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HFpEF: Gender difference in sacubitril/valsartan response remains mystery
The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.
“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.
The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).
In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.
Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.
Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.
Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.
The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.
Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.
“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.
Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.
Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.
SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.
The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.
“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.
The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).
In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.
Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.
Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.
Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.
The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.
Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.
“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.
Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.
Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.
SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.
The explanation for the impressive clinical benefits of sacubitril/valsartan in women with heart failure with preserved ejection fraction in the PARAGON-HF trial – but not in the men – remains elusive, Jonathan W. Cunningham, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.
“We’ve all been trying to unravel the explanation for the differential effects between men and women in the primary trial. I don’t know that this NT-proBNP substudy gives a clear answer because we did see similar reduction in NT-proBNP in the men and women,” said Dr. Cunningham of Brigham and Women’s Hospital, Boston.
“Unfortunately, I think we’re still looking for the underlying physiological explanation for that very interesting interaction,” he added.
The PARAGON-HF trial included 4,796 patients with heart failure with preserved ejection fraction (HFpEF) who were randomized double-blind to sacubitril/valsartan (Entresto) or valsartan on top of background guideline-directed medical therapy and followed for a median of 34 months (N Engl J Med. 2019 Oct 24;381[17]:1609-20). The sacubitril/valsartan group’s 13% relative risk reduction in the primary composite endpoint of cardiovascular death and total heart failure hospitalizations fell tantalizingly short of statistical significance (P = 0.058).
In women, however, who comprised more than half of the study population, the benefit of sacubitril/valsartan was larger: a 27% relative risk reduction compared to valsartan alone. That’s a statistically significant difference in a prespecified subgroup analysis, but according to the rules of clinical trials and statistics it must be considered hypothesis-generating and nondefinitive, since the overall trial was negative. Men randomized to sacubitril/valsartan had a modest 3% increased risk of the primary endpoint compared to men on valsartan.
Because of the enormous unmet need for effective therapy for HFpEF, and the fact that HFpEF is more common in women than men, the search is on for an explanation that would account for the striking gender difference in outcome in PARAGON-HF. At ACC 2020, Dr. Cunningham presented a secondary analysis of the trial focusing on the relationships between baseline and on-treatment N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and clinical outcomes.
Among the key findings was that the higher the baseline NT-proBNP, the greater the likelihood of the primary endpoint. Also, sacubitril/valsartan reduced NT-proBNP to a similar extent in men and women: For example, by 20% compared to valsartan in men and by 18% in women when measured 16 weeks after randomization. And reduction in NT-proBNP was associated with reduced risk of cardiovascular death and heart failure hospitalizations; indeed, 60% of participants in PARAGON-HF experienced a decrease in NT-proBNP, and they had a 23% lower event rate compared to patients whose NT-proBNP increased during the course of the study.
Another intriguing finding in the parent PARAGON-HF trial was that HFpEF patients with an LVEF of 45%-57% had a 22% lower rate of the primary endpoint than those with an LVEF of 58% or more. But as with the gender difference in clinical outcomes in response to sacubitril/valsartan, the difference in outcomes based on ejection fraction was not mediated by the drug’s impact on NT-proBNP, since sacubitril/valsartan reduced NT-proBNP to a similar degree in HFpEF patients with an LVEF above or below 57%.
The difference in outcomes by ejection fraction wasn’t entirely surprising, because those low-normal–range ejection fractions where sacubitril/valsartan had a favorable impact approach those characteristic of heart failure with reduced ejection fraction (HFrEF), and guidelines give sacubitril/valsartan a class I recommendation in patients with HFrEF on the strength of the medication’s demonstrated reduction in morbidity and mortality in the PARADIGM-HF trial.
Discussant Lee R. Goldberg, MD, predicted this analysis will have an impact on the design of future clinical trials in HFpEF, which up until now have required certain minimum NT-proBNP levels for participation.
“Maybe this is why so many of our trials in HFpEF have been unsuccessful. It’s a very heterogeneous population and perhaps NT-proBNP cutoffs are leading to a lot of mischief or heterogeneity that causes us some difficulty,” said Dr. Goldberg, professor of medicine and chief of the section of advanced heart failure and cardiac transplantation at the University of Pennsylvania, Philadelphia.
Dr. Cunningham reported having no financial conflicts regarding his study. The PARAGON-HF trial was funded by Novartis.
Simultaneously with Dr. Cunningham’s presentation at ACC 2020, the study results were published online (JACC Heart Fail. 2020 Mar 26; doi: 10.1016/j.jchf.2020.03.002.
SOURCE: Cunningham JW. ACC 2020, Abstract 412-08.
FROM ACC 2020
Protean manifestations of COVID-19: “Our ignorance is profound”
Although a cause-and-effect relationship is unknown, people with the virus have presented with or developed heart disease, acute liver injury, ongoing GI issues, skin manifestations, neurologic damage, and other problems, especially among sicker people.
For example, French physicians described an association with encephalopathy, agitation, confusion, and corticospinal tract signs among 58 people hospitalized with acute respiratory distress (N Engl J Med. 2020 Apr 15. doi: 10.1056/NEJMc2008597).
In particular, Yale New Haven (Conn.) Hospital is dealing with unexpected complications up close. Almost half of the beds there are occupied by COVID-19 patients. Over 100 people are in the ICU, and almost 70 intubated. Of the more than 750 COVID admissions so far, only about 350 have been discharged. “Even in a bad flu season, you never see something like this; it’s just unheard of,” said Harlan Krumholz, MD, a Yale cardiologist and professor of medicine helping lead the efforts there.
Kidney injuries prominent
“When they get to the ICU, we are seeing lots of people with acute kidney injuries; lots of people developing endocrine problems; people having blood sugar control issues, coagulation issues, blood clots. We are just waking up to the wide range of ways this virus can affect people. Our ignorance is profound,” Dr. Krumholz said, but physicians “recognize that this thing has the capability of attacking almost every single organ system, and it may or may not present with respiratory symptoms.”
It’s a similar story at Mt. Sinai South Nassau, a hospital in Oceanside, N.Y. “We’ve seen a lot of renal injury in people having complications, a lot of acute dialysis,” but it’s unclear how much is caused by the virus and how much is simply because people are so sick, said Aaron Glatt, MD, infectious disease professor and chair of medicine at the hospital. However, he said things are looking brighter than at Yale.
“We are not seeing the same level of increase in cases that we had previously, and we are starting to see extubations and discharges. We’ve treated a number of patients with plasma therapy, and hopefully that will be of benefit. We’ve seen some response to” the immunosuppressive “tocilizumab [Actemra], and a lot of response to very good respiratory therapy. I think we are starting to flatten the curve,” Dr. Glatt said.
“Look for tricky symptoms”
The growing awareness of COVID’s protean manifestations is evident in Medscape’s Consult forum, an online community where physicians and medical students share information and seek advice; there’s been over 200 COVID-19 cases and questions since January.
Early on, traffic was mostly about typical pulmonary presentations, but lately it’s shifted to nonrespiratory involvement. Physicians want to know if what they are seeing is related to the virus, and if other people are seeing the same things.
There’s a case on Consult of a 37-year-old man with stomach pain, vomiting, and diarrhea, but no respiratory symptoms and a positive COVID test. A chest CT incidental to his abdominal scan revealed significant bilateral lung involvement.
A 69-year-old woman with a history of laparotomy and new onset intestinal subocclusion had only adhesions on a subsequent exploratory laparotomy, and was doing okay otherwise. She suddenly went into respiratory failure with progressive bradycardia and died 3 days later. Aspiration pneumonia, pulmonary embolism, and MI had been ruled out. “The pattern of cardiovascular failure was in favor of myocarditis, but we don’t have any other clue,” the physician said after describing a second similar case.
Another doctor on the forum reported elevated cardiac enzymes without coronary artery obstruction in a positive patient who went into shock, with an ejection fraction of 40% and markedly increased heart wall thickness, but no lung involvement. There are also two cases of idiopathic thrombocytopenia without fever of hypoxia.
An Italian gastroenterologist said: “Look for tricky symptoms.” Expand “patient history, asking about the sudden occurrence of dysgeusia and/or anosmia. These symptoms have become my guiding diagnostic light” in Verona. “Most patients become nauseated, [and] the taste of any food is unbearable. When I find these symptoms by history, the patient is COVID positive 100%.”
‘Make sure that they didn’t die in vain’
There was interest in those and other reports on Consult, and comments from physicians who have theories, but no certain answers about what is, and is not, caused by the virus.
Direct viral attack is likely a part of it, said Stanley Perlman, MD, PhD, a professor of microbiology and immunology at the University of Iowa, Iowa City.
The ACE2 receptor the virus uses to enter cells is common in many organs, plus there were extrapulmonary manifestations with severe acute respiratory syndrome (SARS), another pandemic caused by a zoonotic coronavirus almost 20 years ago. At least with SARS, “many organs were infected when examined at autopsy,” he said.
The body’s inflammatory response is almost certainly also in play. Progressive derangements in inflammatory markers – C-reactive protein, D-dimer, ferritin – correlate with worse prognosis, and “the cytokine storm that occurs in these patients can lead to a degree of encephalopathy, myocarditis, liver impairment, and kidney impairment; multiorgan dysfunction, in other words,” said William Shaffner, MD, a professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center, Nashville, Tenn.
But in some cases, the virus might simply be a bystander to an unrelated disease process; in others, the experimental treatments being used might cause problems. Indeed, cardiology groups recently warned of torsade de pointes – a dangerously abnormal heart rhythm – with hydroxychloroquine and azithromycin.
“We think it’s some combination,” but don’t really know, Dr. Krumholz said. In the meantime, “we are forced to treat patients by instinct and first principles,” and long-term sequelae are unknown. “We don’t want to be in this position for long.”
To that end, he said, “this is the time for us all to hold hands and be together because we need to learn rapidly from each other. Our job is both to care for the people in front of us and make sure that they didn’t die in vain, that the experience they had is funneled into a larger set of data to make sure the next person is better off.”
Although a cause-and-effect relationship is unknown, people with the virus have presented with or developed heart disease, acute liver injury, ongoing GI issues, skin manifestations, neurologic damage, and other problems, especially among sicker people.
For example, French physicians described an association with encephalopathy, agitation, confusion, and corticospinal tract signs among 58 people hospitalized with acute respiratory distress (N Engl J Med. 2020 Apr 15. doi: 10.1056/NEJMc2008597).
In particular, Yale New Haven (Conn.) Hospital is dealing with unexpected complications up close. Almost half of the beds there are occupied by COVID-19 patients. Over 100 people are in the ICU, and almost 70 intubated. Of the more than 750 COVID admissions so far, only about 350 have been discharged. “Even in a bad flu season, you never see something like this; it’s just unheard of,” said Harlan Krumholz, MD, a Yale cardiologist and professor of medicine helping lead the efforts there.
Kidney injuries prominent
“When they get to the ICU, we are seeing lots of people with acute kidney injuries; lots of people developing endocrine problems; people having blood sugar control issues, coagulation issues, blood clots. We are just waking up to the wide range of ways this virus can affect people. Our ignorance is profound,” Dr. Krumholz said, but physicians “recognize that this thing has the capability of attacking almost every single organ system, and it may or may not present with respiratory symptoms.”
It’s a similar story at Mt. Sinai South Nassau, a hospital in Oceanside, N.Y. “We’ve seen a lot of renal injury in people having complications, a lot of acute dialysis,” but it’s unclear how much is caused by the virus and how much is simply because people are so sick, said Aaron Glatt, MD, infectious disease professor and chair of medicine at the hospital. However, he said things are looking brighter than at Yale.
