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COVID-19 neurologic effects: Does the virus directly attack the brain?
A new review article summarizes what is known so far, and what clinicians need to look out for.
“We frequently see neurological conditions in people with COVID-19, but we understand very little about these effects. Is it the virus entering the brain/nerves or are they a result of a general inflammation or immune response – a bystander effect of people being severely ill. It is probably a combination of both,” said senior author Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology; division chief of neurological infections & global neurology; and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.
“Our message is that there are fairly frequent neurological sequelae of COVID-19 and we need to be alert to these, and to try to understand the potential long-term consequences,” she said.
The review was published online May 29 in JAMA Neurology.
Brain changes linked to loss of smell
In a separate article also published online in JAMA Neurology the same day, an Italian group describes a COVID-19 patient with anosmia (loss of sense of smell) who showed brain abnormalities on MRI in the areas associated with smell – the right gyrus rectus and the olfactory bulbs. These changes were resolved on later scan and the patient recovered her sense of smell.
“Based on the MRI findings, we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway,” conclude the researchers, led by first author Letterio S. Politi, MD, of the department of neuroradiology at IRCCS Istituto Clinico Humanitas and Humanitas University, Milan, Italy.
Can coronaviruses enter the CNS?
Dr. Spudich described this case report as “compelling evidence suggesting that loss of smell is a neurologic effect.”
“Loss of smell and/or taste is a common symptom in COVID-19, so this may suggest that an awful lot of people have some neurological involvement,” Dr. Spudich commented. “While a transient loss of smell or taste is not serious, if the virus has infected brain tissue the question is could this then spread to other parts of the brain and cause other more serious neurological effects,” she added.
In their review article, Dr. Spudich and colleagues present evidence showing that coronaviruses can enter the CNS.
“We know that SARS-1 and MERS have been shown to enter the nervous system and several coronaviruses have been shown to cause direct brain effects,” she said. “There is also some evidence that SARS-CoV-2 can do this too. As well as these latest MRI findings linked to loss of smell, there is a report of the virus being found in endothelial cells in the brain and a French autopsy study has also detected virus in the brain.”
Complications of other systemic effects?
Dr. Spudich is a neurologist specializing in neurologic consequences of infectious disease. “We don’t normally have such vast numbers of patients but in the last 3 months there has been an avalanche,” she says. From her personal experience, she believes the majority of neurologic symptoms in COVID-19 patients are most probably complications of other systemic effects, such as kidney, heart, or liver problems. But there is likely also a direct viral effect on the CNS in some patients.
“Reports from China suggested that serious neurologic effects were present in about one-third of hospitalized COVID-19 patients. I would say in our experience the figure would be less than that – maybe around 10%,” she noted.
Some COVID-19 patients are presenting with primary neurologic symptoms. For example, an elderly person may first develop confusion rather than a cough or shortness of breath; others have had severe headache as an initial COVID-19 symptom, Dr. Spudich reported. “Medical staff need to be aware of this – a severe headache in a patient who doesn’t normally get headaches could be a sign of the virus.”
Some of the neurologic symptoms could be caused by autoimmunity. Dr. Spudich explained that, in acute HIV infection a small proportion of patients can first present with autoimmune neurologic effects such as Guillain-Barré syndrome, an autoimmune condition of the nerves which causes a tingling sensation in the hands and feet. “This is well described in HIV, but we are also now seeing this in COVID-19 patients too,” she said. “A panoply of conditions can be caused by autoimmunity.”
On the increase in strokes that has been reported in COVID-19 patients, Dr. Spudich said, “this could be due to direct effects of the virus (e.g., causing an increase in coagulation or infecting the endothelial cells in the brain) or it could just be the final trigger for patients who were at risk of stroke anyway.”
There have been some very high-profile reports of younger patients with major strokes, she said, “but we haven’t seen that in our hospital. For the most part in my experience, strokes are happening in older COVID-19 patients with stroke risk factors such as AF [atrial fibrillation], hypertension, and diabetes. We haven’t seen a preponderance of strokes in young, otherwise healthy people.”
Even in patients who have neurologic effects as the first sign of COVID-19 infection, it is not known whether these symptoms are caused directly by the virus.
“We know that flu can cause people to have headaches, but that is because of an increase in inflammatory cytokines. On the other hand, patients with acute HIV infection often have headaches as a result of the virus getting into the brain. We don’t know where in this [cluster] COVID-19 virus falls,” Dr. Spudich said.
Much is still unknown
“The information we have is very sparse at this point. We need far more systematic information on this from CSF samples and imaging.” Dr. Spudich urged clinicians to try to collect such information in patients with neurologic symptoms.
Acknowledging that fewer such tests are being done at present because of concerns over infection risk, Dr. Spudich suggested that some changes in procedure may help. “In our hospital we have a portable MRI scanner which can be brought to the patient. This means the patient does not have to move across the hospital for a scan. This helps us to decide whether the patient has had a stroke, which can be missed when patients are on a ventilator.”
It is also unclear whether the neurologic effects seen during COVID-19 infection will last long term.
Dr. Spudich noted that there have been reports of COVID-19 patients discharged from intensive care having difficulty with higher cognitive function for some time thereafter. “This can happen after being in ICU but is it more pronounced in COVID-19 patients? An ongoing study is underway to look at this,” she said.
This article first appeared on Medscape.com.
A new review article summarizes what is known so far, and what clinicians need to look out for.
“We frequently see neurological conditions in people with COVID-19, but we understand very little about these effects. Is it the virus entering the brain/nerves or are they a result of a general inflammation or immune response – a bystander effect of people being severely ill. It is probably a combination of both,” said senior author Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology; division chief of neurological infections & global neurology; and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.
“Our message is that there are fairly frequent neurological sequelae of COVID-19 and we need to be alert to these, and to try to understand the potential long-term consequences,” she said.
The review was published online May 29 in JAMA Neurology.
Brain changes linked to loss of smell
In a separate article also published online in JAMA Neurology the same day, an Italian group describes a COVID-19 patient with anosmia (loss of sense of smell) who showed brain abnormalities on MRI in the areas associated with smell – the right gyrus rectus and the olfactory bulbs. These changes were resolved on later scan and the patient recovered her sense of smell.
“Based on the MRI findings, we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway,” conclude the researchers, led by first author Letterio S. Politi, MD, of the department of neuroradiology at IRCCS Istituto Clinico Humanitas and Humanitas University, Milan, Italy.
Can coronaviruses enter the CNS?
Dr. Spudich described this case report as “compelling evidence suggesting that loss of smell is a neurologic effect.”
“Loss of smell and/or taste is a common symptom in COVID-19, so this may suggest that an awful lot of people have some neurological involvement,” Dr. Spudich commented. “While a transient loss of smell or taste is not serious, if the virus has infected brain tissue the question is could this then spread to other parts of the brain and cause other more serious neurological effects,” she added.
In their review article, Dr. Spudich and colleagues present evidence showing that coronaviruses can enter the CNS.
“We know that SARS-1 and MERS have been shown to enter the nervous system and several coronaviruses have been shown to cause direct brain effects,” she said. “There is also some evidence that SARS-CoV-2 can do this too. As well as these latest MRI findings linked to loss of smell, there is a report of the virus being found in endothelial cells in the brain and a French autopsy study has also detected virus in the brain.”
Complications of other systemic effects?
Dr. Spudich is a neurologist specializing in neurologic consequences of infectious disease. “We don’t normally have such vast numbers of patients but in the last 3 months there has been an avalanche,” she says. From her personal experience, she believes the majority of neurologic symptoms in COVID-19 patients are most probably complications of other systemic effects, such as kidney, heart, or liver problems. But there is likely also a direct viral effect on the CNS in some patients.
“Reports from China suggested that serious neurologic effects were present in about one-third of hospitalized COVID-19 patients. I would say in our experience the figure would be less than that – maybe around 10%,” she noted.
Some COVID-19 patients are presenting with primary neurologic symptoms. For example, an elderly person may first develop confusion rather than a cough or shortness of breath; others have had severe headache as an initial COVID-19 symptom, Dr. Spudich reported. “Medical staff need to be aware of this – a severe headache in a patient who doesn’t normally get headaches could be a sign of the virus.”
Some of the neurologic symptoms could be caused by autoimmunity. Dr. Spudich explained that, in acute HIV infection a small proportion of patients can first present with autoimmune neurologic effects such as Guillain-Barré syndrome, an autoimmune condition of the nerves which causes a tingling sensation in the hands and feet. “This is well described in HIV, but we are also now seeing this in COVID-19 patients too,” she said. “A panoply of conditions can be caused by autoimmunity.”
On the increase in strokes that has been reported in COVID-19 patients, Dr. Spudich said, “this could be due to direct effects of the virus (e.g., causing an increase in coagulation or infecting the endothelial cells in the brain) or it could just be the final trigger for patients who were at risk of stroke anyway.”
There have been some very high-profile reports of younger patients with major strokes, she said, “but we haven’t seen that in our hospital. For the most part in my experience, strokes are happening in older COVID-19 patients with stroke risk factors such as AF [atrial fibrillation], hypertension, and diabetes. We haven’t seen a preponderance of strokes in young, otherwise healthy people.”
Even in patients who have neurologic effects as the first sign of COVID-19 infection, it is not known whether these symptoms are caused directly by the virus.
“We know that flu can cause people to have headaches, but that is because of an increase in inflammatory cytokines. On the other hand, patients with acute HIV infection often have headaches as a result of the virus getting into the brain. We don’t know where in this [cluster] COVID-19 virus falls,” Dr. Spudich said.
Much is still unknown
“The information we have is very sparse at this point. We need far more systematic information on this from CSF samples and imaging.” Dr. Spudich urged clinicians to try to collect such information in patients with neurologic symptoms.
Acknowledging that fewer such tests are being done at present because of concerns over infection risk, Dr. Spudich suggested that some changes in procedure may help. “In our hospital we have a portable MRI scanner which can be brought to the patient. This means the patient does not have to move across the hospital for a scan. This helps us to decide whether the patient has had a stroke, which can be missed when patients are on a ventilator.”
It is also unclear whether the neurologic effects seen during COVID-19 infection will last long term.
Dr. Spudich noted that there have been reports of COVID-19 patients discharged from intensive care having difficulty with higher cognitive function for some time thereafter. “This can happen after being in ICU but is it more pronounced in COVID-19 patients? An ongoing study is underway to look at this,” she said.
This article first appeared on Medscape.com.
A new review article summarizes what is known so far, and what clinicians need to look out for.
“We frequently see neurological conditions in people with COVID-19, but we understand very little about these effects. Is it the virus entering the brain/nerves or are they a result of a general inflammation or immune response – a bystander effect of people being severely ill. It is probably a combination of both,” said senior author Serena Spudich, MD, Gilbert H. Glaser Professor of Neurology; division chief of neurological infections & global neurology; and codirector of the Center for Neuroepidemiology and Clinical Neurological Research at Yale University, New Haven, Conn.
“Our message is that there are fairly frequent neurological sequelae of COVID-19 and we need to be alert to these, and to try to understand the potential long-term consequences,” she said.
The review was published online May 29 in JAMA Neurology.
Brain changes linked to loss of smell
In a separate article also published online in JAMA Neurology the same day, an Italian group describes a COVID-19 patient with anosmia (loss of sense of smell) who showed brain abnormalities on MRI in the areas associated with smell – the right gyrus rectus and the olfactory bulbs. These changes were resolved on later scan and the patient recovered her sense of smell.
“Based on the MRI findings, we can speculate that SARS-CoV-2 might invade the brain through the olfactory pathway,” conclude the researchers, led by first author Letterio S. Politi, MD, of the department of neuroradiology at IRCCS Istituto Clinico Humanitas and Humanitas University, Milan, Italy.
Can coronaviruses enter the CNS?
Dr. Spudich described this case report as “compelling evidence suggesting that loss of smell is a neurologic effect.”
