleagues noted that their findings are in line with studies that reported similar declines for STEMI interventions in the United States and Spain during the pandemic (J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.04.011; REC Interv Cardiol. 2020. doi: 10.24875/RECIC.M20000120).

Additionally, a group at Kaiser Permanente in Northern California also reported a 50% decline in the incidence of AMI hospitalizations during the pandemic (N Engl J Med. 2020 May 19. doi: 10.1056/NEJMc2015630). Likewise, a study of aortic dissections in New York reported a sharp decline in procedures during the pandemic in the city, from 13 to 3 a month (J Am Coll Cardiol. 2020 May 15. doi: 10.1016/j.jacc.2020.05.022)

The researchers in Italy didn’t aim to determine the reasons for the decline in AMI hospitalizations, but Dr. De Rosa and colleagues speculated on the following explanations: Fear of contagion in response to media reports, concentration of resources to address COVID-19 may have engendered a sense to defer less urgent care among patients and health care systems, and a true reduction in acute cardiovascular disease because people under stay-at-home orders had low physical stress.

“The concern is fewer MIs most likely means people are dying at home or presenting later as this study suggests,” said Martha Gulati, MD, chief of cardiology at the University of Arizona, Phoenix, in interpreting the results of the Italian study.

That could be a result of a mixed message from the media about accessing health care during the pandemic. “What it suggests to a lot of us is that the media has transmitted this notion that hospitals are busy taking care of COVID-19 patients, but we never said don’t come to hospital if you’re having a heart attack,” Dr. Gulati said. “I think we created some sort of fear that patients if they didn’t have COVID-19 they didn’t want to bother physicians.”

Dr. Gulati, whose practice focuses on women with CVD, said the study’s findings that interventions in women dropped more precipitously than men were concerning. “We know already that women don’t do as well after a heart attack, compared to men, and now we see it worsen it even further when women aren’t presenting,” she said. “We’re worried that this is going to increase the gap.”

Dr. DeRosa and colleagues have no relevant financial relationships to disclose.

SOURCE: De Rosa S et al. Euro Heart J. 2020 May 15. doi: 10.1093/eurheartj/ehaa409.