“We are not seeing the same level of increase in cases that we had previously, and we are starting to see extubations and discharges. We’ve treated a number of patients with plasma therapy, and hopefully that will be of benefit. We’ve seen some response to” the immunosuppressive “tocilizumab [Actemra], and a lot of response to very good respiratory therapy. I think we are starting to flatten the curve,” Dr. Glatt said.
“Look for tricky symptoms”
The growing awareness of COVID’s protean manifestations is evident in Medscape’s Consult forum, an online community where physicians and medical students share information and seek advice; there’s been over 200 COVID-19 cases and questions since January.
Early on, traffic was mostly about typical pulmonary presentations, but lately it’s shifted to nonrespiratory involvement. Physicians want to know if what they are seeing is related to the virus, and if other people are seeing the same things.
There’s a case on Consult of a 37-year-old man with stomach pain, vomiting, and diarrhea, but no respiratory symptoms and a positive COVID test. A chest CT incidental to his abdominal scan revealed significant bilateral lung involvement.
A 69-year-old woman with a history of laparotomy and new onset intestinal subocclusion had only adhesions on a subsequent exploratory laparotomy, and was doing okay otherwise. She suddenly went into respiratory failure with progressive bradycardia and died 3 days later. Aspiration pneumonia, pulmonary embolism, and MI had been ruled out. “The pattern of cardiovascular failure was in favor of myocarditis, but we don’t have any other clue,” the physician said after describing a second similar case.
Another doctor on the forum reported elevated cardiac enzymes without coronary artery obstruction in a positive patient who went into shock, with an ejection fraction of 40% and markedly increased heart wall thickness, but no lung involvement. There are also two cases of idiopathic thrombocytopenia without fever of hypoxia.
An Italian gastroenterologist said: “Look for tricky symptoms.” Expand “patient history, asking about the sudden occurrence of dysgeusia and/or anosmia. These symptoms have become my guiding diagnostic light” in Verona. “Most patients become nauseated, [and] the taste of any food is unbearable. When I find these symptoms by history, the patient is COVID positive 100%.”
‘Make sure that they didn’t die in vain’
There was interest in those and other reports on Consult, and comments from physicians who have theories, but no certain answers about what is, and is not, caused by the virus.
Direct viral attack is likely a part of it, said Stanley Perlman, MD, PhD, a professor of microbiology and immunology at the University of Iowa, Iowa City.
The ACE2 receptor the virus uses to enter cells is common in many organs, plus there were extrapulmonary manifestations with severe acute respiratory syndrome (SARS), another pandemic caused by a zoonotic coronavirus almost 20 years ago. At least with SARS, “many organs were infected when examined at autopsy,” he said.
The body’s inflammatory response is almost certainly also in play. Progressive derangements in inflammatory markers – C-reactive protein, D-dimer, ferritin – correlate with worse prognosis, and “the cytokine storm that occurs in these patients can lead to a degree of encephalopathy, myocarditis, liver impairment, and kidney impairment; multiorgan dysfunction, in other words,” said William Shaffner, MD, a professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center, Nashville, Tenn.
But in some cases, the virus might simply be a bystander to an unrelated disease process; in others, the experimental treatments being used might cause problems. Indeed, cardiology groups recently warned of torsade de pointes – a dangerously abnormal heart rhythm – with hydroxychloroquine and azithromycin.
“We think it’s some combination,” but don’t really know, Dr. Krumholz said. In the meantime, “we are forced to treat patients by instinct and first principles,” and long-term sequelae are unknown. “We don’t want to be in this position for long.”
To that end, he said, “this is the time for us all to hold hands and be together because we need to learn rapidly from each other. Our job is both to care for the people in front of us and make sure that they didn’t die in vain, that the experience they had is funneled into a larger set of data to make sure the next person is better off.”
Although a cause-and-effect relationship is unknown, people with the virus have presented with or developed heart disease, acute liver injury, ongoing GI issues, skin manifestations, neurologic damage, and other problems, especially among sicker people.
For example, French physicians described an association with encephalopathy, agitation, confusion, and corticospinal tract signs among 58 people hospitalized with acute respiratory distress (N Engl J Med. 2020 Apr 15. doi: 10.1056/NEJMc2008597).
In particular, Yale New Haven (Conn.) Hospital is dealing with unexpected complications up close. Almost half of the beds there are occupied by COVID-19 patients. Over 100 people are in the ICU, and almost 70 intubated. Of the more than 750 COVID admissions so far, only about 350 have been discharged. “Even in a bad flu season, you never see something like this; it’s just unheard of,” said Harlan Krumholz, MD, a Yale cardiologist and professor of medicine helping lead the efforts there.
Kidney injuries prominent
“When they get to the ICU, we are seeing lots of people with acute kidney injuries; lots of people developing endocrine problems; people having blood sugar control issues, coagulation issues, blood clots. We are just waking up to the wide range of ways this virus can affect people. Our ignorance is profound,” Dr. Krumholz said, but physicians “recognize that this thing has the capability of attacking almost every single organ system, and it may or may not present with respiratory symptoms.”
It’s a similar story at Mt. Sinai South Nassau, a hospital in Oceanside, N.Y. “We’ve seen a lot of renal injury in people having complications, a lot of acute dialysis,” but it’s unclear how much is caused by the virus and how much is simply because people are so sick, said Aaron Glatt, MD, infectious disease professor and chair of medicine at the hospital. However, he said things are looking brighter than at Yale.
“We are not seeing the same level of increase in cases that we had previously, and we are starting to see extubations and discharges. We’ve treated a number of patients with plasma therapy, and hopefully that will be of benefit. We’ve seen some response to” the immunosuppressive “tocilizumab [Actemra], and a lot of response to very good respiratory therapy. I think we are starting to flatten the curve,” Dr. Glatt said.
“Look for tricky symptoms”
The growing awareness of COVID’s protean manifestations is evident in Medscape’s Consult forum, an online community where physicians and medical students share information and seek advice; there’s been over 200 COVID-19 cases and questions since January.
Early on, traffic was mostly about typical pulmonary presentations, but lately it’s shifted to nonrespiratory involvement. Physicians want to know if what they are seeing is related to the virus, and if other people are seeing the same things.
There’s a case on Consult of a 37-year-old man with stomach pain, vomiting, and diarrhea, but no respiratory symptoms and a positive COVID test. A chest CT incidental to his abdominal scan revealed significant bilateral lung involvement.
A 69-year-old woman with a history of laparotomy and new onset intestinal subocclusion had only adhesions on a subsequent exploratory laparotomy, and was doing okay otherwise. She suddenly went into respiratory failure with progressive bradycardia and died 3 days later. Aspiration pneumonia, pulmonary embolism, and MI had been ruled out. “The pattern of cardiovascular failure was in favor of myocarditis, but we don’t have any other clue,” the physician said after describing a second similar case.
Another doctor on the forum reported elevated cardiac enzymes without coronary artery obstruction in a positive patient who went into shock, with an ejection fraction of 40% and markedly increased heart wall thickness, but no lung involvement. There are also two cases of idiopathic thrombocytopenia without fever of hypoxia.
An Italian gastroenterologist said: “Look for tricky symptoms.” Expand “patient history, asking about the sudden occurrence of dysgeusia and/or anosmia. These symptoms have become my guiding diagnostic light” in Verona. “Most patients become nauseated, [and] the taste of any food is unbearable. When I find these symptoms by history, the patient is COVID positive 100%.”
‘Make sure that they didn’t die in vain’
There was interest in those and other reports on Consult, and comments from physicians who have theories, but no certain answers about what is, and is not, caused by the virus.
Direct viral attack is likely a part of it, said Stanley Perlman, MD, PhD, a professor of microbiology and immunology at the University of Iowa, Iowa City.
The ACE2 receptor the virus uses to enter cells is common in many organs, plus there were extrapulmonary manifestations with severe acute respiratory syndrome (SARS), another pandemic caused by a zoonotic coronavirus almost 20 years ago. At least with SARS, “many organs were infected when examined at autopsy,” he said.
The body’s inflammatory response is almost certainly also in play. Progressive derangements in inflammatory markers – C-reactive protein, D-dimer, ferritin – correlate with worse prognosis, and “the cytokine storm that occurs in these patients can lead to a degree of encephalopathy, myocarditis, liver impairment, and kidney impairment; multiorgan dysfunction, in other words,” said William Shaffner, MD, a professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center, Nashville, Tenn.
But in some cases, the virus might simply be a bystander to an unrelated disease process; in others, the experimental treatments being used might cause problems. Indeed, cardiology groups recently warned of torsade de pointes – a dangerously abnormal heart rhythm – with hydroxychloroquine and azithromycin.
“We think it’s some combination,” but don’t really know, Dr. Krumholz said. In the meantime, “we are forced to treat patients by instinct and first principles,” and long-term sequelae are unknown. “We don’t want to be in this position for long.”
To that end, he said, “this is the time for us all to hold hands and be together because we need to learn rapidly from each other. Our job is both to care for the people in front of us and make sure that they didn’t die in vain, that the experience they had is funneled into a larger set of data to make sure the next person is better off.”
Evidence suggests possible RAS-blocker benefit in COVID-19 patients
Patients infected by the COVID-19 virus may benefit from treatments that dampen the renin-angiotensin system, according to a review of several animal studies. These preclinical findings generally support the positions taken in recent week by several cardiology societies that recommended patients taking drugs that moderate the renin-angiotensin system stay on these treatments.
“In patients with cardiovascular disease and SARS-CoV2, the use of ACE inhibitors, ARBs [angiotensin receptor blockers], or MRAs [mineralocorticoid-receptor antagonists] may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, antifibrotic, and antithrombotic support as well as reduction in progression of vascular/cardiac remodeling and heart failure,” wrote Jeffrey Bander, MD, and his associates in a report published online (J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.jacc.2020.04.028).
“Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS [renin-angiotensin system] inhibitors given the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk to COVID-19,” said the researchers, who are affiliated with the Icahn School of Medicine at Mount Sinai in New York.
The ACE2 protein, found both in human blood as well as in cell membranes, especially cells of the lungs, heart, kidneys, and gastrointestinal tissues, functions as both a key enzyme in RAS regulation as well as the primary cell receptor for entry of SARS-CoV2.
Their conclusion jibed with both a joint statement in March from the American College of Cardiology, American Heart Association, and the Heart Failure Society of America; and with the conclusions of a review organized by the European Society of Hypertension’s COVID-19 Task Force (Cardiovasc Res. 2020 Apr 15. doi: 10.1093/cvr/cvaa097).
In their review, the Mount Sinai authors described results from several animal studies suggesting that ACE2 and its associated signaling proteins could potentially be a “valuable therapeutic target.” They also highlighted several clinical intervention studies recently launched to target ACE2, related proteins, and regulation of this arm of the RAS.
Currently, “no data support any conclusive effects of the use of RAS inhibitors in patients with COVID-19,” they concluded. They acknowledged that “the question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection,” but emphasized that “adequate data on the effects of RAS inhibition in COVID-19 patients is not available,” with more data becoming available soon from ongoing clinical studies.
None of the authors had any disclosures.
Patients infected by the COVID-19 virus may benefit from treatments that dampen the renin-angiotensin system, according to a review of several animal studies. These preclinical findings generally support the positions taken in recent week by several cardiology societies that recommended patients taking drugs that moderate the renin-angiotensin system stay on these treatments.
“In patients with cardiovascular disease and SARS-CoV2, the use of ACE inhibitors, ARBs [angiotensin receptor blockers], or MRAs [mineralocorticoid-receptor antagonists] may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, antifibrotic, and antithrombotic support as well as reduction in progression of vascular/cardiac remodeling and heart failure,” wrote Jeffrey Bander, MD, and his associates in a report published online (J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.jacc.2020.04.028).
“Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS [renin-angiotensin system] inhibitors given the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk to COVID-19,” said the researchers, who are affiliated with the Icahn School of Medicine at Mount Sinai in New York.