“Loss of smell and/or taste is a common symptom in COVID-19, so this may suggest that an awful lot of people have some neurological involvement,” Dr. Spudich commented. “While a transient loss of smell or taste is not serious, if the virus has infected brain tissue the question is could this then spread to other parts of the brain and cause other more serious neurological effects,” she added.
In their review article, Dr. Spudich and colleagues present evidence showing that coronaviruses can enter the CNS.
“We know that SARS-1 and MERS have been shown to enter the nervous system and several coronaviruses have been shown to cause direct brain effects,” she said. “There is also some evidence that SARS-CoV-2 can do this too. As well as these latest MRI findings linked to loss of smell, there is a report of the virus being found in endothelial cells in the brain and a French autopsy study has also detected virus in the brain.”
Complications of other systemic effects?
Dr. Spudich is a neurologist specializing in neurologic consequences of infectious disease. “We don’t normally have such vast numbers of patients but in the last 3 months there has been an avalanche,” she says. From her personal experience, she believes the majority of neurologic symptoms in COVID-19 patients are most probably complications of other systemic effects, such as kidney, heart, or liver problems. But there is likely also a direct viral effect on the CNS in some patients.
“Reports from China suggested that serious neurologic effects were present in about one-third of hospitalized COVID-19 patients. I would say in our experience the figure would be less than that – maybe around 10%,” she noted.
Some COVID-19 patients are presenting with primary neurologic symptoms. For example, an elderly person may first develop confusion rather than a cough or shortness of breath; others have had severe headache as an initial COVID-19 symptom, Dr. Spudich reported. “Medical staff need to be aware of this – a severe headache in a patient who doesn’t normally get headaches could be a sign of the virus.”
Some of the neurologic symptoms could be caused by autoimmunity. Dr. Spudich explained that, in acute HIV infection a small proportion of patients can first present with autoimmune neurologic effects such as Guillain-Barré syndrome, an autoimmune condition of the nerves which causes a tingling sensation in the hands and feet. “This is well described in HIV, but we are also now seeing this in COVID-19 patients too,” she said. “A panoply of conditions can be caused by autoimmunity.”
On the increase in strokes that has been reported in COVID-19 patients, Dr. Spudich said, “this could be due to direct effects of the virus (e.g., causing an increase in coagulation or infecting the endothelial cells in the brain) or it could just be the final trigger for patients who were at risk of stroke anyway.”
There have been some very high-profile reports of younger patients with major strokes, she said, “but we haven’t seen that in our hospital. For the most part in my experience, strokes are happening in older COVID-19 patients with stroke risk factors such as AF [atrial fibrillation], hypertension, and diabetes. We haven’t seen a preponderance of strokes in young, otherwise healthy people.”
Even in patients who have neurologic effects as the first sign of COVID-19 infection, it is not known whether these symptoms are caused directly by the virus.
“We know that flu can cause people to have headaches, but that is because of an increase in inflammatory cytokines. On the other hand, patients with acute HIV infection often have headaches as a result of the virus getting into the brain. We don’t know where in this [cluster] COVID-19 virus falls,” Dr. Spudich said.
Much is still unknown
“The information we have is very sparse at this point. We need far more systematic information on this from CSF samples and imaging.” Dr. Spudich urged clinicians to try to collect such information in patients with neurologic symptoms.
Acknowledging that fewer such tests are being done at present because of concerns over infection risk, Dr. Spudich suggested that some changes in procedure may help. “In our hospital we have a portable MRI scanner which can be brought to the patient. This means the patient does not have to move across the hospital for a scan. This helps us to decide whether the patient has had a stroke, which can be missed when patients are on a ventilator.”
It is also unclear whether the neurologic effects seen during COVID-19 infection will last long term.
Dr. Spudich noted that there have been reports of COVID-19 patients discharged from intensive care having difficulty with higher cognitive function for some time thereafter. “This can happen after being in ICU but is it more pronounced in COVID-19 patients? An ongoing study is underway to look at this,” she said.
This article first appeared on Medscape.com.
No benefit of three commonly used medications for MS fatigue
The TRIUMPHANT study found no difference between the effects of amantadine, modafinil, methylphenidate, and placebo in the Modified Fatigue Impact Scale (MFIS) in a study involving 141 patients with MS.
There was also no difference between any of the drugs and placebo in any of the preplanned subgroups which included different Expanded Disability Status Scale scores, depressive scores, use of disease-modifying therapy, or type of MS (relapsing remitting or progressive).
The research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
“These three drugs are used very commonly used for MS fatigue by neurologists, psychiatrists, and primary care doctors, but they don’t seem to be any better than placebo. They were all associated with increased side effects compared with placebo even with short-term use,” said lead investigator Bardia Nourbakhsh, MD, assistant professor of neurology at Johns Hopkins University, Baltimore.
However, in a post hoc analysis there was an improvement in daytime sleepiness with two of the drugs – methylphenidate and modafinil. “These two agents reduced daytime sleepiness in patients with high daytime sleepiness scores at baseline, with about a 4-point difference versus placebo, which was significant. But as this was not a preplanned analysis, we have to be cautious in its interpretation,” Dr. Nourbakhsh said. “However, this finding may not be too surprising as both these drugs are licensed as stimulants for use in narcolepsy patients with excessive daytime sleepiness.”
“Our recommendations are that as amantadine was not better than placebo in any subgroup its use should be discouraged in MS fatigue,” Dr. Nourbakhsh commented. “Modafinil and methylphenidate may possibly be considered for MS patients with excessive daytime sleepiness, but this should really be confirmed in further studies.”
Fatigue is a common and debilitating symptom of MS, occurring in about 70%-80% of patients with MS. There is no approved drug treatment. However nonpharmacologic therapies have shown some success: studies of exercise and cognitive-behavioral therapy (CBT) have shown these may be effective without causing side effects, Dr. Nourbakhsh noted. “So we should be getting patients to try exercise and CBT before jumping to medication.”
Dr. Nourbakhsh said he was disappointed with the results of the study but not terribly surprised. “We use these three medications frequently in the clinic and we have not been seeing great benefits so we wondered whether they were actually effective.”
He said that the trial was adequately powered and the question has been answered. “These are valuable results – they will hopefully encourage doctors to think twice before prescribing these medications that could be harmful and have no clear benefit,” Dr. Nourbakhsh concluded.
For the randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, 141 patients with MS and fatigue received twice-daily oral amantadine (maximum 200 mg/day), modafinil (maximum 200 mg/day), methylphenidate (maximum 20 mg/day), or placebo, each given for up to 6 weeks with a 2-week washout between each medication.
Patients had a mean baseline MFIS score of 51.3 and were randomly assigned to one of four medication administration sequences. Data from 136 participants were available for the analysis of the primary outcome (change in MFIS score), and 111 participants completed all four medication periods.
In the intent-to-treat analysis, the least-squares means of total MFIS scores at the maximally tolerated dose were as follows: 40.7 with placebo, 41.2 with amantadine, 39.0 with modafinil, and 38.7 with methylphenidate (P = .20 for the overall medication effect; P > .05 for all pairwise comparisons). “All medications and placebo reduced the MS fatigue score by 10-12 points from baseline, so there was quite a substantial placebo effect,” Dr. Nourbakhsh noted. There was no statistically significant difference in the physical and cognitive subscales of MFIS and quality of life measures between any of the study medications and placebo. All three drugs were associated with an increase in adverse effects versus placebo.
Dr. Nourbakhsh says he is hopeful that this negative study may stimulate further research into new targets and medications for MS fatigue.
His group has recently conducted a pilot study of intravenous ketamine in MS fatigue with some encouraging results, but he stressed it needs to be tested in a larger study before it can be recommended for use in clinical practice. “While an IV medication is not ideal, the effect did seem to be quite long-lived with a difference still evident at 28 days, so it could perhaps be dosed once a month, which could be feasible,” he said.
Commenting on the TRIUMPHANT study, Jeffrey Cohen, MD, of the Cleveland Clinic, said that “fatigue is a common, often disabling, symptom of MS. It is poorly understood and probably encompasses several mechanisms. There currently is no generally effective treatment for MS-related fatigue.”
“These results are not surprising and confirm previous studies,” Dr. Cohen said. “Despite no benefit from these medicines for patients as a group, they are occasionally helpful for individual patients, so they are frequently tried empirically.
“It also is important to address any factors besides MS that may be causing or contributing to fatigue, for example, sleep disruption, medication side effects, depression, other medical conditions such as anemia or hypothyroidism,” he added.
Dr. Nourbakhsh has reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities for Jazz Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
The TRIUMPHANT study found no difference between the effects of amantadine, modafinil, methylphenidate, and placebo in the Modified Fatigue Impact Scale (MFIS) in a study involving 141 patients with MS.
There was also no difference between any of the drugs and placebo in any of the preplanned subgroups which included different Expanded Disability Status Scale scores, depressive scores, use of disease-modifying therapy, or type of MS (relapsing remitting or progressive).
The research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
“These three drugs are used very commonly used for MS fatigue by neurologists, psychiatrists, and primary care doctors, but they don’t seem to be any better than placebo. They were all associated with increased side effects compared with placebo even with short-term use,” said lead investigator Bardia Nourbakhsh, MD, assistant professor of neurology at Johns Hopkins University, Baltimore.
However, in a post hoc analysis there was an improvement in daytime sleepiness with two of the drugs – methylphenidate and modafinil. “These two agents reduced daytime sleepiness in patients with high daytime sleepiness scores at baseline, with about a 4-point difference versus placebo, which was significant. But as this was not a preplanned analysis, we have to be cautious in its interpretation,” Dr. Nourbakhsh said. “However, this finding may not be too surprising as both these drugs are licensed as stimulants for use in narcolepsy patients with excessive daytime sleepiness.”
“Our recommendations are that as amantadine was not better than placebo in any subgroup its use should be discouraged in MS fatigue,” Dr. Nourbakhsh commented. “Modafinil and methylphenidate may possibly be considered for MS patients with excessive daytime sleepiness, but this should really be confirmed in further studies.”
Fatigue is a common and debilitating symptom of MS, occurring in about 70%-80% of patients with MS. There is no approved drug treatment. However nonpharmacologic therapies have shown some success: studies of exercise and cognitive-behavioral therapy (CBT) have shown these may be effective without causing side effects, Dr. Nourbakhsh noted. “So we should be getting patients to try exercise and CBT before jumping to medication.”
Dr. Nourbakhsh said he was disappointed with the results of the study but not terribly surprised. “We use these three medications frequently in the clinic and we have not been seeing great benefits so we wondered whether they were actually effective.”
He said that the trial was adequately powered and the question has been answered. “These are valuable results – they will hopefully encourage doctors to think twice before prescribing these medications that could be harmful and have no clear benefit,” Dr. Nourbakhsh concluded.
For the randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, 141 patients with MS and fatigue received twice-daily oral amantadine (maximum 200 mg/day), modafinil (maximum 200 mg/day), methylphenidate (maximum 20 mg/day), or placebo, each given for up to 6 weeks with a 2-week washout between each medication.
Patients had a mean baseline MFIS score of 51.3 and were randomly assigned to one of four medication administration sequences. Data from 136 participants were available for the analysis of the primary outcome (change in MFIS score), and 111 participants completed all four medication periods.
In the intent-to-treat analysis, the least-squares means of total MFIS scores at the maximally tolerated dose were as follows: 40.7 with placebo, 41.2 with amantadine, 39.0 with modafinil, and 38.7 with methylphenidate (P = .20 for the overall medication effect; P > .05 for all pairwise comparisons). “All medications and placebo reduced the MS fatigue score by 10-12 points from baseline, so there was quite a substantial placebo effect,” Dr. Nourbakhsh noted. There was no statistically significant difference in the physical and cognitive subscales of MFIS and quality of life measures between any of the study medications and placebo. All three drugs were associated with an increase in adverse effects versus placebo.
Dr. Nourbakhsh says he is hopeful that this negative study may stimulate further research into new targets and medications for MS fatigue.
His group has recently conducted a pilot study of intravenous ketamine in MS fatigue with some encouraging results, but he stressed it needs to be tested in a larger study before it can be recommended for use in clinical practice. “While an IV medication is not ideal, the effect did seem to be quite long-lived with a difference still evident at 28 days, so it could perhaps be dosed once a month, which could be feasible,” he said.
Commenting on the TRIUMPHANT study, Jeffrey Cohen, MD, of the Cleveland Clinic, said that “fatigue is a common, often disabling, symptom of MS. It is poorly understood and probably encompasses several mechanisms. There currently is no generally effective treatment for MS-related fatigue.”
“These results are not surprising and confirm previous studies,” Dr. Cohen said. “Despite no benefit from these medicines for patients as a group, they are occasionally helpful for individual patients, so they are frequently tried empirically.
“It also is important to address any factors besides MS that may be causing or contributing to fatigue, for example, sleep disruption, medication side effects, depression, other medical conditions such as anemia or hypothyroidism,” he added.
Dr. Nourbakhsh has reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities for Jazz Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
The TRIUMPHANT study found no difference between the effects of amantadine, modafinil, methylphenidate, and placebo in the Modified Fatigue Impact Scale (MFIS) in a study involving 141 patients with MS.
There was also no difference between any of the drugs and placebo in any of the preplanned subgroups which included different Expanded Disability Status Scale scores, depressive scores, use of disease-modifying therapy, or type of MS (relapsing remitting or progressive).
The research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
“These three drugs are used very commonly used for MS fatigue by neurologists, psychiatrists, and primary care doctors, but they don’t seem to be any better than placebo. They were all associated with increased side effects compared with placebo even with short-term use,” said lead investigator Bardia Nourbakhsh, MD, assistant professor of neurology at Johns Hopkins University, Baltimore.
However, in a post hoc analysis there was an improvement in daytime sleepiness with two of the drugs – methylphenidate and modafinil. “These two agents reduced daytime sleepiness in patients with high daytime sleepiness scores at baseline, with about a 4-point difference versus placebo, which was significant. But as this was not a preplanned analysis, we have to be cautious in its interpretation,” Dr. Nourbakhsh said. “However, this finding may not be too surprising as both these drugs are licensed as stimulants for use in narcolepsy patients with excessive daytime sleepiness.”
“Our recommendations are that as amantadine was not better than placebo in any subgroup its use should be discouraged in MS fatigue,” Dr. Nourbakhsh commented. “Modafinil and methylphenidate may possibly be considered for MS patients with excessive daytime sleepiness, but this should really be confirmed in further studies.”
Fatigue is a common and debilitating symptom of MS, occurring in about 70%-80% of patients with MS. There is no approved drug treatment. However nonpharmacologic therapies have shown some success: studies of exercise and cognitive-behavioral therapy (CBT) have shown these may be effective without causing side effects, Dr. Nourbakhsh noted. “So we should be getting patients to try exercise and CBT before jumping to medication.”
Dr. Nourbakhsh said he was disappointed with the results of the study but not terribly surprised. “We use these three medications frequently in the clinic and we have not been seeing great benefits so we wondered whether they were actually effective.”
He said that the trial was adequately powered and the question has been answered. “These are valuable results – they will hopefully encourage doctors to think twice before prescribing these medications that could be harmful and have no clear benefit,” Dr. Nourbakhsh concluded.
For the randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, 141 patients with MS and fatigue received twice-daily oral amantadine (maximum 200 mg/day), modafinil (maximum 200 mg/day), methylphenidate (maximum 20 mg/day), or placebo, each given for up to 6 weeks with a 2-week washout between each medication.
Patients had a mean baseline MFIS score of 51.3 and were randomly assigned to one of four medication administration sequences. Data from 136 participants were available for the analysis of the primary outcome (change in MFIS score), and 111 participants completed all four medication periods.
In the intent-to-treat analysis, the least-squares means of total MFIS scores at the maximally tolerated dose were as follows: 40.7 with placebo, 41.2 with amantadine, 39.0 with modafinil, and 38.7 with methylphenidate (P = .20 for the overall medication effect; P > .05 for all pairwise comparisons). “All medications and placebo reduced the MS fatigue score by 10-12 points from baseline, so there was quite a substantial placebo effect,” Dr. Nourbakhsh noted. There was no statistically significant difference in the physical and cognitive subscales of MFIS and quality of life measures between any of the study medications and placebo. All three drugs were associated with an increase in adverse effects versus placebo.
Dr. Nourbakhsh says he is hopeful that this negative study may stimulate further research into new targets and medications for MS fatigue.
His group has recently conducted a pilot study of intravenous ketamine in MS fatigue with some encouraging results, but he stressed it needs to be tested in a larger study before it can be recommended for use in clinical practice. “While an IV medication is not ideal, the effect did seem to be quite long-lived with a difference still evident at 28 days, so it could perhaps be dosed once a month, which could be feasible,” he said.
Commenting on the TRIUMPHANT study, Jeffrey Cohen, MD, of the Cleveland Clinic, said that “fatigue is a common, often disabling, symptom of MS. It is poorly understood and probably encompasses several mechanisms. There currently is no generally effective treatment for MS-related fatigue.”
“These results are not surprising and confirm previous studies,” Dr. Cohen said. “Despite no benefit from these medicines for patients as a group, they are occasionally helpful for individual patients, so they are frequently tried empirically.
“It also is important to address any factors besides MS that may be causing or contributing to fatigue, for example, sleep disruption, medication side effects, depression, other medical conditions such as anemia or hypothyroidism,” he added.
Dr. Nourbakhsh has reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities for Jazz Pharmaceuticals.
A version of this article originally appeared on Medscape.com.
More from REDUCE-IT: Icosapent ethyl cuts revascularization by a third
A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.
The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.
REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.
The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.
“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.
This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.
“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.
“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.
Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).
Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).
The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”
Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.
REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.
“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.
“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.
Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”
Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”
Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”
REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.
A version of this article originally appeared on Medscape.com.
A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.
The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.
REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.
The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.
“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.
This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.
“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.
“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.
Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).
Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).
The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”
Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.
REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.
“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.
“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.
Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”
Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”
Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”
REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.
A version of this article originally appeared on Medscape.com.
A new analysis from the REDUCE-IT trial has shown that the high-strength eicosapentaenoic acid product icosapent ethyl (Vascepa; Amarin) reduced the number of revascularization procedures by more than one-third in statin-treated patients whose triglyceride levels were elevated and who were at increased cardiovascular risk.
The new data were presented at the Society for Cardiovascular Angiography & Interventions virtual annual scientific sessions.
REDUCE-IT, a multicenter, double-blind, placebo-controlled trial, randomly assigned statin-treated patients whose triglyceride levels were elevated (135-499 mg/dL), whose LDL cholesterol levels were controlled (41-100 mg/dL), and who had established cardiovascular disease or diabetes plus risk factors to receive either icosapent ethyl 4 g daily or placebo.
The primary composite and other cardiovascular endpoints were substantially reduced. Prespecified analyses examined all coronary revascularizations, recurrent revascularizations, and revascularization subtypes.
“Compared with placebo, icosapent ethyl 4 g/day significantly reduced first and total revascularization events by 34% and 36%, respectively,” REDUCE-IT investigator Benjamin Peterson, MD, of Brigham and Women’s Hospital, Boston, concluded during his presentation.
This reduction was consistent with respect to urgent, emergent, and elective revascularization procedures overall, as well as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) individually, he reported.
“Prior therapies aimed at patients with elevated triglycerides have not demonstrated a consistent benefit in reducing coronary revascularization, and to the best of our knowledge, this is the first non–LDL cholesterol intervention in a major randomized trial in which statin-treated patients underwent fewer CABG surgeries,” Dr. Peterson stated.
“These data highlight the substantial impact of icosapent ethyl on the underlying atherothrombotic burden in the at-risk REDUCE-IT population,” he added.
Detailed results showed that the percentage of patients who underwent first revascularizations was 9.2% with icosapent ethyl versus 13.3% with placebo (hazard ratio, 0.66; P < .0001; number needed to treat, 25).
Similar reductions were observed in total (first and subsequent) revascularizations (risk ratio, 0.64; P < .0001) and across urgent, emergent, and elective revascularizations. Icosapent ethyl significantly reduced the need for PCI (HR, 0.68; P < .0001) and CABG (HR, 0.61; P = .0005).
The moderator of a SCAI press conference, Kirk Garratt, MD, of the Center for Heart and Vascular Health at Christiana Care Health System in Wilmington, Del., said that “this is an impressive impact. I couldn’t count the number of zeros in the P value.”
Timothy Henry, MD, of Christ Hospital in Cincinnati, said that REDUCE-IT was an important trial. “It showed a very impressive effect on revascularizations along with all the other benefits.” But he suggested that the uptake in usage of icosapent ethyl in the United States has been slow, and he asked what could be done to enhance this.
REDUCE-IT senior investigator Deepak Bhatt, MD, replied that the product was only approved for the REDUCE-IT indication in December 2019, and he suggested that initial uptake may have been affected by the current COVID-19 pandemic.
“This new REDUCE-IT indication ― patients with established cardiovascular disease or diabetes plus risk factors who have moderately elevated triglycerides and controlled LDL ― includes a lot of patients, between 15% and 50% of all cardiovascular patients,” he said.
“We wanted to present this revascularization data at the SCAI meeting, as it is superimportant that interventional cardiologists know about this. Interventionalists have now taken ownership of LDL and make sure patients are on statins, and we hope they will now do the same thing for triglycerides,” Dr. Bhatt commented.
Dr. Henry agreed. “It should be a simple thing to take all secondary prevention patients with eligible triglycerides and be aggressive with this new therapy.”
Dr. Bhatt noted that a cost-effectiveness analysis of the REDUCE-IT trial that was presented at last year’s American Heart Association meeting “has shown the drug to be highly cost effective and actually cost saving at the current list price.”
Asked what the mechanism of benefit is, Dr. Bhatt said that “there has been good basic science showing that EPA [eicosapentaenoic acid] stabilizes cell membranes and reduces plaque vulnerability and progression.”
REDUCE-IT was sponsored by Amarin. Brigham and Women’s Hospital receives research funding from Amarin for Dr. Bhatt’s role as chair of the trial.
A version of this article originally appeared on Medscape.com.
ACE inhibitors and severe COVID-19: Protective in older patients?
.
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.
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?”
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.
.
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.
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?”
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.
.
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.
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?”
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.
Statins and ICH: new meta-analysis
The meta-analysis was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Coauthor Abhi Pandhi, MD, the University of Tennessee Health Science Center, Memphis, explained that some previous studies have suggested that statin therapy may be associated with an increased risk for ICH, especially at higher doses. Other studies, however, have failed to confirm this and have shown an increase in cardiovascular events if statins are stopped.
To look further into this issue, Dr. Pandhi and colleagues conducted a meta-analysis of 19 clinical studies involving patients who had a history of cardiovascular or cerebrovascular events and who had been treated with statins. A total of 35,842 patients were included.
Results showed that statin use was not significantly associated with the risk for combined primary and secondary ICH (relative risk, 1.03; 95% confidence interval, 0.85–1.08). But the risk for cerebral ischemia (stroke and transient ischemic attack) was significantly lower in those who received statins (RR, 0.79; 95% CI, 0.61–0.87).
“Overall, we found no effect of statins on the risk of ICH, and benefits on reducing ischemic events are clear,” Dr. Pandhi said.
Increased secondary ICH?
However, a sensitivity analysis showed a trend toward a higher risk for secondary ICH among those who were assigned to statin treatment (odds ratio, 1.87; 95% CI, 0.91–3.86).
“While this may suggest an increased risk of secondary ICH, when we look at the big picture, putting all the data together, and given that ischemic events are far more common than ICH, the risk of stopping statins and losing the protection against ischemic events is probably greater than any harm even in patients with underlying risk factors for ICH,” Dr. Pandhi concluded.
Commenting on the study, Michael Szarek, PhD, who has also conducted research in this field, said: “The results of this meta-analysis appear to be consistent with individual randomized trials of statins in patients with cerebrovascular disease that have shown clear benefit in terms of ischemic stroke or TIA and potential harm in terms of hemorrhagic stroke.”