The ACE2 protein, found both in human blood as well as in cell membranes, especially cells of the lungs, heart, kidneys, and gastrointestinal tissues, functions as both a key enzyme in RAS regulation as well as the primary cell receptor for entry of SARS-CoV2.
Their conclusion jibed with both a joint statement in March from the American College of Cardiology, American Heart Association, and the Heart Failure Society of America; and with the conclusions of a review organized by the European Society of Hypertension’s COVID-19 Task Force (Cardiovasc Res. 2020 Apr 15. doi: 10.1093/cvr/cvaa097).
In their review, the Mount Sinai authors described results from several animal studies suggesting that ACE2 and its associated signaling proteins could potentially be a “valuable therapeutic target.” They also highlighted several clinical intervention studies recently launched to target ACE2, related proteins, and regulation of this arm of the RAS.
Currently, “no data support any conclusive effects of the use of RAS inhibitors in patients with COVID-19,” they concluded. They acknowledged that “the question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection,” but emphasized that “adequate data on the effects of RAS inhibition in COVID-19 patients is not available,” with more data becoming available soon from ongoing clinical studies.
None of the authors had any disclosures.
Patients infected by the COVID-19 virus may benefit from treatments that dampen the renin-angiotensin system, according to a review of several animal studies. These preclinical findings generally support the positions taken in recent week by several cardiology societies that recommended patients taking drugs that moderate the renin-angiotensin system stay on these treatments.
“In patients with cardiovascular disease and SARS-CoV2, the use of ACE inhibitors, ARBs [angiotensin receptor blockers], or MRAs [mineralocorticoid-receptor antagonists] may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, antifibrotic, and antithrombotic support as well as reduction in progression of vascular/cardiac remodeling and heart failure,” wrote Jeffrey Bander, MD, and his associates in a report published online (J Am Coll Cardiol. 2020 Apr 15. doi: 10.1016/j.jacc.2020.04.028).
“Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS [renin-angiotensin system] inhibitors given the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk to COVID-19,” said the researchers, who are affiliated with the Icahn School of Medicine at Mount Sinai in New York.
The ACE2 protein, found both in human blood as well as in cell membranes, especially cells of the lungs, heart, kidneys, and gastrointestinal tissues, functions as both a key enzyme in RAS regulation as well as the primary cell receptor for entry of SARS-CoV2.
Their conclusion jibed with both a joint statement in March from the American College of Cardiology, American Heart Association, and the Heart Failure Society of America; and with the conclusions of a review organized by the European Society of Hypertension’s COVID-19 Task Force (Cardiovasc Res. 2020 Apr 15. doi: 10.1093/cvr/cvaa097).
In their review, the Mount Sinai authors described results from several animal studies suggesting that ACE2 and its associated signaling proteins could potentially be a “valuable therapeutic target.” They also highlighted several clinical intervention studies recently launched to target ACE2, related proteins, and regulation of this arm of the RAS.
Currently, “no data support any conclusive effects of the use of RAS inhibitors in patients with COVID-19,” they concluded. They acknowledged that “the question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection,” but emphasized that “adequate data on the effects of RAS inhibition in COVID-19 patients is not available,” with more data becoming available soon from ongoing clinical studies.
None of the authors had any disclosures.
REPORTING FROM JACC
No hydroxychloroquine benefit in small, randomized COVID-19 trial
However, two experts caution that, because of confounding, the trial is unable to answer convincingly the question of whether HCQ can benefit COVID-19 patients.
Wei Tang, with the Departments of Pulmonology and Critical Care Medicine at Ruijin Hospital, in Shanghai, China, and colleagues enrolled patients with COVID-19 from 16 treatment centers in China in February. They posted their findings on the medRxiv preprint server, but their paper has not been peer reviewed. A coauthor told Medscape Medical News the work has been submitted to a journal.
The overall 28-day negative conversion rate of SARS-CoV-2, which was the primary endpoint, was similar in the two 75-patient treatment groups. The Kaplan-Meier estimate for negative conversion rate was 85.4% in the HCQ plus standard of care (SOC) arm, vs 81.3% in the SOC-only group (P = .341). Negative conversion rates for the two groups were similar at days 4, 7, 10, 14, and 21.
Adverse events were reported in 8.8% of patients in the control group compared with 30% in the HCQ group. Diarrhea was the most common side effect, occurring in 10% of patients in the HCQ group vs none in the control group. Two patients in the HCQ arm had serious adverse events; one experienced disease progression, and the other experienced upper respiratory tract infection.
Patients in the HCQ group received a high loading dose of 1200 mg daily for 3 days followed by a maintenance dose of 800 mg daily for the remaining days. Total duration was 2 weeks for patients with mild or moderate disease and 3 weeks for those with severe disease.
No Difference in Relief of Symptoms
The two arms were similar in alleviation of symptoms by day 28: 59.9% with HCQ plus SOC vs 66.6% with SOC alone.
However, the researchers said that in a post hoc analysis, they found a significant reduction of symptoms after adjusting for the confounding effects of antiviral agents (hazard ratio, 8.83; 95% confidence interval, 1.09 – 71.3).
In addition, Tang and colleagues report a significantly greater reduction of C-reactive protein (CRP), a biomarker for inflammation, from baseline to day 28 in the HCQ group in comparison with the control group (6.986 vs 2.723 mg/L).
The authors suggest the alleviation of symptoms may come from HCQ’s anti-inflammatory effects.
The mean age of the patients was 46 years, and 55% were male. Almost all patients had mild or moderate disease; two had severe disease.
Experts Say Study Arms May Not Have Been Comparable
J. Michelle Kahlenberg, MD, PhD, research professor of rheumatology at the University of Michigan in Ann Arbor, told Medscape Medical News that it’s important to note that in the post hoc analysis, 89% of the patients in this trial were receiving other therapy in addition to HCQ.
“When [the researchers] say they saw improvement in symptoms when they removed the confounders, what they actually did was remove the patients from the analysis that got antivirals, and that left 14 patients in each arm,” Kahlenberg said.
Moreover, Kahlenberg noted, 20% of patients who received HCQ had mild symptoms, whereas only 9% of those in the SOC group did.
“We don’t know how those patients played out in the post hoc analysis — whether it was the patients who were really mild that didn’t get the antivirals that were left in the hydroxychloroquine group and that’s why they had a slightly faster resolution of symptoms,” she said.
She said that in this study, the researchers calculated CRP in milligrams per liter, whereas in the United States, it is measured in milligrams per deciliter. The conversion highlights the fact that the reduction in CRP was not terribly noteworthy, she said.
“The patients with COVID who tend to tank and have cytokine storms ― their CRP is much higher,” she said. “So the small improvement in CRP wasn’t that exciting.
“I don’t think this gets us anywhere closer to an answer. It’s another muddy study,” she said.
Similarly, Christopher V. Plowe, MD, MPH, director of the Global Health Institute at Duke University in Durham, North Carolina, told Medscape Medical News he sees no convincing answers in this study.
Plowe, professor of medicine, molecular genetics, microbiology, and global health at Duke, also noted differences between the two groups at enrollment.
For example, the HCQ group had more than three times the number of patients with shortness of breath (22.1% vs 5.9%); more with sputum production (16.2 vs 5.9%); and more with cough (51.5% vs 38.2%). In addition, the average age was 4 years higher in the HCQ group.
“It makes me wonder whether the randomization was truly random,” Plowe said.
Plowe also questioned the authors’ statement that they didn’t see cardiac arrhythmia events, such as prolonged QT intervals. “I can’t see any evidence that they did an EKG on anybody,” he said.
“This study leaves the door open to the possibility that hydroxychloroquine may have a clinical benefit. If there is a benefit, it seems to be related to the drug’s anti-inflammatory properties. If that’s the case, I’m not sure this particular drug, as opposed to others, would be the way to go,” Plowe said.
Mixed Results in Other Studies
“Our negative results on the anti-viral efficacy of HCQ obtained in this trial are on the contrary to the encouraging in-vitro results and to the recently reported promising results from a non-randomized trial with 36 COVID-19 patients,” the authors write.
However, the 36-patient trial to which they refer has since been called into question, as previously reported by Retraction Watch.
Despite lack of clear evidence of benefit, HCQ is recommended off label for the treatment of COVID-19 by the Chinese National guideline, and the US Food and Drug Administration has issued an emergency-use authorization for the treatment of adult patients with COVID-19.
By contrast, the Infectious Diseases Society of America recently concluded that because of insufficient data, they could not recommend any particular treatment for patients with COVID-19.
The work was supported by the Emergent Projects of National Science and Technology; the National Natural Science Foundation of China; the National Key Research and Development Program of China; the Shanghai Municipal Key Clinical Specialty; the National Innovative Research Team of High-Level Local Universities in Shanghai; the Shanghai Key Discipline for Respiratory Diseases; the National Major Scientific and Technological Special Project for Significant New Drugs Development; and Key Projects in the National Science and Technology Pillar Program. The authors, Kahlenberg, and Plowe have disclosed no relevant financial relationships.
This story first appeared on Medscape.com.
However, two experts caution that, because of confounding, the trial is unable to answer convincingly the question of whether HCQ can benefit COVID-19 patients.
Wei Tang, with the Departments of Pulmonology and Critical Care Medicine at Ruijin Hospital, in Shanghai, China, and colleagues enrolled patients with COVID-19 from 16 treatment centers in China in February. They posted their findings on the medRxiv preprint server, but their paper has not been peer reviewed. A coauthor told Medscape Medical News the work has been submitted to a journal.
The overall 28-day negative conversion rate of SARS-CoV-2, which was the primary endpoint, was similar in the two 75-patient treatment groups. The Kaplan-Meier estimate for negative conversion rate was 85.4% in the HCQ plus standard of care (SOC) arm, vs 81.3% in the SOC-only group (P = .341). Negative conversion rates for the two groups were similar at days 4, 7, 10, 14, and 21.
Adverse events were reported in 8.8% of patients in the control group compared with 30% in the HCQ group. Diarrhea was the most common side effect, occurring in 10% of patients in the HCQ group vs none in the control group. Two patients in the HCQ arm had serious adverse events; one experienced disease progression, and the other experienced upper respiratory tract infection.
Patients in the HCQ group received a high loading dose of 1200 mg daily for 3 days followed by a maintenance dose of 800 mg daily for the remaining days. Total duration was 2 weeks for patients with mild or moderate disease and 3 weeks for those with severe disease.
No Difference in Relief of Symptoms
The two arms were similar in alleviation of symptoms by day 28: 59.9% with HCQ plus SOC vs 66.6% with SOC alone.
However, the researchers said that in a post hoc analysis, they found a significant reduction of symptoms after adjusting for the confounding effects of antiviral agents (hazard ratio, 8.83; 95% confidence interval, 1.09 – 71.3).
In addition, Tang and colleagues report a significantly greater reduction of C-reactive protein (CRP), a biomarker for inflammation, from baseline to day 28 in the HCQ group in comparison with the control group (6.986 vs 2.723 mg/L).
The authors suggest the alleviation of symptoms may come from HCQ’s anti-inflammatory effects.
The mean age of the patients was 46 years, and 55% were male. Almost all patients had mild or moderate disease; two had severe disease.
Experts Say Study Arms May Not Have Been Comparable
J. Michelle Kahlenberg, MD, PhD, research professor of rheumatology at the University of Michigan in Ann Arbor, told Medscape Medical News that it’s important to note that in the post hoc analysis, 89% of the patients in this trial were receiving other therapy in addition to HCQ.
“When [the researchers] say they saw improvement in symptoms when they removed the confounders, what they actually did was remove the patients from the analysis that got antivirals, and that left 14 patients in each arm,” Kahlenberg said.