Dr. Szarek is chair and professor in the Department of Epidemiology and Biostatistics at the SUNY Downstate Health Sciences University, New York City.
“However, the much greater frequency of ischemic events, coupled with benefits in coronary and peripheral vascular territories, suggest the risk/benefit of statin treatment remains favorable in this patient population, with the possible exception of patients with a history of hemorrhagic stroke,” he added.
Also commenting on this latest meta-analysis, Pamela Rist, ScD, associate epidemiologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston, who has also authored studies in this area, said the results of this study seem similar to prior results from meta-analyses of clinical trials.
“It will be interesting to see the full manuscript to learn more about the sensitivity analyses they conducted and why they may have observed a nonsignificant increased risk of secondary ICH among some individuals using statins,” Dr. Rist added.
“Based on prior published meta-analyses of statin use and ICH, any potential increase in risk of hemorrhagic stroke is probably outweighed by the reduction in ischemic stroke and other cardiovascular events,” she concluded.
Dr. Pandhi has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Ishfaq A et al. AAN 2020. Abstract S9.010.
The meta-analysis was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Coauthor Abhi Pandhi, MD, the University of Tennessee Health Science Center, Memphis, explained that some previous studies have suggested that statin therapy may be associated with an increased risk for ICH, especially at higher doses. Other studies, however, have failed to confirm this and have shown an increase in cardiovascular events if statins are stopped.
To look further into this issue, Dr. Pandhi and colleagues conducted a meta-analysis of 19 clinical studies involving patients who had a history of cardiovascular or cerebrovascular events and who had been treated with statins. A total of 35,842 patients were included.
Results showed that statin use was not significantly associated with the risk for combined primary and secondary ICH (relative risk, 1.03; 95% confidence interval, 0.85–1.08). But the risk for cerebral ischemia (stroke and transient ischemic attack) was significantly lower in those who received statins (RR, 0.79; 95% CI, 0.61–0.87).
“Overall, we found no effect of statins on the risk of ICH, and benefits on reducing ischemic events are clear,” Dr. Pandhi said.
Increased secondary ICH?
However, a sensitivity analysis showed a trend toward a higher risk for secondary ICH among those who were assigned to statin treatment (odds ratio, 1.87; 95% CI, 0.91–3.86).
“While this may suggest an increased risk of secondary ICH, when we look at the big picture, putting all the data together, and given that ischemic events are far more common than ICH, the risk of stopping statins and losing the protection against ischemic events is probably greater than any harm even in patients with underlying risk factors for ICH,” Dr. Pandhi concluded.
Commenting on the study, Michael Szarek, PhD, who has also conducted research in this field, said: “The results of this meta-analysis appear to be consistent with individual randomized trials of statins in patients with cerebrovascular disease that have shown clear benefit in terms of ischemic stroke or TIA and potential harm in terms of hemorrhagic stroke.”
Dr. Szarek is chair and professor in the Department of Epidemiology and Biostatistics at the SUNY Downstate Health Sciences University, New York City.
“However, the much greater frequency of ischemic events, coupled with benefits in coronary and peripheral vascular territories, suggest the risk/benefit of statin treatment remains favorable in this patient population, with the possible exception of patients with a history of hemorrhagic stroke,” he added.
Also commenting on this latest meta-analysis, Pamela Rist, ScD, associate epidemiologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston, who has also authored studies in this area, said the results of this study seem similar to prior results from meta-analyses of clinical trials.
“It will be interesting to see the full manuscript to learn more about the sensitivity analyses they conducted and why they may have observed a nonsignificant increased risk of secondary ICH among some individuals using statins,” Dr. Rist added.
“Based on prior published meta-analyses of statin use and ICH, any potential increase in risk of hemorrhagic stroke is probably outweighed by the reduction in ischemic stroke and other cardiovascular events,” she concluded.
Dr. Pandhi has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Ishfaq A et al. AAN 2020. Abstract S9.010.
The meta-analysis was presented online as part of the 2020 American Academy of Neurology Science Highlights.
Coauthor Abhi Pandhi, MD, the University of Tennessee Health Science Center, Memphis, explained that some previous studies have suggested that statin therapy may be associated with an increased risk for ICH, especially at higher doses. Other studies, however, have failed to confirm this and have shown an increase in cardiovascular events if statins are stopped.
To look further into this issue, Dr. Pandhi and colleagues conducted a meta-analysis of 19 clinical studies involving patients who had a history of cardiovascular or cerebrovascular events and who had been treated with statins. A total of 35,842 patients were included.
Results showed that statin use was not significantly associated with the risk for combined primary and secondary ICH (relative risk, 1.03; 95% confidence interval, 0.85–1.08). But the risk for cerebral ischemia (stroke and transient ischemic attack) was significantly lower in those who received statins (RR, 0.79; 95% CI, 0.61–0.87).
“Overall, we found no effect of statins on the risk of ICH, and benefits on reducing ischemic events are clear,” Dr. Pandhi said.
Increased secondary ICH?
However, a sensitivity analysis showed a trend toward a higher risk for secondary ICH among those who were assigned to statin treatment (odds ratio, 1.87; 95% CI, 0.91–3.86).
“While this may suggest an increased risk of secondary ICH, when we look at the big picture, putting all the data together, and given that ischemic events are far more common than ICH, the risk of stopping statins and losing the protection against ischemic events is probably greater than any harm even in patients with underlying risk factors for ICH,” Dr. Pandhi concluded.
Commenting on the study, Michael Szarek, PhD, who has also conducted research in this field, said: “The results of this meta-analysis appear to be consistent with individual randomized trials of statins in patients with cerebrovascular disease that have shown clear benefit in terms of ischemic stroke or TIA and potential harm in terms of hemorrhagic stroke.”
Dr. Szarek is chair and professor in the Department of Epidemiology and Biostatistics at the SUNY Downstate Health Sciences University, New York City.
“However, the much greater frequency of ischemic events, coupled with benefits in coronary and peripheral vascular territories, suggest the risk/benefit of statin treatment remains favorable in this patient population, with the possible exception of patients with a history of hemorrhagic stroke,” he added.
Also commenting on this latest meta-analysis, Pamela Rist, ScD, associate epidemiologist at Brigham and Women’s Hospital and assistant professor of medicine at Harvard Medical School, Boston, who has also authored studies in this area, said the results of this study seem similar to prior results from meta-analyses of clinical trials.
“It will be interesting to see the full manuscript to learn more about the sensitivity analyses they conducted and why they may have observed a nonsignificant increased risk of secondary ICH among some individuals using statins,” Dr. Rist added.
“Based on prior published meta-analyses of statin use and ICH, any potential increase in risk of hemorrhagic stroke is probably outweighed by the reduction in ischemic stroke and other cardiovascular events,” she concluded.
Dr. Pandhi has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
SOURCE: Ishfaq A et al. AAN 2020. Abstract S9.010.
AAN 2020
New angiotensin studies in COVID-19 give more reassurance
Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.
Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.
Although all the studies are observational in design and have some confounding factors, overall, However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.
Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
Was it ‘Much ado about nothing’?
Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”
But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.
In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).
In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.
In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).
The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”
“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.
A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.
A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.
In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.
“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.
In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.
In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.
Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.
Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.
In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.
“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.
In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.
After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
Are there different effects between ACE inhibitors and ARBs?
A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.
Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.
“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.
“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.
In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”
The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”
Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.
“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.
He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”
Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”
Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.
A version of this article originally appeared on Medscape.com.
Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.
Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.
Although all the studies are observational in design and have some confounding factors, overall, However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.
Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
Was it ‘Much ado about nothing’?
Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”
But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.
In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).
In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.
In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).
The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”
“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.
A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.
A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.
In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.
“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.
In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.
In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.
Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.
Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.
In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.
“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.
In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.
After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
Are there different effects between ACE inhibitors and ARBs?
A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.
Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.
“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.
“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.
In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”
The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”
Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.
“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.
He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”
Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”
Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.
A version of this article originally appeared on Medscape.com.
Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.
Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.
Although all the studies are observational in design and have some confounding factors, overall, However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.
Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
Was it ‘Much ado about nothing’?
Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”
But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.
In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).
In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.
In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).
The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”
“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.
A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.
A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.
In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.
“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.
In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.
In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.
Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.
Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.
In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.
“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.
In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.
After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
Are there different effects between ACE inhibitors and ARBs?
A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.
Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.
“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.
“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.
In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”
The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”
Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.
“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.
He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”
Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”
Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.
A version of this article originally appeared on Medscape.com.
Diastolic dysfunction is a common risk factor for cognitive decline
a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.
“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.
“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.
This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.
Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.
“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.
“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.
Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.
The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.
Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).
An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.
Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).
Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).
The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.
The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.
Earlier interventions
Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”
Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”
Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.
Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.
“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.
With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.
About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.
Dr. Parker has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.
“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.
“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.
This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.
Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.
“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.
“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.
Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.
The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.
Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).
An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.
Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).
Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).
The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.
The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.
Earlier interventions
Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”
Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”
Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.
Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.
“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.
With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.
About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.
Dr. Parker has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.
“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.
“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.
This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.
Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.
“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.
“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.
Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.
The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.
Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).
An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.
Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).
Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).
The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.
The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.
Earlier interventions
Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”
Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”
Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.
Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.
“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.
With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.
About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.
Dr. Parker has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Remdesivir now ‘standard of care’ for COVID-19, Fauci says
, according to a preliminary data analysis from a U.S.-led randomized, controlled trial.
On the basis of as yet unpublished data, remdesivir “will be the standard of care” for patients with COVID-19, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), said during a press conference at the White House April 29.
The randomized, placebo-controlled international trial was sponsored by NIAID, which is part of the National Institutes of Health, and enrolled 1,063 patients. It began on Feb. 21.
The interim results, discussed in the press conference and in a NIAID press release, show that time to recovery (i.e., being well enough for hospital discharge or to return to normal activity level) was 31% faster for patients who received remdesivir than for those who received placebo (P < .001).
The median time to recovery was 11 days for patients treated with remdesivir, compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir and 11.6% for the patients who received placebo (P = .059).
The study, known as the Adaptive COVID-19 Treatment Trial (ACTT), is the first clinical trial launched in the United States to evaluate an experimental treatment for COVID-19. It is being conducted at 68 sites – 47 in the United States and 21 in countries in Europe and Asia.
The data are being released after an interim review by the independent data safety monitoring board found significant benefit with the drug, Dr. Fauci said.
“The reason we are making the announcement now is something that people don’t fully appreciate: Whenever you have clear-cut evidence that a drug works, you have an ethical obligation to let the people in the placebo group know so they could have access,” he explained.
“When I was looking at the data with our team the other night, it was reminiscent of 34 years ago in 1986 when we were struggling for drugs for HIV,” said Dr. Fauci, who was a key figure in HIV/AIDS research. “We did the first randomized, placebo-controlled trial with AZT. It turned out to have an effect that was modest but that was not the endgame because, building on that, every year after, we did better and better.”
Similarly, new trials of drugs for COVID-19 will build on remdesivir, with other agents being added to block other pathways or viral enzymes, Dr. Fauci said.
The study will be submitted to a journal for peer review, he noted, but the New York Times is reporting that the Food and Drug Administration will approve remdesivir for emergency use soon.
In contrast to the positive results Dr. Fauci described from the NIAID-sponsored trial, a randomized, placebo-controlled clinical trial of remdesivir among hospitalized patients with severe COVID-19 in China was inconclusive.
The study, published online in The Lancet, showed some nonsignificant trends toward benefit but did not meet its primary endpoint.
The study was stopped early after 237 of the intended 453 patients were enrolled, owing to a lack of additional patients who met the eligibility criteria. The trial was thus underpowered.
Results showed that treatment with remdesivir did not significantly speed recovery or reduce deaths from COVID-19, but with regard to prespecified secondary outcomes, time to clinical improvement and duration of invasive mechanical ventilation were shorter among a subgroup of patients who began undergoing treatment with remdesivir within 10 days of showing symptoms, in comparison with patients who received standard care.