Moreover, Kahlenberg noted, 20% of patients who received HCQ had mild symptoms, whereas only 9% of those in the SOC group did.
“We don’t know how those patients played out in the post hoc analysis — whether it was the patients who were really mild that didn’t get the antivirals that were left in the hydroxychloroquine group and that’s why they had a slightly faster resolution of symptoms,” she said.
She said that in this study, the researchers calculated CRP in milligrams per liter, whereas in the United States, it is measured in milligrams per deciliter. The conversion highlights the fact that the reduction in CRP was not terribly noteworthy, she said.
“The patients with COVID who tend to tank and have cytokine storms ― their CRP is much higher,” she said. “So the small improvement in CRP wasn’t that exciting.
“I don’t think this gets us anywhere closer to an answer. It’s another muddy study,” she said.
Similarly, Christopher V. Plowe, MD, MPH, director of the Global Health Institute at Duke University in Durham, North Carolina, told Medscape Medical News he sees no convincing answers in this study.
Plowe, professor of medicine, molecular genetics, microbiology, and global health at Duke, also noted differences between the two groups at enrollment.
For example, the HCQ group had more than three times the number of patients with shortness of breath (22.1% vs 5.9%); more with sputum production (16.2 vs 5.9%); and more with cough (51.5% vs 38.2%). In addition, the average age was 4 years higher in the HCQ group.
“It makes me wonder whether the randomization was truly random,” Plowe said.
Plowe also questioned the authors’ statement that they didn’t see cardiac arrhythmia events, such as prolonged QT intervals. “I can’t see any evidence that they did an EKG on anybody,” he said.
“This study leaves the door open to the possibility that hydroxychloroquine may have a clinical benefit. If there is a benefit, it seems to be related to the drug’s anti-inflammatory properties. If that’s the case, I’m not sure this particular drug, as opposed to others, would be the way to go,” Plowe said.
Mixed Results in Other Studies
“Our negative results on the anti-viral efficacy of HCQ obtained in this trial are on the contrary to the encouraging in-vitro results and to the recently reported promising results from a non-randomized trial with 36 COVID-19 patients,” the authors write.
However, the 36-patient trial to which they refer has since been called into question, as previously reported by Retraction Watch.
Despite lack of clear evidence of benefit, HCQ is recommended off label for the treatment of COVID-19 by the Chinese National guideline, and the US Food and Drug Administration has issued an emergency-use authorization for the treatment of adult patients with COVID-19.
By contrast, the Infectious Diseases Society of America recently concluded that because of insufficient data, they could not recommend any particular treatment for patients with COVID-19.
The work was supported by the Emergent Projects of National Science and Technology; the National Natural Science Foundation of China; the National Key Research and Development Program of China; the Shanghai Municipal Key Clinical Specialty; the National Innovative Research Team of High-Level Local Universities in Shanghai; the Shanghai Key Discipline for Respiratory Diseases; the National Major Scientific and Technological Special Project for Significant New Drugs Development; and Key Projects in the National Science and Technology Pillar Program. The authors, Kahlenberg, and Plowe have disclosed no relevant financial relationships.
This story first appeared on Medscape.com.
However, two experts caution that, because of confounding, the trial is unable to answer convincingly the question of whether HCQ can benefit COVID-19 patients.
Wei Tang, with the Departments of Pulmonology and Critical Care Medicine at Ruijin Hospital, in Shanghai, China, and colleagues enrolled patients with COVID-19 from 16 treatment centers in China in February. They posted their findings on the medRxiv preprint server, but their paper has not been peer reviewed. A coauthor told Medscape Medical News the work has been submitted to a journal.
The overall 28-day negative conversion rate of SARS-CoV-2, which was the primary endpoint, was similar in the two 75-patient treatment groups. The Kaplan-Meier estimate for negative conversion rate was 85.4% in the HCQ plus standard of care (SOC) arm, vs 81.3% in the SOC-only group (P = .341). Negative conversion rates for the two groups were similar at days 4, 7, 10, 14, and 21.
Adverse events were reported in 8.8% of patients in the control group compared with 30% in the HCQ group. Diarrhea was the most common side effect, occurring in 10% of patients in the HCQ group vs none in the control group. Two patients in the HCQ arm had serious adverse events; one experienced disease progression, and the other experienced upper respiratory tract infection.
Patients in the HCQ group received a high loading dose of 1200 mg daily for 3 days followed by a maintenance dose of 800 mg daily for the remaining days. Total duration was 2 weeks for patients with mild or moderate disease and 3 weeks for those with severe disease.
No Difference in Relief of Symptoms
The two arms were similar in alleviation of symptoms by day 28: 59.9% with HCQ plus SOC vs 66.6% with SOC alone.
However, the researchers said that in a post hoc analysis, they found a significant reduction of symptoms after adjusting for the confounding effects of antiviral agents (hazard ratio, 8.83; 95% confidence interval, 1.09 – 71.3).
In addition, Tang and colleagues report a significantly greater reduction of C-reactive protein (CRP), a biomarker for inflammation, from baseline to day 28 in the HCQ group in comparison with the control group (6.986 vs 2.723 mg/L).
The authors suggest the alleviation of symptoms may come from HCQ’s anti-inflammatory effects.
The mean age of the patients was 46 years, and 55% were male. Almost all patients had mild or moderate disease; two had severe disease.
Experts Say Study Arms May Not Have Been Comparable
J. Michelle Kahlenberg, MD, PhD, research professor of rheumatology at the University of Michigan in Ann Arbor, told Medscape Medical News that it’s important to note that in the post hoc analysis, 89% of the patients in this trial were receiving other therapy in addition to HCQ.
“When [the researchers] say they saw improvement in symptoms when they removed the confounders, what they actually did was remove the patients from the analysis that got antivirals, and that left 14 patients in each arm,” Kahlenberg said.
Moreover, Kahlenberg noted, 20% of patients who received HCQ had mild symptoms, whereas only 9% of those in the SOC group did.
“We don’t know how those patients played out in the post hoc analysis — whether it was the patients who were really mild that didn’t get the antivirals that were left in the hydroxychloroquine group and that’s why they had a slightly faster resolution of symptoms,” she said.
She said that in this study, the researchers calculated CRP in milligrams per liter, whereas in the United States, it is measured in milligrams per deciliter. The conversion highlights the fact that the reduction in CRP was not terribly noteworthy, she said.
“The patients with COVID who tend to tank and have cytokine storms ― their CRP is much higher,” she said. “So the small improvement in CRP wasn’t that exciting.
“I don’t think this gets us anywhere closer to an answer. It’s another muddy study,” she said.
Similarly, Christopher V. Plowe, MD, MPH, director of the Global Health Institute at Duke University in Durham, North Carolina, told Medscape Medical News he sees no convincing answers in this study.
Plowe, professor of medicine, molecular genetics, microbiology, and global health at Duke, also noted differences between the two groups at enrollment.
For example, the HCQ group had more than three times the number of patients with shortness of breath (22.1% vs 5.9%); more with sputum production (16.2 vs 5.9%); and more with cough (51.5% vs 38.2%). In addition, the average age was 4 years higher in the HCQ group.
“It makes me wonder whether the randomization was truly random,” Plowe said.
Plowe also questioned the authors’ statement that they didn’t see cardiac arrhythmia events, such as prolonged QT intervals. “I can’t see any evidence that they did an EKG on anybody,” he said.
“This study leaves the door open to the possibility that hydroxychloroquine may have a clinical benefit. If there is a benefit, it seems to be related to the drug’s anti-inflammatory properties. If that’s the case, I’m not sure this particular drug, as opposed to others, would be the way to go,” Plowe said.
Mixed Results in Other Studies
“Our negative results on the anti-viral efficacy of HCQ obtained in this trial are on the contrary to the encouraging in-vitro results and to the recently reported promising results from a non-randomized trial with 36 COVID-19 patients,” the authors write.
However, the 36-patient trial to which they refer has since been called into question, as previously reported by Retraction Watch.
Despite lack of clear evidence of benefit, HCQ is recommended off label for the treatment of COVID-19 by the Chinese National guideline, and the US Food and Drug Administration has issued an emergency-use authorization for the treatment of adult patients with COVID-19.
By contrast, the Infectious Diseases Society of America recently concluded that because of insufficient data, they could not recommend any particular treatment for patients with COVID-19.
The work was supported by the Emergent Projects of National Science and Technology; the National Natural Science Foundation of China; the National Key Research and Development Program of China; the Shanghai Municipal Key Clinical Specialty; the National Innovative Research Team of High-Level Local Universities in Shanghai; the Shanghai Key Discipline for Respiratory Diseases; the National Major Scientific and Technological Special Project for Significant New Drugs Development; and Key Projects in the National Science and Technology Pillar Program. The authors, Kahlenberg, and Plowe have disclosed no relevant financial relationships.
This story first appeared on Medscape.com.
COVID-19 mythconceptions
Let’s start with a case:
A 37-year-old woman is seen in clinic for a 5-day history of cough, fever, chest tightness, and onset of dyspnea on the day of her office visit.
An exam reveals her blood pressure is 100/60 mm Hg, her pulse is 100 beats per minute, her temperature is 38.7° C, her oxygen saturation is 93%, and her respiratory rate is 20 breaths per minute.
Auscultation of the chest revealed bilateral wheezing and rhonchi. A nasopharyngeal swab is sent for COVID-19 and is negative; she also tests negative for influenza.
Her hemoglobin level is 13 g/dL, hematocrit was 39%, platelet count was 155,000 per mcL of blood, and D-dimer level was 8.4 mcg/mL (normal is less than 0.4 mcg/mL.) Her white blood cell count was 6,000 per mcL of blood (neutrophils, 4,900; lymphocytes, 800; basophils, 200). Her chest x-ray showed bilateral lower lobe infiltrates.
What do you recommend?
A. Begin azithromycin plus ceftriaxone
B. Begin azithromycin
C. Begin oseltamivir
D. Obtain chest CT
E. Repeat COVID-19 test
With the massive amount of information coming out every day on COVID-19, it is hard to keep up with all of it, and sort out accurate, reviewed studies. We are in a position where we need to take in what we can and assess the best data available.
In the case above, I think choices D or E would make sense. This patient very likely has COVID-19 based on clinical symptoms and lab parameters. The negative COVID-19 test gives us pause, but several studies show that false negative tests are not uncommon.
Long et al. reported on 36 patients who had received both chest CT and real-time reverse transcription polymerase chain reaction (rRT-PCR) for COVID-19.1 All were eventually diagnosed with COVID-19 pneumonia. The CT scan had a very high sensitivity (35/36) of 97.2%, whereas the rRT-PCR had a lower sensitivity (30/36) of 83%. All six of the patients with a negative COVID-19 test initially were positive on repeat testing (three on the second test, three on the third test).
There are concerns about what the sensitivity of the rRT-PCR tests being run in the United States are. At this point, I think that, when the pretest probability of COVID-19 infection is very high based on local epidemiology and clinical symptoms, a negative COVID rRT-PCR does not eliminate the diagnosis. In many cases, COVID-19 may still be the most likely diagnosis.
Early in the pandemic, the symptoms that were emphasized were fever, cough, and dyspnea. Those were all crucial symptoms for a disease that causes pneumonia. GI symptoms were initially deemphasized. In an early study released from Wuhan, China, only about 5% of COVID-19 patients had nausea or diarrhea.2 In a study of 305 patients focused on gastrointestinal symptoms, half of the patients had diarrhea, half had anorexia and 30% had nausea.3 In a small series of nine patients who presented with only GI symptoms, four of these patients never developed fever or pulmonary symptoms.3
On March 14, the French health minister, Olivier Véran, tweeted that “taking anti-inflammatory drugs (ibuprofen, cortisone ...) could be an aggravating factor for the infection. If you have a fever, take paracetamol.” This was picked up by many news services, and soon became standard recommendations, despite no data.