“To me, the studies reported here in The Lancet appear to be less promising than some statements released today from the NIH, so the situation is a bit puzzling to me,” said Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, who was not involved in the study. “I would need to look more closely at the data which NIH is looking at to understand the differences.”
Trial details
The published trial was conducted at 10 hospitals in Hubei, China. Enrollment criteria included being admitted to hospital with laboratory-confirmed SARS-CoV-2 infection within 12 days of symptom onset, having oxygen saturation of 94% or less, and having radiologically confirmed pneumonia.
Patients were randomly assigned in a 2:1 ratio to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids.
The primary endpoint was time to clinical improvement to day 28, defined as the time (in days) from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (on that scale, 1 indicated that the patient was discharged, and 6 indicated death) or to the patient’s being discharged alive from hospital, whichever came first.
The trial was stopped early because stringent public health measures used in Wuhan led to marked reductions in new patient presentations and because lack of available hospital beds resulted in most patients being enrolled later in the course of disease.
Between Feb. 6, 2020, and March 12, 2020, 237 patients were enrolled and were randomly assigned to receive either remdesivir (n = 158) or placebo (n = 79).
Results showed that use of remdesivir was not associated with a difference in time to clinical improvement (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.87-1.75).
Although not statistically significant, time to clinical improvement was numerically faster for patients who received remdesivir than for those who received placebo among patients with symptom duration of 10 days or less (median, 18 days vs. 23 days; HR, 1.52; 95% CI, 0.95-2.43).
The mortality rates were similar for the two groups (14% of patients who received remdesivir died vs. 13% of those who received placebo). There was no signal that viral load decreased differentially over time between the two groups.
Adverse events were reported in 66% of remdesivir recipients, vs. 64% of those who received placebo. Remdesivir was stopped early because of adverse events in 12% of patients; it was stopped early for 5% of those who received placebo.
The authors, led by Yeming Wang, MD, China-Japan Friendship Hospital, Beijing, noted that compared with a previous study of compassionate use of remdesivir, the population in the current study was less ill and was treated somewhat earlier in the disease course (median, 10 days vs. 12 days).
Because the study was terminated early, the researchers said they could not adequately assess whether earlier treatment with remdesivir might have provided clinical benefit.
“However, among patients who were treated within 10 days of symptom onset, remdesivir was not a significant factor but was associated with a numerical reduction of 5 days in median time to clinical improvement,” they stated.
They added that remdesivir was adequately tolerated and that no new safety concerns were identified.
In an accompanying comment in The Lancet, John David Norrie, MD, Edinburgh Clinical Trials Unit, United Kingdom, pointed out that this study “has not shown a statistically significant finding that confirms a remdesivir treatment benefit of at least the minimally clinically important difference, nor has it ruled such a benefit out.”
Dr. Norrie was cautious about the fact that the subgroup analysis suggested possible benefit for those treated within 10 days.
Although he said it seems biologically plausible that treating patients earlier could be more effective, he added that “as well as being vigilant against overinterpretation, we need to ensure that hypotheses generated in efficacy-based trials, even in subgroups, are confirmed or refuted in subsequent adequately powered trials or meta-analyses.”
Noting that several other trials of remdesivir are underway, he concluded: “With each individual study at heightened risk of being incomplete, pooling data across possibly several underpowered but high-quality studies looks like our best way to obtain robust insights into what works, safely, and on whom.”
A version of this article originally appeared on Medscape.com.
, according to a preliminary data analysis from a U.S.-led randomized, controlled trial.
On the basis of as yet unpublished data, remdesivir “will be the standard of care” for patients with COVID-19, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), said during a press conference at the White House April 29.
The randomized, placebo-controlled international trial was sponsored by NIAID, which is part of the National Institutes of Health, and enrolled 1,063 patients. It began on Feb. 21.
The interim results, discussed in the press conference and in a NIAID press release, show that time to recovery (i.e., being well enough for hospital discharge or to return to normal activity level) was 31% faster for patients who received remdesivir than for those who received placebo (P < .001).
The median time to recovery was 11 days for patients treated with remdesivir, compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir and 11.6% for the patients who received placebo (P = .059).
The study, known as the Adaptive COVID-19 Treatment Trial (ACTT), is the first clinical trial launched in the United States to evaluate an experimental treatment for COVID-19. It is being conducted at 68 sites – 47 in the United States and 21 in countries in Europe and Asia.
The data are being released after an interim review by the independent data safety monitoring board found significant benefit with the drug, Dr. Fauci said.
“The reason we are making the announcement now is something that people don’t fully appreciate: Whenever you have clear-cut evidence that a drug works, you have an ethical obligation to let the people in the placebo group know so they could have access,” he explained.
“When I was looking at the data with our team the other night, it was reminiscent of 34 years ago in 1986 when we were struggling for drugs for HIV,” said Dr. Fauci, who was a key figure in HIV/AIDS research. “We did the first randomized, placebo-controlled trial with AZT. It turned out to have an effect that was modest but that was not the endgame because, building on that, every year after, we did better and better.”
Similarly, new trials of drugs for COVID-19 will build on remdesivir, with other agents being added to block other pathways or viral enzymes, Dr. Fauci said.
The study will be submitted to a journal for peer review, he noted, but the New York Times is reporting that the Food and Drug Administration will approve remdesivir for emergency use soon.
In contrast to the positive results Dr. Fauci described from the NIAID-sponsored trial, a randomized, placebo-controlled clinical trial of remdesivir among hospitalized patients with severe COVID-19 in China was inconclusive.
The study, published online in The Lancet, showed some nonsignificant trends toward benefit but did not meet its primary endpoint.
The study was stopped early after 237 of the intended 453 patients were enrolled, owing to a lack of additional patients who met the eligibility criteria. The trial was thus underpowered.
Results showed that treatment with remdesivir did not significantly speed recovery or reduce deaths from COVID-19, but with regard to prespecified secondary outcomes, time to clinical improvement and duration of invasive mechanical ventilation were shorter among a subgroup of patients who began undergoing treatment with remdesivir within 10 days of showing symptoms, in comparison with patients who received standard care.
“To me, the studies reported here in The Lancet appear to be less promising than some statements released today from the NIH, so the situation is a bit puzzling to me,” said Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, who was not involved in the study. “I would need to look more closely at the data which NIH is looking at to understand the differences.”
Trial details
The published trial was conducted at 10 hospitals in Hubei, China. Enrollment criteria included being admitted to hospital with laboratory-confirmed SARS-CoV-2 infection within 12 days of symptom onset, having oxygen saturation of 94% or less, and having radiologically confirmed pneumonia.
Patients were randomly assigned in a 2:1 ratio to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids.
The primary endpoint was time to clinical improvement to day 28, defined as the time (in days) from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (on that scale, 1 indicated that the patient was discharged, and 6 indicated death) or to the patient’s being discharged alive from hospital, whichever came first.
The trial was stopped early because stringent public health measures used in Wuhan led to marked reductions in new patient presentations and because lack of available hospital beds resulted in most patients being enrolled later in the course of disease.
Between Feb. 6, 2020, and March 12, 2020, 237 patients were enrolled and were randomly assigned to receive either remdesivir (n = 158) or placebo (n = 79).
Results showed that use of remdesivir was not associated with a difference in time to clinical improvement (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.87-1.75).
Although not statistically significant, time to clinical improvement was numerically faster for patients who received remdesivir than for those who received placebo among patients with symptom duration of 10 days or less (median, 18 days vs. 23 days; HR, 1.52; 95% CI, 0.95-2.43).
The mortality rates were similar for the two groups (14% of patients who received remdesivir died vs. 13% of those who received placebo). There was no signal that viral load decreased differentially over time between the two groups.
Adverse events were reported in 66% of remdesivir recipients, vs. 64% of those who received placebo. Remdesivir was stopped early because of adverse events in 12% of patients; it was stopped early for 5% of those who received placebo.
The authors, led by Yeming Wang, MD, China-Japan Friendship Hospital, Beijing, noted that compared with a previous study of compassionate use of remdesivir, the population in the current study was less ill and was treated somewhat earlier in the disease course (median, 10 days vs. 12 days).
Because the study was terminated early, the researchers said they could not adequately assess whether earlier treatment with remdesivir might have provided clinical benefit.
“However, among patients who were treated within 10 days of symptom onset, remdesivir was not a significant factor but was associated with a numerical reduction of 5 days in median time to clinical improvement,” they stated.
They added that remdesivir was adequately tolerated and that no new safety concerns were identified.
In an accompanying comment in The Lancet, John David Norrie, MD, Edinburgh Clinical Trials Unit, United Kingdom, pointed out that this study “has not shown a statistically significant finding that confirms a remdesivir treatment benefit of at least the minimally clinically important difference, nor has it ruled such a benefit out.”
Dr. Norrie was cautious about the fact that the subgroup analysis suggested possible benefit for those treated within 10 days.
Although he said it seems biologically plausible that treating patients earlier could be more effective, he added that “as well as being vigilant against overinterpretation, we need to ensure that hypotheses generated in efficacy-based trials, even in subgroups, are confirmed or refuted in subsequent adequately powered trials or meta-analyses.”
Noting that several other trials of remdesivir are underway, he concluded: “With each individual study at heightened risk of being incomplete, pooling data across possibly several underpowered but high-quality studies looks like our best way to obtain robust insights into what works, safely, and on whom.”
A version of this article originally appeared on Medscape.com.
, according to a preliminary data analysis from a U.S.-led randomized, controlled trial.
On the basis of as yet unpublished data, remdesivir “will be the standard of care” for patients with COVID-19, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), said during a press conference at the White House April 29.
The randomized, placebo-controlled international trial was sponsored by NIAID, which is part of the National Institutes of Health, and enrolled 1,063 patients. It began on Feb. 21.
The interim results, discussed in the press conference and in a NIAID press release, show that time to recovery (i.e., being well enough for hospital discharge or to return to normal activity level) was 31% faster for patients who received remdesivir than for those who received placebo (P < .001).
The median time to recovery was 11 days for patients treated with remdesivir, compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir and 11.6% for the patients who received placebo (P = .059).
The study, known as the Adaptive COVID-19 Treatment Trial (ACTT), is the first clinical trial launched in the United States to evaluate an experimental treatment for COVID-19. It is being conducted at 68 sites – 47 in the United States and 21 in countries in Europe and Asia.
The data are being released after an interim review by the independent data safety monitoring board found significant benefit with the drug, Dr. Fauci said.
“The reason we are making the announcement now is something that people don’t fully appreciate: Whenever you have clear-cut evidence that a drug works, you have an ethical obligation to let the people in the placebo group know so they could have access,” he explained.
“When I was looking at the data with our team the other night, it was reminiscent of 34 years ago in 1986 when we were struggling for drugs for HIV,” said Dr. Fauci, who was a key figure in HIV/AIDS research. “We did the first randomized, placebo-controlled trial with AZT. It turned out to have an effect that was modest but that was not the endgame because, building on that, every year after, we did better and better.”
Similarly, new trials of drugs for COVID-19 will build on remdesivir, with other agents being added to block other pathways or viral enzymes, Dr. Fauci said.
The study will be submitted to a journal for peer review, he noted, but the New York Times is reporting that the Food and Drug Administration will approve remdesivir for emergency use soon.
In contrast to the positive results Dr. Fauci described from the NIAID-sponsored trial, a randomized, placebo-controlled clinical trial of remdesivir among hospitalized patients with severe COVID-19 in China was inconclusive.
The study, published online in The Lancet, showed some nonsignificant trends toward benefit but did not meet its primary endpoint.
The study was stopped early after 237 of the intended 453 patients were enrolled, owing to a lack of additional patients who met the eligibility criteria. The trial was thus underpowered.
Results showed that treatment with remdesivir did not significantly speed recovery or reduce deaths from COVID-19, but with regard to prespecified secondary outcomes, time to clinical improvement and duration of invasive mechanical ventilation were shorter among a subgroup of patients who began undergoing treatment with remdesivir within 10 days of showing symptoms, in comparison with patients who received standard care.