There is reason for concern for NSAIDs, as regular NSAID use has been tied to more complications in patients with respiratory tract infections.4 I have never been a proponent of regular NSAID use in patients who are infected, because the likelihood of toxicity is elevated in patients who are volume depleted or under physiologic stress. But at this time, there is no evidence on problems with episodic NSAID use in patients with COVID-19.
Another widely disseminated decree was that patients with COVID-19 should not use ACE inhibitors and angiotensin II receptor blockers (ARBs). COVID-19 binds to their target cells through ACE2, which is expressed by epithelial cells of the lung, intestine and kidney. Patients who are treated with ACE inhibitors and ARBs have been shown to have more ACE2 expression.
In a letter to the editor by Fang et al. published in Lancet Respiratory Medicine, the authors raised the question of whether patients might be better served to be switched from ACE inhibitors and ARBs to calcium-channel blockers for the treatment of hypertension.5 A small study by Meng et al. looked at outcomes of patients on these drugs who had COVID-19 infection.6 They looked at 417 patients admitted to a hospital in China with COVID-19 infection. A total of 42 patients were on medications for hypertension. Group 1 were patients on ACE inhibitors/ARBs (17 patients) and group 2 were patients on other antihypertensives (25 patients). During hospitalization 12 patients (48%) in group 2 were categorized as having severe disease and 1 patient died. In group 1 (the ACE inhibitor/ARB–treated patients) only four (23%) were categorized as having severe disease, and no patients in this group died.
Vaduganathan et al. published a special report in the New England Journal of Medicine strongly arguing the point that “[u]ntil further data are available, we think that [renin-angiotensin-aldosterone system] inhibitors should be continued in patients in otherwise stable condition who are at risk for, being evaluated for, or with COVID-19”.7 This position is supported by the American Heart Association, the American College of Cardiology, the American College of Physicians, and 11 other medical organizations.
Take-home messages
- Testing isn’t perfect – if you have strong suspicion for COVID-19 disease, retest.
- GI symptoms appear to be common, and rarely may be the only symptoms initially.
- NSAIDs are always risky in really sick patients, but data specific to COVID-19 is lacking.
- ACE inhibitors/ARBs should not be avoided in patients with COVID-19.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact Dr. Paauw at imnews@mdedge.com.
References
1. Long C et al. Diagnosis of the Coronavirus disease (COVID-19): rRT-PCR or CT? Eur J Radiol. 2020 Mar 25;126:108961.
2. Zhou F et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-62.
3. Tian Y et al. Review article: Gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther. 2020;00:1–9.
4. Voiriot G et al. Risks related to the use of nonsteroidal anti-inflammatory drugs in community-acquired pneumonia in adult and pediatric patients. J Clin Med. 2019;8:E786.
5. Fang L et al. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Mar 11. doi:10.1016/S2213-2600(20)30116-8.
6. Meng J et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020 Dec;9(1):757-60.
7. Vaduganathan M et al. Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19. N Engl J Med. 2020 Mar 30. doi: 10.1056/NEJMsr2005760.
Let’s start with a case:
A 37-year-old woman is seen in clinic for a 5-day history of cough, fever, chest tightness, and onset of dyspnea on the day of her office visit.
An exam reveals her blood pressure is 100/60 mm Hg, her pulse is 100 beats per minute, her temperature is 38.7° C, her oxygen saturation is 93%, and her respiratory rate is 20 breaths per minute.
Auscultation of the chest revealed bilateral wheezing and rhonchi. A nasopharyngeal swab is sent for COVID-19 and is negative; she also tests negative for influenza.
Her hemoglobin level is 13 g/dL, hematocrit was 39%, platelet count was 155,000 per mcL of blood, and D-dimer level was 8.4 mcg/mL (normal is less than 0.4 mcg/mL.) Her white blood cell count was 6,000 per mcL of blood (neutrophils, 4,900; lymphocytes, 800; basophils, 200). Her chest x-ray showed bilateral lower lobe infiltrates.
What do you recommend?
A. Begin azithromycin plus ceftriaxone
B. Begin azithromycin
C. Begin oseltamivir
D. Obtain chest CT
E. Repeat COVID-19 test
With the massive amount of information coming out every day on COVID-19, it is hard to keep up with all of it, and sort out accurate, reviewed studies. We are in a position where we need to take in what we can and assess the best data available.
In the case above, I think choices D or E would make sense. This patient very likely has COVID-19 based on clinical symptoms and lab parameters. The negative COVID-19 test gives us pause, but several studies show that false negative tests are not uncommon.
Long et al. reported on 36 patients who had received both chest CT and real-time reverse transcription polymerase chain reaction (rRT-PCR) for COVID-19.1 All were eventually diagnosed with COVID-19 pneumonia. The CT scan had a very high sensitivity (35/36) of 97.2%, whereas the rRT-PCR had a lower sensitivity (30/36) of 83%. All six of the patients with a negative COVID-19 test initially were positive on repeat testing (three on the second test, three on the third test).
There are concerns about what the sensitivity of the rRT-PCR tests being run in the United States are. At this point, I think that, when the pretest probability of COVID-19 infection is very high based on local epidemiology and clinical symptoms, a negative COVID rRT-PCR does not eliminate the diagnosis. In many cases, COVID-19 may still be the most likely diagnosis.
Early in the pandemic, the symptoms that were emphasized were fever, cough, and dyspnea. Those were all crucial symptoms for a disease that causes pneumonia. GI symptoms were initially deemphasized. In an early study released from Wuhan, China, only about 5% of COVID-19 patients had nausea or diarrhea.2 In a study of 305 patients focused on gastrointestinal symptoms, half of the patients had diarrhea, half had anorexia and 30% had nausea.3 In a small series of nine patients who presented with only GI symptoms, four of these patients never developed fever or pulmonary symptoms.3
On March 14, the French health minister, Olivier Véran, tweeted that “taking anti-inflammatory drugs (ibuprofen, cortisone ...) could be an aggravating factor for the infection. If you have a fever, take paracetamol.” This was picked up by many news services, and soon became standard recommendations, despite no data.
There is reason for concern for NSAIDs, as regular NSAID use has been tied to more complications in patients with respiratory tract infections.4 I have never been a proponent of regular NSAID use in patients who are infected, because the likelihood of toxicity is elevated in patients who are volume depleted or under physiologic stress. But at this time, there is no evidence on problems with episodic NSAID use in patients with COVID-19.
Another widely disseminated decree was that patients with COVID-19 should not use ACE inhibitors and angiotensin II receptor blockers (ARBs). COVID-19 binds to their target cells through ACE2, which is expressed by epithelial cells of the lung, intestine and kidney. Patients who are treated with ACE inhibitors and ARBs have been shown to have more ACE2 expression.
In a letter to the editor by Fang et al. published in Lancet Respiratory Medicine, the authors raised the question of whether patients might be better served to be switched from ACE inhibitors and ARBs to calcium-channel blockers for the treatment of hypertension.5 A small study by Meng et al. looked at outcomes of patients on these drugs who had COVID-19 infection.6 They looked at 417 patients admitted to a hospital in China with COVID-19 infection. A total of 42 patients were on medications for hypertension. Group 1 were patients on ACE inhibitors/ARBs (17 patients) and group 2 were patients on other antihypertensives (25 patients). During hospitalization 12 patients (48%) in group 2 were categorized as having severe disease and 1 patient died. In group 1 (the ACE inhibitor/ARB–treated patients) only four (23%) were categorized as having severe disease, and no patients in this group died.
Vaduganathan et al. published a special report in the New England Journal of Medicine strongly arguing the point that “[u]ntil further data are available, we think that [renin-angiotensin-aldosterone system] inhibitors should be continued in patients in otherwise stable condition who are at risk for, being evaluated for, or with COVID-19”.7 This position is supported by the American Heart Association, the American College of Cardiology, the American College of Physicians, and 11 other medical organizations.
Take-home messages
- Testing isn’t perfect – if you have strong suspicion for COVID-19 disease, retest.
- GI symptoms appear to be common, and rarely may be the only symptoms initially.
- NSAIDs are always risky in really sick patients, but data specific to COVID-19 is lacking.
- ACE inhibitors/ARBs should not be avoided in patients with COVID-19.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact Dr. Paauw at imnews@mdedge.com.
References
1. Long C et al. Diagnosis of the Coronavirus disease (COVID-19): rRT-PCR or CT? Eur J Radiol. 2020 Mar 25;126:108961.
2. Zhou F et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-62.
3. Tian Y et al. Review article: Gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther. 2020;00:1–9.
4. Voiriot G et al. Risks related to the use of nonsteroidal anti-inflammatory drugs in community-acquired pneumonia in adult and pediatric patients. J Clin Med. 2019;8:E786.
5. Fang L et al. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Mar 11. doi:10.1016/S2213-2600(20)30116-8.
6. Meng J et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020 Dec;9(1):757-60.
7. Vaduganathan M et al. Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19. N Engl J Med. 2020 Mar 30. doi: 10.1056/NEJMsr2005760.
Let’s start with a case:
A 37-year-old woman is seen in clinic for a 5-day history of cough, fever, chest tightness, and onset of dyspnea on the day of her office visit.
An exam reveals her blood pressure is 100/60 mm Hg, her pulse is 100 beats per minute, her temperature is 38.7° C, her oxygen saturation is 93%, and her respiratory rate is 20 breaths per minute.
Auscultation of the chest revealed bilateral wheezing and rhonchi. A nasopharyngeal swab is sent for COVID-19 and is negative; she also tests negative for influenza.
Her hemoglobin level is 13 g/dL, hematocrit was 39%, platelet count was 155,000 per mcL of blood, and D-dimer level was 8.4 mcg/mL (normal is less than 0.4 mcg/mL.) Her white blood cell count was 6,000 per mcL of blood (neutrophils, 4,900; lymphocytes, 800; basophils, 200). Her chest x-ray showed bilateral lower lobe infiltrates.
What do you recommend?
A. Begin azithromycin plus ceftriaxone
B. Begin azithromycin
C. Begin oseltamivir
D. Obtain chest CT
E. Repeat COVID-19 test
With the massive amount of information coming out every day on COVID-19, it is hard to keep up with all of it, and sort out accurate, reviewed studies. We are in a position where we need to take in what we can and assess the best data available.
In the case above, I think choices D or E would make sense. This patient very likely has COVID-19 based on clinical symptoms and lab parameters. The negative COVID-19 test gives us pause, but several studies show that false negative tests are not uncommon.
Long et al. reported on 36 patients who had received both chest CT and real-time reverse transcription polymerase chain reaction (rRT-PCR) for COVID-19.1 All were eventually diagnosed with COVID-19 pneumonia. The CT scan had a very high sensitivity (35/36) of 97.2%, whereas the rRT-PCR had a lower sensitivity (30/36) of 83%. All six of the patients with a negative COVID-19 test initially were positive on repeat testing (three on the second test, three on the third test).
There are concerns about what the sensitivity of the rRT-PCR tests being run in the United States are. At this point, I think that, when the pretest probability of COVID-19 infection is very high based on local epidemiology and clinical symptoms, a negative COVID rRT-PCR does not eliminate the diagnosis. In many cases, COVID-19 may still be the most likely diagnosis.
Early in the pandemic, the symptoms that were emphasized were fever, cough, and dyspnea. Those were all crucial symptoms for a disease that causes pneumonia. GI symptoms were initially deemphasized. In an early study released from Wuhan, China, only about 5% of COVID-19 patients had nausea or diarrhea.2 In a study of 305 patients focused on gastrointestinal symptoms, half of the patients had diarrhea, half had anorexia and 30% had nausea.3 In a small series of nine patients who presented with only GI symptoms, four of these patients never developed fever or pulmonary symptoms.3
On March 14, the French health minister, Olivier Véran, tweeted that “taking anti-inflammatory drugs (ibuprofen, cortisone ...) could be an aggravating factor for the infection. If you have a fever, take paracetamol.” This was picked up by many news services, and soon became standard recommendations, despite no data.
There is reason for concern for NSAIDs, as regular NSAID use has been tied to more complications in patients with respiratory tract infections.4 I have never been a proponent of regular NSAID use in patients who are infected, because the likelihood of toxicity is elevated in patients who are volume depleted or under physiologic stress. But at this time, there is no evidence on problems with episodic NSAID use in patients with COVID-19.
Another widely disseminated decree was that patients with COVID-19 should not use ACE inhibitors and angiotensin II receptor blockers (ARBs). COVID-19 binds to their target cells through ACE2, which is expressed by epithelial cells of the lung, intestine and kidney. Patients who are treated with ACE inhibitors and ARBs have been shown to have more ACE2 expression.
In a letter to the editor by Fang et al. published in Lancet Respiratory Medicine, the authors raised the question of whether patients might be better served to be switched from ACE inhibitors and ARBs to calcium-channel blockers for the treatment of hypertension.5 A small study by Meng et al. looked at outcomes of patients on these drugs who had COVID-19 infection.6 They looked at 417 patients admitted to a hospital in China with COVID-19 infection. A total of 42 patients were on medications for hypertension. Group 1 were patients on ACE inhibitors/ARBs (17 patients) and group 2 were patients on other antihypertensives (25 patients). During hospitalization 12 patients (48%) in group 2 were categorized as having severe disease and 1 patient died. In group 1 (the ACE inhibitor/ARB–treated patients) only four (23%) were categorized as having severe disease, and no patients in this group died.
Vaduganathan et al. published a special report in the New England Journal of Medicine strongly arguing the point that “[u]ntil further data are available, we think that [renin-angiotensin-aldosterone system] inhibitors should be continued in patients in otherwise stable condition who are at risk for, being evaluated for, or with COVID-19”.7 This position is supported by the American Heart Association, the American College of Cardiology, the American College of Physicians, and 11 other medical organizations.
Take-home messages
- Testing isn’t perfect – if you have strong suspicion for COVID-19 disease, retest.
- GI symptoms appear to be common, and rarely may be the only symptoms initially.
- NSAIDs are always risky in really sick patients, but data specific to COVID-19 is lacking.
- ACE inhibitors/ARBs should not be avoided in patients with COVID-19.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact Dr. Paauw at imnews@mdedge.com.
References
1. Long C et al. Diagnosis of the Coronavirus disease (COVID-19): rRT-PCR or CT? Eur J Radiol. 2020 Mar 25;126:108961.
2. Zhou F et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-62.
3. Tian Y et al. Review article: Gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther. 2020;00:1–9.
4. Voiriot G et al. Risks related to the use of nonsteroidal anti-inflammatory drugs in community-acquired pneumonia in adult and pediatric patients. J Clin Med. 2019;8:E786.
5. Fang L et al. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Mar 11. doi:10.1016/S2213-2600(20)30116-8.
6. Meng J et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020 Dec;9(1):757-60.
7. Vaduganathan M et al. Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19. N Engl J Med. 2020 Mar 30. doi: 10.1056/NEJMsr2005760.
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.
COVID-19 cases highlight longstanding racial disparities in health care
African Americans are overrepresented among patients who have died as a result of the COVID-19 pandemic, but the current crisis puts a spotlight on long-standing racial disparities in health care and health access in the United States, according to David R. Williams, PhD, a professor of public health at the Harvard T.H. Chan School of Public Health in Boston.
Dr. Williams, a social scientist specializing in the link between race and health, is a professor of African and African American Studies and of Sociology at Harvard. He spoke on the topic of racial disparities amid the COVID-19 pandemic in a teleconference sponsored by the Robert Wood Johnson Foundation.
“Many Americans are shocked” by the higher mortality rates among African American COVID-19 patients, said Dr. Williams. However, data from decades of research show that “black people in America live sicker and shorter lives,” he said.
Keys to the increased mortality among African Americans include an increased prevalence of risk factors, increased risk for exposure to the virus because of socioeconomic factors, and less access to health care if they do become ill, he said.
Many minority individuals work outside the home in areas deemed essential during the pandemic, such as transit, delivery, maintenance, cleaning, and in businesses such as grocery stores, although in general “race continues to matter for health at every level of income and education,” Dr. Williams said.
In addition, social distance guidelines are not realistic for many people in high-density, low-income areas, who often live in shared, multigenerational housing, he said.
Data show that individuals with chronic conditions such as diabetes and cardiovascular disease are more likely to die as a result of COVID-19, and minority populations are more likely to develop these conditions at younger ages, Dr. Williams noted. Access to health care also plays a role. Many minority individuals of lower socioeconomic status are less likely to have health insurance, or if they do, may have Medicaid, which is not consistently accepted, he said. Also, some low-income neighborhoods lack convenient access to primary care and thus to screening services, he noted.
Dr. Williams said the COVID-19 pandemic could serve as an opportunity to examine and improve health care services for underserved communities. In the short term, “we need to collect data so we can see patterns” and address pressing needs, he said, but long-term goals should “prioritize investments that would create healthy homes and communities,” he emphasized.
A recent study from the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report cited COVID-NET (the COVID-19 Associated Hospitalization Surveillance Network) as showing that, in their catchment population, “approximately 59% of residents are white, 18% are black, and 14% are Hispanic; however, among 580 hospitalized COVID-19 patients with race/ethnicity data, approximately 45% were white, 33% were black, and 8% were Hispanic, suggesting that black populations might be disproportionately affected by COVID-19,” the researchers said.
“These findings, including the potential impact of both sex and race on COVID-19–associated hospitalization rates, need to be confirmed with additional data,” according to the report.
Collecting racial/ethnic information is not always feasible on the front lines, and many areas still face shortages of ventilators and protective equipment, said Dr. Williams.
“I want to salute the providers on the front lines of this pandemic, many putting their own lives at risk, I want to acknowledge the good that they are doing,” Dr. Williams emphasized. He noted that all of us, himself included, may have conscious or unconscious stereotypes, but the key is to acknowledge the potential for these thoughts and feelings and continue to provide the best care.
Clyde W. Yancy, MD, of Northwestern University in Chicago, expressed similar concerns about disparity in COVID-19 cases in an editorial published on April 15 in JAMA.
“Researchers have emphasized older age, male sex, hypertension, diabetes, obesity, concomitant cardiovascular diseases (including coronary artery disease and heart failure), and myocardial injury as important risk factors associated with worse outcomes,” wrote Dr. Yancy. However, evidence also suggests that “persons who are African American or black are contracting SARS-CoV-2 at higher rates and are more likely to die,” he said.
“Why is this uniquely important to me? I am an academic cardiologist; I study health care disparities; and I am a black man,” he wrote.
“Even though these data are preliminary and further study is warranted, the pattern is irrefutable: Underrepresented minorities are developing COVID-19 infection more frequently and dying disproportionately,” said Dr. Yancy.
Dr. Williams’ and Dr. Yancy’s comments were supported by an analysis of COVID-19 patient data from several areas of the country conducted by the Washington Post. In that analysis, data showed that several counties with a majority black population showed three times the rate of COVID-19 infections and approximately six times as many deaths compared with counties with a majority of white residents.
“The U.S. has needed a trigger to fully address health care disparities; COVID-19 may be that bellwether event,” said Dr. Yancy. “Certainly, within the broad and powerful economic and legislative engines of the US, there is room to definitively address a scourge even worse than COVID-19: health care disparities. It only takes will. It is time to end the refrain,” he said.
Dr. Williams had no financial conflicts to disclose. Dr. Yancy had no financial conflicts to disclose.
SOURCES: Yancy CW. JAMA 2020 Apr 15. doi: 10.1001/jama.2020.6548Garg S et al. MMWR Morb Mortal Wkly Rep 2020 Apr 8;69:458-64.
Thebault R et al. The coronavirus is infecting and killing black Americans at an alarmingly high rate. Washington Post. 2020 Apr 7.
African Americans are overrepresented among patients who have died as a result of the COVID-19 pandemic, but the current crisis puts a spotlight on long-standing racial disparities in health care and health access in the United States, according to David R. Williams, PhD, a professor of public health at the Harvard T.H. Chan School of Public Health in Boston.
Dr. Williams, a social scientist specializing in the link between race and health, is a professor of African and African American Studies and of Sociology at Harvard. He spoke on the topic of racial disparities amid the COVID-19 pandemic in a teleconference sponsored by the Robert Wood Johnson Foundation.
“Many Americans are shocked” by the higher mortality rates among African American COVID-19 patients, said Dr. Williams. However, data from decades of research show that “black people in America live sicker and shorter lives,” he said.
Keys to the increased mortality among African Americans include an increased prevalence of risk factors, increased risk for exposure to the virus because of socioeconomic factors, and less access to health care if they do become ill, he said.
Many minority individuals work outside the home in areas deemed essential during the pandemic, such as transit, delivery, maintenance, cleaning, and in businesses such as grocery stores, although in general “race continues to matter for health at every level of income and education,” Dr. Williams said.
In addition, social distance guidelines are not realistic for many people in high-density, low-income areas, who often live in shared, multigenerational housing, he said.
Data show that individuals with chronic conditions such as diabetes and cardiovascular disease are more likely to die as a result of COVID-19, and minority populations are more likely to develop these conditions at younger ages, Dr. Williams noted. Access to health care also plays a role. Many minority individuals of lower socioeconomic status are less likely to have health insurance, or if they do, may have Medicaid, which is not consistently accepted, he said. Also, some low-income neighborhoods lack convenient access to primary care and thus to screening services, he noted.
Dr. Williams said the COVID-19 pandemic could serve as an opportunity to examine and improve health care services for underserved communities. In the short term, “we need to collect data so we can see patterns” and address pressing needs, he said, but long-term goals should “prioritize investments that would create healthy homes and communities,” he emphasized.
A recent study from the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report cited COVID-NET (the COVID-19 Associated Hospitalization Surveillance Network) as showing that, in their catchment population, “approximately 59% of residents are white, 18% are black, and 14% are Hispanic; however, among 580 hospitalized COVID-19 patients with race/ethnicity data, approximately 45% were white, 33% were black, and 8% were Hispanic, suggesting that black populations might be disproportionately affected by COVID-19,” the researchers said.
“These findings, including the potential impact of both sex and race on COVID-19–associated hospitalization rates, need to be confirmed with additional data,” according to the report.
Collecting racial/ethnic information is not always feasible on the front lines, and many areas still face shortages of ventilators and protective equipment, said Dr. Williams.
“I want to salute the providers on the front lines of this pandemic, many putting their own lives at risk, I want to acknowledge the good that they are doing,” Dr. Williams emphasized. He noted that all of us, himself included, may have conscious or unconscious stereotypes, but the key is to acknowledge the potential for these thoughts and feelings and continue to provide the best care.
Clyde W. Yancy, MD, of Northwestern University in Chicago, expressed similar concerns about disparity in COVID-19 cases in an editorial published on April 15 in JAMA.
“Researchers have emphasized older age, male sex, hypertension, diabetes, obesity, concomitant cardiovascular diseases (including coronary artery disease and heart failure), and myocardial injury as important risk factors associated with worse outcomes,” wrote Dr. Yancy. However, evidence also suggests that “persons who are African American or black are contracting SARS-CoV-2 at higher rates and are more likely to die,” he said.
“Why is this uniquely important to me? I am an academic cardiologist; I study health care disparities; and I am a black man,” he wrote.