“To me, the studies reported here in The Lancet appear to be less promising than some statements released today from the NIH, so the situation is a bit puzzling to me,” said Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, who was not involved in the study. “I would need to look more closely at the data which NIH is looking at to understand the differences.”
Trial details
The published trial was conducted at 10 hospitals in Hubei, China. Enrollment criteria included being admitted to hospital with laboratory-confirmed SARS-CoV-2 infection within 12 days of symptom onset, having oxygen saturation of 94% or less, and having radiologically confirmed pneumonia.
Patients were randomly assigned in a 2:1 ratio to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir-ritonavir, interferons, and corticosteroids.
The primary endpoint was time to clinical improvement to day 28, defined as the time (in days) from randomization to the point of a decline of two levels on a six-point ordinal scale of clinical status (on that scale, 1 indicated that the patient was discharged, and 6 indicated death) or to the patient’s being discharged alive from hospital, whichever came first.
The trial was stopped early because stringent public health measures used in Wuhan led to marked reductions in new patient presentations and because lack of available hospital beds resulted in most patients being enrolled later in the course of disease.
Between Feb. 6, 2020, and March 12, 2020, 237 patients were enrolled and were randomly assigned to receive either remdesivir (n = 158) or placebo (n = 79).
Results showed that use of remdesivir was not associated with a difference in time to clinical improvement (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.87-1.75).
Although not statistically significant, time to clinical improvement was numerically faster for patients who received remdesivir than for those who received placebo among patients with symptom duration of 10 days or less (median, 18 days vs. 23 days; HR, 1.52; 95% CI, 0.95-2.43).
The mortality rates were similar for the two groups (14% of patients who received remdesivir died vs. 13% of those who received placebo). There was no signal that viral load decreased differentially over time between the two groups.
Adverse events were reported in 66% of remdesivir recipients, vs. 64% of those who received placebo. Remdesivir was stopped early because of adverse events in 12% of patients; it was stopped early for 5% of those who received placebo.
The authors, led by Yeming Wang, MD, China-Japan Friendship Hospital, Beijing, noted that compared with a previous study of compassionate use of remdesivir, the population in the current study was less ill and was treated somewhat earlier in the disease course (median, 10 days vs. 12 days).
Because the study was terminated early, the researchers said they could not adequately assess whether earlier treatment with remdesivir might have provided clinical benefit.
“However, among patients who were treated within 10 days of symptom onset, remdesivir was not a significant factor but was associated with a numerical reduction of 5 days in median time to clinical improvement,” they stated.
They added that remdesivir was adequately tolerated and that no new safety concerns were identified.
In an accompanying comment in The Lancet, John David Norrie, MD, Edinburgh Clinical Trials Unit, United Kingdom, pointed out that this study “has not shown a statistically significant finding that confirms a remdesivir treatment benefit of at least the minimally clinically important difference, nor has it ruled such a benefit out.”
Dr. Norrie was cautious about the fact that the subgroup analysis suggested possible benefit for those treated within 10 days.
Although he said it seems biologically plausible that treating patients earlier could be more effective, he added that “as well as being vigilant against overinterpretation, we need to ensure that hypotheses generated in efficacy-based trials, even in subgroups, are confirmed or refuted in subsequent adequately powered trials or meta-analyses.”
Noting that several other trials of remdesivir are underway, he concluded: “With each individual study at heightened risk of being incomplete, pooling data across possibly several underpowered but high-quality studies looks like our best way to obtain robust insights into what works, safely, and on whom.”
A version of this article originally appeared on Medscape.com.
Angiotensin drugs and COVID-19: More reassuring data
Initial data from one Chinese center on the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients hospitalized with COVID-19 appear to give some further reassurance about continued use of these drugs.
The report from one hospital in Wuhan found that among patients with hypertension hospitalized with the COVID-19 virus, there was no difference in disease severity or death rate in patients taking ACE inhibitors or ARBs and those not taking such medications.
The data were published online April 23 in JAMA Cardiology.
The study adds to another recent report in a larger number of COVID-19 patients from nine Chinese hospitals that suggested a beneficial effect of ACE inhibitors or ARBs on mortality.
Additional studies
Two other similar studies have also been recently released. Another study from China, published online March 31 in Emerging Microbes & Infections, included a small sample of 42 hospitalized patients with COVID-19 on antihypertensive therapy. Those on ACE inhibitor/ARB therapy had a lower rate of severe disease and a trend toward a lower level of IL-6 in peripheral blood. In addition, patients on ACE inhibitor/ARB therapy had increased CD3+ and CD8+ T-cell counts in peripheral blood and decreased peak viral load compared with other antihypertensive drugs.
And a preliminary study from the UK, which has not yet been peer reviewed, found that treatment with ACE inhibitors was associated with a reduced risk of rapidly deteriorating severe COVID-19 disease.
The study, available online on MedRxiv, a preprint server for health sciences, reports on 205 acute inpatients with COVID-19 at King’s College Hospital and Princess Royal University Hospital, London.
Of these, 51.2% had hypertension, 30.2% had diabetes, and 14.6% had ischemic heart disease or heart failure. Of the 37 patients on ACE inhibitors, five (14%) died or required critical care support compared with 29% (48/168) of patients not taking an ACE inhibitor.
New Wuhan study
The authors of the new article published in JAMA Cardiology, led by Juyi Li, MD, reported on a case series of 1,178 patients hospitalized with COVID-19 at the Central Hospital of Wuhan, Hubei, China, between Jan. 15 and March 15, 2020.
Patients were a median age of 55 years, and 46% were men. They had an overall in-hospital mortality rate of 11%.
Of the 1,178 patients, 362 (30.7%) had a diagnosis of hypertension. These patients were older (median age, 66 years) and had a greater prevalence of chronic diseases. Patients with hypertension also had more severe manifestations of COVID-19 compared to those without hypertension, including higher rates of acute respiratory distress syndrome and in-hospital mortality (21.3% vs. 6.5%).
Of the 362 patients with hypertension, 31.8% were taking ACE inhibitors or ARBs.
Apart from a greater prevalence of coronary artery disease, patients taking ACE inhibitors or ARBs had similar comorbidities to those not taking these medications, and also similar laboratory profile results including blood counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers, although those taking ACE inhibitors/ARBs had higher levels of alkaline phosphatase.
The most commonly used antihypertensive drugs were calcium blockers. The percentage of patients with hypertension taking any drug or drug combination did not differ between those with severe and nonsevere infections and between those who survived and those who died.
Specifically regarding ACE inhibitors/ARBs, there was no difference between those with severe versus nonsevere illness in the use of ACE inhibitors (9.2% vs. 10.1%; P = .80), ARBs (24.9% vs. 21.2%; P = .40), or the composite of ACE inhibitors or ARBs (32.9% vs. 30.7%; P = .65).
Similarly, there were no differences in nonsurvivors and survivors in the use of ACE inhibitors (9.1% vs. 9.8%; P = .85); ARBs (19.5% vs. 23.9%; P = .42), or the composite of ACE inhibitors or ARBs (27.3% vs. 33.0%; P = .34).
The frequency of severe illness and death also did not differ between those treated with and without ACE inhibitors/ARBs in patients with hypertension and other various chronic conditions including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease.
The authors noted that these data confirm previous reports showing that patients with hypertension have more severe illness and higher mortality rates associated with COVID-19 than those without hypertension.
But they added: “Our data provide some reassurance that ACE inhibitors/ARBs are not associated with the progression or outcome of COVID-19 hospitalizations in patients with hypertension.”
They also noted that these results support the recommendations from almost all major cardiovascular societies that patients do not discontinue ACE inhibitors or ARBs because of worries about COVID-19.
However, the authors did point out some limitations of their study, which included a small number of patients with hypertension taking ACE inhibitors or ARBs and the fact that a nonsevere disease course was still severe enough to require hospitalization. In addition, it was not clear whether ACE inhibitor/ARB treatment at baseline was maintained throughout hospitalization for all patients.
This was also an observational comparison and may be biased by differences in patients taking versus not taking ACE inhibitors or ARBs at the time of hospitalization, although the measured baseline characteristics were similar in both groups.
But the authors also highlighted the finding that, in this cohort, patients with hypertension had three times the mortality rate of all other patients hospitalized with COVID-19.
“Hypertension combined with cardiovascular and cerebrovascular disease, diabetes, and chronic kidney disease would predispose patients to an increased risk of severity and mortality of COVID-19. Therefore, patients with these underlying conditions who develop COVID-19 require particularly intensive surveillance and care,” they wrote.
Experts cautiously optimistic
Some cardiovascular experts were cautiously optimistic about these latest results.
Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, and editor-in-chief of the Journal of Clinical Hypertension, said: “This new report from Wuhan, China, gives modest reassurance that the use of ACE inhibitors or ARBs in hypertensive patients with COVID-19 disease does not increase the risk of clinical deterioration or death.
“Ongoing, more definitive studies should help resolve competing hypotheses regarding the effects of these agents: whether the increased ACE2 enzyme levels they produce can worsen outcomes by increasing access of the COVID virus to lung tissue; or whether there is a benefit linked to a protective effect of increased ACE2 on alveolar cell function,” Dr. Weber noted.
“Though the number of patients included in this new report is small, it is startling that hypertensive patients were three times as likely as nonhypertensives to have a fatal outcome, presumably reflecting vulnerability due to the cardiovascular and metabolic comorbidities associated with hypertension,” he added.
“In any case, for now, clinicians should continue treating hypertensive patients with whichever drugs, including ACE inhibitors and ARBs, best provide protection from adverse outcomes,” Dr. Weber concluded.
John McMurray, MD, professor of medical cardiology, University of Glasgow, Scotland, commented: “This study from Wuhan provides some reassurance about one of the two questions about ACEI/ARBs: Do these drugs increase susceptibility to infection? And if [the patient is] infected, do they increase the severity of infection? This study addresses the latter question and appears to suggest no increased severity.”
However, Dr. McMurray pointed out that the study had many limitations. There were only small patient numbers and the data were unadjusted, “although it looks like the ACE inhibitor/ARB treated patients were higher risk to start with.” It was an observational study, and patients were not randomized and were predominantly treated with ARBs, and not ACE inhibitors, so “we don’t know if the concerns apply equally to these two classes of drug.
“Other data published and unpublished supporting this (even showing better outcomes in patients treated with an ACE inhibitor/ARB), and, to date, any concerns about these drugs remain unsubstantiated and the guidance from medical societies to continue treatment with these agents in patients prescribed them seems wise,” Dr. McMurray added.
Franz H. Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “The study from Wuhan is not a great study. They didn’t even do a multivariable analysis. They could have done a bit more with the data, but it still gives some reassurance.”
Dr. Messerli said it was “interesting” that 30% of the patients hospitalized with COVID-19 in the sample had hypertension. “That corresponds to the general population, so does not suggest that having hypertension increases susceptibility to infection – but it does seem to increase the risk of a bad outcome.”
Dr. Messerli noted that there are two more similar studies due to be published soon, both said to suggest either a beneficial or neutral effect of ACE inhibitors/ARBs on COVID-19 outcomes in hospitalized patients.
“This does help with confidence in prescribing these agents and reinforces the recommendations for patients to stay on these drugs,” he said.
“However, none of these studies address the infectivity issue – whether their use upregulates the ACE2 receptor, which the virus uses to gain entry to cells, thereby increasing susceptibility to the infection,” Dr. Messerli cautioned. “But the similar or better outcomes on these drugs are encouraging,” he added.
The Wuhan study was supported by the Health and Family Planning Commission of Wuhan City, China. The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Initial data from one Chinese center on the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients hospitalized with COVID-19 appear to give some further reassurance about continued use of these drugs.
The report from one hospital in Wuhan found that among patients with hypertension hospitalized with the COVID-19 virus, there was no difference in disease severity or death rate in patients taking ACE inhibitors or ARBs and those not taking such medications.
The data were published online April 23 in JAMA Cardiology.
The study adds to another recent report in a larger number of COVID-19 patients from nine Chinese hospitals that suggested a beneficial effect of ACE inhibitors or ARBs on mortality.
Additional studies
Two other similar studies have also been recently released. Another study from China, published online March 31 in Emerging Microbes & Infections, included a small sample of 42 hospitalized patients with COVID-19 on antihypertensive therapy. Those on ACE inhibitor/ARB therapy had a lower rate of severe disease and a trend toward a lower level of IL-6 in peripheral blood. In addition, patients on ACE inhibitor/ARB therapy had increased CD3+ and CD8+ T-cell counts in peripheral blood and decreased peak viral load compared with other antihypertensive drugs.
And a preliminary study from the UK, which has not yet been peer reviewed, found that treatment with ACE inhibitors was associated with a reduced risk of rapidly deteriorating severe COVID-19 disease.
The study, available online on MedRxiv, a preprint server for health sciences, reports on 205 acute inpatients with COVID-19 at King’s College Hospital and Princess Royal University Hospital, London.
Of these, 51.2% had hypertension, 30.2% had diabetes, and 14.6% had ischemic heart disease or heart failure. Of the 37 patients on ACE inhibitors, five (14%) died or required critical care support compared with 29% (48/168) of patients not taking an ACE inhibitor.
New Wuhan study
The authors of the new article published in JAMA Cardiology, led by Juyi Li, MD, reported on a case series of 1,178 patients hospitalized with COVID-19 at the Central Hospital of Wuhan, Hubei, China, between Jan. 15 and March 15, 2020.
Patients were a median age of 55 years, and 46% were men. They had an overall in-hospital mortality rate of 11%.
Of the 1,178 patients, 362 (30.7%) had a diagnosis of hypertension. These patients were older (median age, 66 years) and had a greater prevalence of chronic diseases. Patients with hypertension also had more severe manifestations of COVID-19 compared to those without hypertension, including higher rates of acute respiratory distress syndrome and in-hospital mortality (21.3% vs. 6.5%).
Of the 362 patients with hypertension, 31.8% were taking ACE inhibitors or ARBs.
Apart from a greater prevalence of coronary artery disease, patients taking ACE inhibitors or ARBs had similar comorbidities to those not taking these medications, and also similar laboratory profile results including blood counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers, although those taking ACE inhibitors/ARBs had higher levels of alkaline phosphatase.
The most commonly used antihypertensive drugs were calcium blockers. The percentage of patients with hypertension taking any drug or drug combination did not differ between those with severe and nonsevere infections and between those who survived and those who died.
Specifically regarding ACE inhibitors/ARBs, there was no difference between those with severe versus nonsevere illness in the use of ACE inhibitors (9.2% vs. 10.1%; P = .80), ARBs (24.9% vs. 21.2%; P = .40), or the composite of ACE inhibitors or ARBs (32.9% vs. 30.7%; P = .65).
Similarly, there were no differences in nonsurvivors and survivors in the use of ACE inhibitors (9.1% vs. 9.8%; P = .85); ARBs (19.5% vs. 23.9%; P = .42), or the composite of ACE inhibitors or ARBs (27.3% vs. 33.0%; P = .34).
The frequency of severe illness and death also did not differ between those treated with and without ACE inhibitors/ARBs in patients with hypertension and other various chronic conditions including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease.
The authors noted that these data confirm previous reports showing that patients with hypertension have more severe illness and higher mortality rates associated with COVID-19 than those without hypertension.
But they added: “Our data provide some reassurance that ACE inhibitors/ARBs are not associated with the progression or outcome of COVID-19 hospitalizations in patients with hypertension.”
They also noted that these results support the recommendations from almost all major cardiovascular societies that patients do not discontinue ACE inhibitors or ARBs because of worries about COVID-19.
However, the authors did point out some limitations of their study, which included a small number of patients with hypertension taking ACE inhibitors or ARBs and the fact that a nonsevere disease course was still severe enough to require hospitalization. In addition, it was not clear whether ACE inhibitor/ARB treatment at baseline was maintained throughout hospitalization for all patients.
This was also an observational comparison and may be biased by differences in patients taking versus not taking ACE inhibitors or ARBs at the time of hospitalization, although the measured baseline characteristics were similar in both groups.
But the authors also highlighted the finding that, in this cohort, patients with hypertension had three times the mortality rate of all other patients hospitalized with COVID-19.
“Hypertension combined with cardiovascular and cerebrovascular disease, diabetes, and chronic kidney disease would predispose patients to an increased risk of severity and mortality of COVID-19. Therefore, patients with these underlying conditions who develop COVID-19 require particularly intensive surveillance and care,” they wrote.
Experts cautiously optimistic
Some cardiovascular experts were cautiously optimistic about these latest results.
Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, and editor-in-chief of the Journal of Clinical Hypertension, said: “This new report from Wuhan, China, gives modest reassurance that the use of ACE inhibitors or ARBs in hypertensive patients with COVID-19 disease does not increase the risk of clinical deterioration or death.
“Ongoing, more definitive studies should help resolve competing hypotheses regarding the effects of these agents: whether the increased ACE2 enzyme levels they produce can worsen outcomes by increasing access of the COVID virus to lung tissue; or whether there is a benefit linked to a protective effect of increased ACE2 on alveolar cell function,” Dr. Weber noted.
“Though the number of patients included in this new report is small, it is startling that hypertensive patients were three times as likely as nonhypertensives to have a fatal outcome, presumably reflecting vulnerability due to the cardiovascular and metabolic comorbidities associated with hypertension,” he added.
“In any case, for now, clinicians should continue treating hypertensive patients with whichever drugs, including ACE inhibitors and ARBs, best provide protection from adverse outcomes,” Dr. Weber concluded.
John McMurray, MD, professor of medical cardiology, University of Glasgow, Scotland, commented: “This study from Wuhan provides some reassurance about one of the two questions about ACEI/ARBs: Do these drugs increase susceptibility to infection? And if [the patient is] infected, do they increase the severity of infection? This study addresses the latter question and appears to suggest no increased severity.”
However, Dr. McMurray pointed out that the study had many limitations. There were only small patient numbers and the data were unadjusted, “although it looks like the ACE inhibitor/ARB treated patients were higher risk to start with.” It was an observational study, and patients were not randomized and were predominantly treated with ARBs, and not ACE inhibitors, so “we don’t know if the concerns apply equally to these two classes of drug.
“Other data published and unpublished supporting this (even showing better outcomes in patients treated with an ACE inhibitor/ARB), and, to date, any concerns about these drugs remain unsubstantiated and the guidance from medical societies to continue treatment with these agents in patients prescribed them seems wise,” Dr. McMurray added.
Franz H. Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “The study from Wuhan is not a great study. They didn’t even do a multivariable analysis. They could have done a bit more with the data, but it still gives some reassurance.”
Dr. Messerli said it was “interesting” that 30% of the patients hospitalized with COVID-19 in the sample had hypertension. “That corresponds to the general population, so does not suggest that having hypertension increases susceptibility to infection – but it does seem to increase the risk of a bad outcome.”
Dr. Messerli noted that there are two more similar studies due to be published soon, both said to suggest either a beneficial or neutral effect of ACE inhibitors/ARBs on COVID-19 outcomes in hospitalized patients.
“This does help with confidence in prescribing these agents and reinforces the recommendations for patients to stay on these drugs,” he said.
“However, none of these studies address the infectivity issue – whether their use upregulates the ACE2 receptor, which the virus uses to gain entry to cells, thereby increasing susceptibility to the infection,” Dr. Messerli cautioned. “But the similar or better outcomes on these drugs are encouraging,” he added.
The Wuhan study was supported by the Health and Family Planning Commission of Wuhan City, China. The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Initial data from one Chinese center on the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients hospitalized with COVID-19 appear to give some further reassurance about continued use of these drugs.
The report from one hospital in Wuhan found that among patients with hypertension hospitalized with the COVID-19 virus, there was no difference in disease severity or death rate in patients taking ACE inhibitors or ARBs and those not taking such medications.
The data were published online April 23 in JAMA Cardiology.
The study adds to another recent report in a larger number of COVID-19 patients from nine Chinese hospitals that suggested a beneficial effect of ACE inhibitors or ARBs on mortality.
Additional studies
Two other similar studies have also been recently released. Another study from China, published online March 31 in Emerging Microbes & Infections, included a small sample of 42 hospitalized patients with COVID-19 on antihypertensive therapy. Those on ACE inhibitor/ARB therapy had a lower rate of severe disease and a trend toward a lower level of IL-6 in peripheral blood. In addition, patients on ACE inhibitor/ARB therapy had increased CD3+ and CD8+ T-cell counts in peripheral blood and decreased peak viral load compared with other antihypertensive drugs.
And a preliminary study from the UK, which has not yet been peer reviewed, found that treatment with ACE inhibitors was associated with a reduced risk of rapidly deteriorating severe COVID-19 disease.
The study, available online on MedRxiv, a preprint server for health sciences, reports on 205 acute inpatients with COVID-19 at King’s College Hospital and Princess Royal University Hospital, London.
Of these, 51.2% had hypertension, 30.2% had diabetes, and 14.6% had ischemic heart disease or heart failure. Of the 37 patients on ACE inhibitors, five (14%) died or required critical care support compared with 29% (48/168) of patients not taking an ACE inhibitor.
New Wuhan study
The authors of the new article published in JAMA Cardiology, led by Juyi Li, MD, reported on a case series of 1,178 patients hospitalized with COVID-19 at the Central Hospital of Wuhan, Hubei, China, between Jan. 15 and March 15, 2020.
Patients were a median age of 55 years, and 46% were men. They had an overall in-hospital mortality rate of 11%.
Of the 1,178 patients, 362 (30.7%) had a diagnosis of hypertension. These patients were older (median age, 66 years) and had a greater prevalence of chronic diseases. Patients with hypertension also had more severe manifestations of COVID-19 compared to those without hypertension, including higher rates of acute respiratory distress syndrome and in-hospital mortality (21.3% vs. 6.5%).
Of the 362 patients with hypertension, 31.8% were taking ACE inhibitors or ARBs.
Apart from a greater prevalence of coronary artery disease, patients taking ACE inhibitors or ARBs had similar comorbidities to those not taking these medications, and also similar laboratory profile results including blood counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers, although those taking ACE inhibitors/ARBs had higher levels of alkaline phosphatase.
The most commonly used antihypertensive drugs were calcium blockers. The percentage of patients with hypertension taking any drug or drug combination did not differ between those with severe and nonsevere infections and between those who survived and those who died.
Specifically regarding ACE inhibitors/ARBs, there was no difference between those with severe versus nonsevere illness in the use of ACE inhibitors (9.2% vs. 10.1%; P = .80), ARBs (24.9% vs. 21.2%; P = .40), or the composite of ACE inhibitors or ARBs (32.9% vs. 30.7%; P = .65).
Similarly, there were no differences in nonsurvivors and survivors in the use of ACE inhibitors (9.1% vs. 9.8%; P = .85); ARBs (19.5% vs. 23.9%; P = .42), or the composite of ACE inhibitors or ARBs (27.3% vs. 33.0%; P = .34).
The frequency of severe illness and death also did not differ between those treated with and without ACE inhibitors/ARBs in patients with hypertension and other various chronic conditions including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease.
The authors noted that these data confirm previous reports showing that patients with hypertension have more severe illness and higher mortality rates associated with COVID-19 than those without hypertension.
But they added: “Our data provide some reassurance that ACE inhibitors/ARBs are not associated with the progression or outcome of COVID-19 hospitalizations in patients with hypertension.”
They also noted that these results support the recommendations from almost all major cardiovascular societies that patients do not discontinue ACE inhibitors or ARBs because of worries about COVID-19.
However, the authors did point out some limitations of their study, which included a small number of patients with hypertension taking ACE inhibitors or ARBs and the fact that a nonsevere disease course was still severe enough to require hospitalization. In addition, it was not clear whether ACE inhibitor/ARB treatment at baseline was maintained throughout hospitalization for all patients.