“Even though these data are preliminary and further study is warranted, the pattern is irrefutable: Underrepresented minorities are developing COVID-19 infection more frequently and dying disproportionately,” said Dr. Yancy.
Dr. Williams’ and Dr. Yancy’s comments were supported by an analysis of COVID-19 patient data from several areas of the country conducted by the Washington Post. In that analysis, data showed that several counties with a majority black population showed three times the rate of COVID-19 infections and approximately six times as many deaths compared with counties with a majority of white residents.
“The U.S. has needed a trigger to fully address health care disparities; COVID-19 may be that bellwether event,” said Dr. Yancy. “Certainly, within the broad and powerful economic and legislative engines of the US, there is room to definitively address a scourge even worse than COVID-19: health care disparities. It only takes will. It is time to end the refrain,” he said.
Dr. Williams had no financial conflicts to disclose. Dr. Yancy had no financial conflicts to disclose.
SOURCES: Yancy CW. JAMA 2020 Apr 15. doi: 10.1001/jama.2020.6548Garg S et al. MMWR Morb Mortal Wkly Rep 2020 Apr 8;69:458-64.
Thebault R et al. The coronavirus is infecting and killing black Americans at an alarmingly high rate. Washington Post. 2020 Apr 7.
African Americans are overrepresented among patients who have died as a result of the COVID-19 pandemic, but the current crisis puts a spotlight on long-standing racial disparities in health care and health access in the United States, according to David R. Williams, PhD, a professor of public health at the Harvard T.H. Chan School of Public Health in Boston.
Dr. Williams, a social scientist specializing in the link between race and health, is a professor of African and African American Studies and of Sociology at Harvard. He spoke on the topic of racial disparities amid the COVID-19 pandemic in a teleconference sponsored by the Robert Wood Johnson Foundation.
“Many Americans are shocked” by the higher mortality rates among African American COVID-19 patients, said Dr. Williams. However, data from decades of research show that “black people in America live sicker and shorter lives,” he said.
Keys to the increased mortality among African Americans include an increased prevalence of risk factors, increased risk for exposure to the virus because of socioeconomic factors, and less access to health care if they do become ill, he said.
Many minority individuals work outside the home in areas deemed essential during the pandemic, such as transit, delivery, maintenance, cleaning, and in businesses such as grocery stores, although in general “race continues to matter for health at every level of income and education,” Dr. Williams said.
In addition, social distance guidelines are not realistic for many people in high-density, low-income areas, who often live in shared, multigenerational housing, he said.
Data show that individuals with chronic conditions such as diabetes and cardiovascular disease are more likely to die as a result of COVID-19, and minority populations are more likely to develop these conditions at younger ages, Dr. Williams noted. Access to health care also plays a role. Many minority individuals of lower socioeconomic status are less likely to have health insurance, or if they do, may have Medicaid, which is not consistently accepted, he said. Also, some low-income neighborhoods lack convenient access to primary care and thus to screening services, he noted.
Dr. Williams said the COVID-19 pandemic could serve as an opportunity to examine and improve health care services for underserved communities. In the short term, “we need to collect data so we can see patterns” and address pressing needs, he said, but long-term goals should “prioritize investments that would create healthy homes and communities,” he emphasized.
A recent study from the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report cited COVID-NET (the COVID-19 Associated Hospitalization Surveillance Network) as showing that, in their catchment population, “approximately 59% of residents are white, 18% are black, and 14% are Hispanic; however, among 580 hospitalized COVID-19 patients with race/ethnicity data, approximately 45% were white, 33% were black, and 8% were Hispanic, suggesting that black populations might be disproportionately affected by COVID-19,” the researchers said.
“These findings, including the potential impact of both sex and race on COVID-19–associated hospitalization rates, need to be confirmed with additional data,” according to the report.
Collecting racial/ethnic information is not always feasible on the front lines, and many areas still face shortages of ventilators and protective equipment, said Dr. Williams.
“I want to salute the providers on the front lines of this pandemic, many putting their own lives at risk, I want to acknowledge the good that they are doing,” Dr. Williams emphasized. He noted that all of us, himself included, may have conscious or unconscious stereotypes, but the key is to acknowledge the potential for these thoughts and feelings and continue to provide the best care.
Clyde W. Yancy, MD, of Northwestern University in Chicago, expressed similar concerns about disparity in COVID-19 cases in an editorial published on April 15 in JAMA.
“Researchers have emphasized older age, male sex, hypertension, diabetes, obesity, concomitant cardiovascular diseases (including coronary artery disease and heart failure), and myocardial injury as important risk factors associated with worse outcomes,” wrote Dr. Yancy. However, evidence also suggests that “persons who are African American or black are contracting SARS-CoV-2 at higher rates and are more likely to die,” he said.
“Why is this uniquely important to me? I am an academic cardiologist; I study health care disparities; and I am a black man,” he wrote.
“Even though these data are preliminary and further study is warranted, the pattern is irrefutable: Underrepresented minorities are developing COVID-19 infection more frequently and dying disproportionately,” said Dr. Yancy.
Dr. Williams’ and Dr. Yancy’s comments were supported by an analysis of COVID-19 patient data from several areas of the country conducted by the Washington Post. In that analysis, data showed that several counties with a majority black population showed three times the rate of COVID-19 infections and approximately six times as many deaths compared with counties with a majority of white residents.
“The U.S. has needed a trigger to fully address health care disparities; COVID-19 may be that bellwether event,” said Dr. Yancy. “Certainly, within the broad and powerful economic and legislative engines of the US, there is room to definitively address a scourge even worse than COVID-19: health care disparities. It only takes will. It is time to end the refrain,” he said.
Dr. Williams had no financial conflicts to disclose. Dr. Yancy had no financial conflicts to disclose.
SOURCES: Yancy CW. JAMA 2020 Apr 15. doi: 10.1001/jama.2020.6548Garg S et al. MMWR Morb Mortal Wkly Rep 2020 Apr 8;69:458-64.
Thebault R et al. The coronavirus is infecting and killing black Americans at an alarmingly high rate. Washington Post. 2020 Apr 7.
FROM A TELECONFERENCE SPONSORED BY THE ROBERT WOOD JOHNSON FOUNDATION
Troponins touted as ‘ally’ in COVID-19 triage, but message is nuanced
, cardiologists in the United Kingdom advise in a recently published viewpoint.
The tests can be used to “inform the triage of patients to critical care, guide the use of supportive treatments, and facilitate targeted cardiac investigations in those most likely to benefit,” Nicholas Mills, MD, PhD, University of Edinburgh, United Kingdom, told theheart.org | Medscape Cardiology. He is senior author on the viewpoint published online April 6 in the journal Circulation.
Older adults and those with a history of underlying cardiovascular disease appear to be at greatest risk of dying from COVID-19. “From early reports it is clear that elevated cardiac troponin concentrations predict in-hospital mortality,” said Mills.
In a recent report on hospitalized patients with COVID-19 in Wuhan, China, for example, cardiac injury (hs-cTn above the 99th-percentile upper reference limit) was seen in 1 in 5 patients and was an independent predictor of dying in the hospital. Mortality was 10-fold higher in those with cardiac injury on presentation.
Elevated cardiac troponin in the setting of COVID-19, Mills said, “may reflect illness severity with myocardial injury arising due to myocardial oxygen supply–demand imbalance. Or it may be due to direct cardiac involvement through viral myocarditis or stress cardiomyopathy, or where the prothrombotic and proinflammatory state is precipitating acute coronary syndromes.”
In their viewpoint, the authors note that circulating cTn is a marker of myocardial injury, “including but not limited to myocardial infarction or myocarditis, and the clinical relevance of this distinction has never been so clear.”
Therefore, the consequence of not measuring cardiac troponin may be to “ignore the plethora of ischemic and nonischemic causes” of myocardial injury related to COVID-19. “Clinicians who have used troponin measurement as a binary test for myocardial infarction independent of clinical context and those who consider an elevated cardiac troponin concentration to be a mandate for invasive coronary angiography must recalibrate,” they write.
“Rather than encouraging avoidance of troponin testing, we must harness the unheralded engagement from the cardiovascular community due to COVID-19 to better understand the utility of this essential biomarker and to educate clinicians on its interpretation and implications for prognosis and clinical decision making.”
Based on “same logic” as recent ACC guidance
The viewpoint was to some extent a response to a recent informal guidance from the American College of Cardiology (ACC) that advised caution in use of troponin and natriuretic peptide tests in patients with COVID-19.
Even so, that ACC guidance and the new viewpoint in Circulation are based on the “same logic,” James Januzzi Jr, MD, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology. Both documents:
- Point out that troponins are frequently abnormal in patients with severe cases of COVID-19
- Caution that clinicians should not equate an abnormal hs-cTn with acute myocardial infarction
- Note that, in most cases, hs-cTn elevations are a result of noncoronary mechanisms
- Recognize the potential risk to caregivers and the continued unchecked spread of SARS-CoV-2 related to downstream testing that might not be needed
“The Circulation opinion piece states that clinicians often use troponin as a binary test for myocardial infarction and a mandate for downstream testing, suggesting clinicians will need to recalibrate that approach, something I agree with and which is the central message of the ACC position,” Januzzi said.
Probably the biggest difference between the two documents, he said, is in the Circulation authors’ apparent enthusiasm to use hs-cTn as a tool to judge disease severity in patients with COVID-19.
It’s been known for more than a decade that myocardial injury is “an important risk predictor” in critical illness, Januzzi explained. “So the link between cardiac injury and outcomes in critical illness is nothing new. The difference is the fact we are seeing so many patients with COVID-19 all at once, and the authors suggest that using troponin might help in triage decision making.”
“There may be [such] a role here, but the data have not been systematically collected, and whether troponin truly adds something beyond information already available at the bedside — for example, does it add anything not already obvious at the bedside? — has not yet been conclusively proven,” Januzzi cautioned.
“As well, there are no prospective data supporting troponin as a trigger for ICU triage or for deciding on specific treatments.”
Positive cTn status “common” in COVID-19 patients
In his experience, Barry Cohen, MD, Morristown Medical Center, New Jersey, told theheart.org | Medscape Cardiology, that positive cTn status is “common in COVID-19 patients and appears to have prognostic value, not only in type 1 MI due to atherothrombotic disease (related to a proinflammatory and prothrombotic state), but more frequently type 2 MI (supply–demand mismatch), viral myocarditis, coronary microvascular ischemia, stress cardiomyopathy or tachyarrhythmias.”
Moreover, Cohen said, hs-cTn “has identified patients at increased risk for ventilation support (invasive and noninvasive), acute respiratory distress syndrome, acute kidney injury, and mortality.”
Echoing both the ACC document and the Circulation report, Cohen also said hs-cTn measurements “appear to help risk stratify COVID-19 patients, but clearly do not mean that a troponin-positive patient needs to go to the cath lab and be treated as having acute coronary syndrome. Only a minority of these patients require this intervention.”
Mills discloses receiving honoraria from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx. Januzzi has previously disclosed receiving personal fees from the American College of Cardiology, Pfizer, Merck, AbbVie, Amgen, Boehringer Ingelheim, and Takeda; grants and personal fees from Novartis, Roche, Abbott, and Janssen; and grants from Singulex and Prevencio. Cohen has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
, cardiologists in the United Kingdom advise in a recently published viewpoint.
The tests can be used to “inform the triage of patients to critical care, guide the use of supportive treatments, and facilitate targeted cardiac investigations in those most likely to benefit,” Nicholas Mills, MD, PhD, University of Edinburgh, United Kingdom, told theheart.org | Medscape Cardiology. He is senior author on the viewpoint published online April 6 in the journal Circulation.