This was also an observational comparison and may be biased by differences in patients taking versus not taking ACE inhibitors or ARBs at the time of hospitalization, although the measured baseline characteristics were similar in both groups.
But the authors also highlighted the finding that, in this cohort, patients with hypertension had three times the mortality rate of all other patients hospitalized with COVID-19.
“Hypertension combined with cardiovascular and cerebrovascular disease, diabetes, and chronic kidney disease would predispose patients to an increased risk of severity and mortality of COVID-19. Therefore, patients with these underlying conditions who develop COVID-19 require particularly intensive surveillance and care,” they wrote.
Experts cautiously optimistic
Some cardiovascular experts were cautiously optimistic about these latest results.
Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, and editor-in-chief of the Journal of Clinical Hypertension, said: “This new report from Wuhan, China, gives modest reassurance that the use of ACE inhibitors or ARBs in hypertensive patients with COVID-19 disease does not increase the risk of clinical deterioration or death.
“Ongoing, more definitive studies should help resolve competing hypotheses regarding the effects of these agents: whether the increased ACE2 enzyme levels they produce can worsen outcomes by increasing access of the COVID virus to lung tissue; or whether there is a benefit linked to a protective effect of increased ACE2 on alveolar cell function,” Dr. Weber noted.
“Though the number of patients included in this new report is small, it is startling that hypertensive patients were three times as likely as nonhypertensives to have a fatal outcome, presumably reflecting vulnerability due to the cardiovascular and metabolic comorbidities associated with hypertension,” he added.
“In any case, for now, clinicians should continue treating hypertensive patients with whichever drugs, including ACE inhibitors and ARBs, best provide protection from adverse outcomes,” Dr. Weber concluded.
John McMurray, MD, professor of medical cardiology, University of Glasgow, Scotland, commented: “This study from Wuhan provides some reassurance about one of the two questions about ACEI/ARBs: Do these drugs increase susceptibility to infection? And if [the patient is] infected, do they increase the severity of infection? This study addresses the latter question and appears to suggest no increased severity.”
However, Dr. McMurray pointed out that the study had many limitations. There were only small patient numbers and the data were unadjusted, “although it looks like the ACE inhibitor/ARB treated patients were higher risk to start with.” It was an observational study, and patients were not randomized and were predominantly treated with ARBs, and not ACE inhibitors, so “we don’t know if the concerns apply equally to these two classes of drug.
“Other data published and unpublished supporting this (even showing better outcomes in patients treated with an ACE inhibitor/ARB), and, to date, any concerns about these drugs remain unsubstantiated and the guidance from medical societies to continue treatment with these agents in patients prescribed them seems wise,” Dr. McMurray added.
Franz H. Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “The study from Wuhan is not a great study. They didn’t even do a multivariable analysis. They could have done a bit more with the data, but it still gives some reassurance.”
Dr. Messerli said it was “interesting” that 30% of the patients hospitalized with COVID-19 in the sample had hypertension. “That corresponds to the general population, so does not suggest that having hypertension increases susceptibility to infection – but it does seem to increase the risk of a bad outcome.”
Dr. Messerli noted that there are two more similar studies due to be published soon, both said to suggest either a beneficial or neutral effect of ACE inhibitors/ARBs on COVID-19 outcomes in hospitalized patients.
“This does help with confidence in prescribing these agents and reinforces the recommendations for patients to stay on these drugs,” he said.
“However, none of these studies address the infectivity issue – whether their use upregulates the ACE2 receptor, which the virus uses to gain entry to cells, thereby increasing susceptibility to the infection,” Dr. Messerli cautioned. “But the similar or better outcomes on these drugs are encouraging,” he added.
The Wuhan study was supported by the Health and Family Planning Commission of Wuhan City, China. The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Sodium nitrite disappoints in cardiac arrest
Among patients who had an out-of-hospital cardiac arrest, intravenous sodium nitrite given by paramedics during resuscitation did not significantly improve their chances of being admitted to or discharged from the hospital alive.
The study was presented at the recent “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).
Lead investigator Francis Kim, MD, professor of medicine at the University of Washington, Seattle, explained that sodium nitrate is an antioxidant; animal studies have suggested that under conditions of hypoxia, it is converted into the vasodilator nitric oxide, which can increase blood flow to the brain and heart tissues.
In animal models of cardiac arrest, the use of sodium nitrite during resuscitation increased survival by almost 50%.
For the current study, 1,502 patients who had an out-of-hospital cardiac arrest were randomly assigned to receive either a low dose (45 mg) or a high dose (60 mg) of sodium nitrite or a placebo. The average age of the patients who were included in the study was 64 years, and 66% were male; 22% had ventricular fibrillation, 43% had asystole, and 29% had pulseless electrical activity.
Results showed no statistically significant differences between the groups who received placebo, low-dose sodium nitrite, or high-dose sodium nitrite on survival to hospital admission (the primary endpoint) or on hospital discharge (the secondary endpoint). There was also no difference in either endpoint in the subgroup with ventricular fibrillation.
“Our results are disappointing, especially after the promising findings in animal studies, but we feel this trial shuts the door on using this drug in this indication,” Kim said.
Discussing the study at an ACC press conference, Dhanunjaya Lakkireddy, MD, University of Kansas Hospital and Medical Center and ACC Electrophysiology Council chair, said this was “an excellent trial in the unending quest to try to improve survival in out-of-hospital cardiac arrest.
“As we all aware, if we don’t get blood circulation to the brain for more than 5 seconds, we pass out, and if don’t get blood circulation to the brain for more than 5 minutes, brain death occurs. When people suffer out-of-hospital cardiac arrest, the rate of survival is therefore dramatically lower when the ability to resuscitate goes beyond 5 minutes,” Lakkireddy noted.
He questioned why the current trial showed no effect when there had been significant early promise in animal studies. He suggested factors that could have been relevant included the time to intervention ― which was an average of 22 minutes from call to randomization ― perfusion of the brain, whether the drug cleared the blood-brain barrier, whether nitric oxide levels in the brain were sufficient, and the patient population that was included in the study.
“A large percentage of patients had asystole or pulseless electrical activity ― these are known to have worse outcomes ― and 60% of patients in the study did not have a witnessed arrest and could have been down for much longer and therefore could have had a significantly higher level of irreversible brain damage,” Lakkireddy pointed out.
“If we can understand some of the issues, we may be able to do another trial in a different subset of patients in whom the duration of arrest is significantly lower,” he commented.
The study was funded by the National Heart, Lung, and Blood Institute. Kim has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Among patients who had an out-of-hospital cardiac arrest, intravenous sodium nitrite given by paramedics during resuscitation did not significantly improve their chances of being admitted to or discharged from the hospital alive.
The study was presented at the recent “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).
Lead investigator Francis Kim, MD, professor of medicine at the University of Washington, Seattle, explained that sodium nitrate is an antioxidant; animal studies have suggested that under conditions of hypoxia, it is converted into the vasodilator nitric oxide, which can increase blood flow to the brain and heart tissues.
In animal models of cardiac arrest, the use of sodium nitrite during resuscitation increased survival by almost 50%.
For the current study, 1,502 patients who had an out-of-hospital cardiac arrest were randomly assigned to receive either a low dose (45 mg) or a high dose (60 mg) of sodium nitrite or a placebo. The average age of the patients who were included in the study was 64 years, and 66% were male; 22% had ventricular fibrillation, 43% had asystole, and 29% had pulseless electrical activity.
Results showed no statistically significant differences between the groups who received placebo, low-dose sodium nitrite, or high-dose sodium nitrite on survival to hospital admission (the primary endpoint) or on hospital discharge (the secondary endpoint). There was also no difference in either endpoint in the subgroup with ventricular fibrillation.
“Our results are disappointing, especially after the promising findings in animal studies, but we feel this trial shuts the door on using this drug in this indication,” Kim said.
Discussing the study at an ACC press conference, Dhanunjaya Lakkireddy, MD, University of Kansas Hospital and Medical Center and ACC Electrophysiology Council chair, said this was “an excellent trial in the unending quest to try to improve survival in out-of-hospital cardiac arrest.
“As we all aware, if we don’t get blood circulation to the brain for more than 5 seconds, we pass out, and if don’t get blood circulation to the brain for more than 5 minutes, brain death occurs. When people suffer out-of-hospital cardiac arrest, the rate of survival is therefore dramatically lower when the ability to resuscitate goes beyond 5 minutes,” Lakkireddy noted.
He questioned why the current trial showed no effect when there had been significant early promise in animal studies. He suggested factors that could have been relevant included the time to intervention ― which was an average of 22 minutes from call to randomization ― perfusion of the brain, whether the drug cleared the blood-brain barrier, whether nitric oxide levels in the brain were sufficient, and the patient population that was included in the study.
“A large percentage of patients had asystole or pulseless electrical activity ― these are known to have worse outcomes ― and 60% of patients in the study did not have a witnessed arrest and could have been down for much longer and therefore could have had a significantly higher level of irreversible brain damage,” Lakkireddy pointed out.
“If we can understand some of the issues, we may be able to do another trial in a different subset of patients in whom the duration of arrest is significantly lower,” he commented.
The study was funded by the National Heart, Lung, and Blood Institute. Kim has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Among patients who had an out-of-hospital cardiac arrest, intravenous sodium nitrite given by paramedics during resuscitation did not significantly improve their chances of being admitted to or discharged from the hospital alive.
The study was presented at the recent “virtual” American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).
Lead investigator Francis Kim, MD, professor of medicine at the University of Washington, Seattle, explained that sodium nitrate is an antioxidant; animal studies have suggested that under conditions of hypoxia, it is converted into the vasodilator nitric oxide, which can increase blood flow to the brain and heart tissues.
In animal models of cardiac arrest, the use of sodium nitrite during resuscitation increased survival by almost 50%.
For the current study, 1,502 patients who had an out-of-hospital cardiac arrest were randomly assigned to receive either a low dose (45 mg) or a high dose (60 mg) of sodium nitrite or a placebo. The average age of the patients who were included in the study was 64 years, and 66% were male; 22% had ventricular fibrillation, 43% had asystole, and 29% had pulseless electrical activity.
Results showed no statistically significant differences between the groups who received placebo, low-dose sodium nitrite, or high-dose sodium nitrite on survival to hospital admission (the primary endpoint) or on hospital discharge (the secondary endpoint). There was also no difference in either endpoint in the subgroup with ventricular fibrillation.
“Our results are disappointing, especially after the promising findings in animal studies, but we feel this trial shuts the door on using this drug in this indication,” Kim said.
Discussing the study at an ACC press conference, Dhanunjaya Lakkireddy, MD, University of Kansas Hospital and Medical Center and ACC Electrophysiology Council chair, said this was “an excellent trial in the unending quest to try to improve survival in out-of-hospital cardiac arrest.
“As we all aware, if we don’t get blood circulation to the brain for more than 5 seconds, we pass out, and if don’t get blood circulation to the brain for more than 5 minutes, brain death occurs. When people suffer out-of-hospital cardiac arrest, the rate of survival is therefore dramatically lower when the ability to resuscitate goes beyond 5 minutes,” Lakkireddy noted.
He questioned why the current trial showed no effect when there had been significant early promise in animal studies. He suggested factors that could have been relevant included the time to intervention ― which was an average of 22 minutes from call to randomization ― perfusion of the brain, whether the drug cleared the blood-brain barrier, whether nitric oxide levels in the brain were sufficient, and the patient population that was included in the study.
“A large percentage of patients had asystole or pulseless electrical activity ― these are known to have worse outcomes ― and 60% of patients in the study did not have a witnessed arrest and could have been down for much longer and therefore could have had a significantly higher level of irreversible brain damage,” Lakkireddy pointed out.
“If we can understand some of the issues, we may be able to do another trial in a different subset of patients in whom the duration of arrest is significantly lower,” he commented.
The study was funded by the National Heart, Lung, and Blood Institute. Kim has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.