Older adults and those with a history of underlying cardiovascular disease appear to be at greatest risk of dying from COVID-19. “From early reports it is clear that elevated cardiac troponin concentrations predict in-hospital mortality,” said Mills.
In a recent report on hospitalized patients with COVID-19 in Wuhan, China, for example, cardiac injury (hs-cTn above the 99th-percentile upper reference limit) was seen in 1 in 5 patients and was an independent predictor of dying in the hospital. Mortality was 10-fold higher in those with cardiac injury on presentation.
Elevated cardiac troponin in the setting of COVID-19, Mills said, “may reflect illness severity with myocardial injury arising due to myocardial oxygen supply–demand imbalance. Or it may be due to direct cardiac involvement through viral myocarditis or stress cardiomyopathy, or where the prothrombotic and proinflammatory state is precipitating acute coronary syndromes.”
In their viewpoint, the authors note that circulating cTn is a marker of myocardial injury, “including but not limited to myocardial infarction or myocarditis, and the clinical relevance of this distinction has never been so clear.”
Therefore, the consequence of not measuring cardiac troponin may be to “ignore the plethora of ischemic and nonischemic causes” of myocardial injury related to COVID-19. “Clinicians who have used troponin measurement as a binary test for myocardial infarction independent of clinical context and those who consider an elevated cardiac troponin concentration to be a mandate for invasive coronary angiography must recalibrate,” they write.
“Rather than encouraging avoidance of troponin testing, we must harness the unheralded engagement from the cardiovascular community due to COVID-19 to better understand the utility of this essential biomarker and to educate clinicians on its interpretation and implications for prognosis and clinical decision making.”
Based on “same logic” as recent ACC guidance
The viewpoint was to some extent a response to a recent informal guidance from the American College of Cardiology (ACC) that advised caution in use of troponin and natriuretic peptide tests in patients with COVID-19.
Even so, that ACC guidance and the new viewpoint in Circulation are based on the “same logic,” James Januzzi Jr, MD, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology. Both documents:
- Point out that troponins are frequently abnormal in patients with severe cases of COVID-19
- Caution that clinicians should not equate an abnormal hs-cTn with acute myocardial infarction
- Note that, in most cases, hs-cTn elevations are a result of noncoronary mechanisms
- Recognize the potential risk to caregivers and the continued unchecked spread of SARS-CoV-2 related to downstream testing that might not be needed
“The Circulation opinion piece states that clinicians often use troponin as a binary test for myocardial infarction and a mandate for downstream testing, suggesting clinicians will need to recalibrate that approach, something I agree with and which is the central message of the ACC position,” Januzzi said.
Probably the biggest difference between the two documents, he said, is in the Circulation authors’ apparent enthusiasm to use hs-cTn as a tool to judge disease severity in patients with COVID-19.
It’s been known for more than a decade that myocardial injury is “an important risk predictor” in critical illness, Januzzi explained. “So the link between cardiac injury and outcomes in critical illness is nothing new. The difference is the fact we are seeing so many patients with COVID-19 all at once, and the authors suggest that using troponin might help in triage decision making.”
“There may be [such] a role here, but the data have not been systematically collected, and whether troponin truly adds something beyond information already available at the bedside — for example, does it add anything not already obvious at the bedside? — has not yet been conclusively proven,” Januzzi cautioned.
“As well, there are no prospective data supporting troponin as a trigger for ICU triage or for deciding on specific treatments.”
Positive cTn status “common” in COVID-19 patients
In his experience, Barry Cohen, MD, Morristown Medical Center, New Jersey, told theheart.org | Medscape Cardiology, that positive cTn status is “common in COVID-19 patients and appears to have prognostic value, not only in type 1 MI due to atherothrombotic disease (related to a proinflammatory and prothrombotic state), but more frequently type 2 MI (supply–demand mismatch), viral myocarditis, coronary microvascular ischemia, stress cardiomyopathy or tachyarrhythmias.”
Moreover, Cohen said, hs-cTn “has identified patients at increased risk for ventilation support (invasive and noninvasive), acute respiratory distress syndrome, acute kidney injury, and mortality.”
Echoing both the ACC document and the Circulation report, Cohen also said hs-cTn measurements “appear to help risk stratify COVID-19 patients, but clearly do not mean that a troponin-positive patient needs to go to the cath lab and be treated as having acute coronary syndrome. Only a minority of these patients require this intervention.”
Mills discloses receiving honoraria from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx. Januzzi has previously disclosed receiving personal fees from the American College of Cardiology, Pfizer, Merck, AbbVie, Amgen, Boehringer Ingelheim, and Takeda; grants and personal fees from Novartis, Roche, Abbott, and Janssen; and grants from Singulex and Prevencio. Cohen has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
, cardiologists in the United Kingdom advise in a recently published viewpoint.
The tests can be used to “inform the triage of patients to critical care, guide the use of supportive treatments, and facilitate targeted cardiac investigations in those most likely to benefit,” Nicholas Mills, MD, PhD, University of Edinburgh, United Kingdom, told theheart.org | Medscape Cardiology. He is senior author on the viewpoint published online April 6 in the journal Circulation.
Older adults and those with a history of underlying cardiovascular disease appear to be at greatest risk of dying from COVID-19. “From early reports it is clear that elevated cardiac troponin concentrations predict in-hospital mortality,” said Mills.
In a recent report on hospitalized patients with COVID-19 in Wuhan, China, for example, cardiac injury (hs-cTn above the 99th-percentile upper reference limit) was seen in 1 in 5 patients and was an independent predictor of dying in the hospital. Mortality was 10-fold higher in those with cardiac injury on presentation.
Elevated cardiac troponin in the setting of COVID-19, Mills said, “may reflect illness severity with myocardial injury arising due to myocardial oxygen supply–demand imbalance. Or it may be due to direct cardiac involvement through viral myocarditis or stress cardiomyopathy, or where the prothrombotic and proinflammatory state is precipitating acute coronary syndromes.”
In their viewpoint, the authors note that circulating cTn is a marker of myocardial injury, “including but not limited to myocardial infarction or myocarditis, and the clinical relevance of this distinction has never been so clear.”
Therefore, the consequence of not measuring cardiac troponin may be to “ignore the plethora of ischemic and nonischemic causes” of myocardial injury related to COVID-19. “Clinicians who have used troponin measurement as a binary test for myocardial infarction independent of clinical context and those who consider an elevated cardiac troponin concentration to be a mandate for invasive coronary angiography must recalibrate,” they write.
“Rather than encouraging avoidance of troponin testing, we must harness the unheralded engagement from the cardiovascular community due to COVID-19 to better understand the utility of this essential biomarker and to educate clinicians on its interpretation and implications for prognosis and clinical decision making.”
Based on “same logic” as recent ACC guidance
The viewpoint was to some extent a response to a recent informal guidance from the American College of Cardiology (ACC) that advised caution in use of troponin and natriuretic peptide tests in patients with COVID-19.
Even so, that ACC guidance and the new viewpoint in Circulation are based on the “same logic,” James Januzzi Jr, MD, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology. Both documents:
- Point out that troponins are frequently abnormal in patients with severe cases of COVID-19
- Caution that clinicians should not equate an abnormal hs-cTn with acute myocardial infarction
- Note that, in most cases, hs-cTn elevations are a result of noncoronary mechanisms
- Recognize the potential risk to caregivers and the continued unchecked spread of SARS-CoV-2 related to downstream testing that might not be needed
“The Circulation opinion piece states that clinicians often use troponin as a binary test for myocardial infarction and a mandate for downstream testing, suggesting clinicians will need to recalibrate that approach, something I agree with and which is the central message of the ACC position,” Januzzi said.
Probably the biggest difference between the two documents, he said, is in the Circulation authors’ apparent enthusiasm to use hs-cTn as a tool to judge disease severity in patients with COVID-19.
It’s been known for more than a decade that myocardial injury is “an important risk predictor” in critical illness, Januzzi explained. “So the link between cardiac injury and outcomes in critical illness is nothing new. The difference is the fact we are seeing so many patients with COVID-19 all at once, and the authors suggest that using troponin might help in triage decision making.”
“There may be [such] a role here, but the data have not been systematically collected, and whether troponin truly adds something beyond information already available at the bedside — for example, does it add anything not already obvious at the bedside? — has not yet been conclusively proven,” Januzzi cautioned.
“As well, there are no prospective data supporting troponin as a trigger for ICU triage or for deciding on specific treatments.”
Positive cTn status “common” in COVID-19 patients
In his experience, Barry Cohen, MD, Morristown Medical Center, New Jersey, told theheart.org | Medscape Cardiology, that positive cTn status is “common in COVID-19 patients and appears to have prognostic value, not only in type 1 MI due to atherothrombotic disease (related to a proinflammatory and prothrombotic state), but more frequently type 2 MI (supply–demand mismatch), viral myocarditis, coronary microvascular ischemia, stress cardiomyopathy or tachyarrhythmias.”
Moreover, Cohen said, hs-cTn “has identified patients at increased risk for ventilation support (invasive and noninvasive), acute respiratory distress syndrome, acute kidney injury, and mortality.”
Echoing both the ACC document and the Circulation report, Cohen also said hs-cTn measurements “appear to help risk stratify COVID-19 patients, but clearly do not mean that a troponin-positive patient needs to go to the cath lab and be treated as having acute coronary syndrome. Only a minority of these patients require this intervention.”
Mills discloses receiving honoraria from Abbott Diagnostics, Roche Diagnostics, Siemens Healthineers, and LumiraDx. Januzzi has previously disclosed receiving personal fees from the American College of Cardiology, Pfizer, Merck, AbbVie, Amgen, Boehringer Ingelheim, and Takeda; grants and personal fees from Novartis, Roche, Abbott, and Janssen; and grants from Singulex and Prevencio. Cohen has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
TWILIGHT-COMPLEX: Tap ticagrelor monotherapy early after complex PCI
Patients who underwent complex PCI for acute coronary syndrome followed by 3 months of dual-antiplatelet therapy (DAPT) with ticagrelor plus aspirin fared significantly better by dropping aspirin at that point in favor of long-term ticagrelor monotherapy than with continued dual-antiplatelet therapy in the TWILIGHT-COMPLEX study.
The rate of clinically relevant bleeding was significantly lower at 12 months of follow-up in the ticagrelor monotherapy group than it was in patients randomized to continued DAPT. Moreover, this major benefit came at no cost in terms of ischemic events, which were actually numerically less frequent in the ticagrelor plus placebo group, George D. Dangas, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“We found that the aspirin just doesn’t add that much, even in complex patients – just bleeding complications, for the most part,” explained Dr. Dangas, professor of medicine and of surgery at the Icahn School of Medicine at Mount Sinai, New York.
The TWILIGHT-COMPLEX study was a secondary post hoc analysis of outcomes in 2,342 participants in the previously reported larger parent TWILIGHT randomized trial who underwent complex PCI. The main TWILIGHT trial included 7,119 patients in 11 countries who underwent PCI for acute coronary syndrome, successfully completed 3 months of DAPT with ticagrelor plus aspirin without incident, and were then randomized double blind to 12 months of ticagrelor plus placebo or to another 12 months of ticagrelor and aspirin.
In the overall TWILIGHT trial, ticagrelor alone resulted in a significantly lower clinically relevant bleeding rate than did long-term ticagrelor plus aspirin, with no increase in the risk of death, MI, or stroke (N Engl J Med 2019; 381:2032-42). But the results left many interventional cardiologists wondering if a ticagrelor monotherapy strategy was really applicable to their more challenging patients undergoing complex PCI given that the risk of ischemic events is known to climb with PCI complexity. The TWILIGHT-COMPLEX study was specifically designed to address that concern.
To be eligible for TWILIGHT-COMPLEX, patients had to meet one or more prespecified angiographic or procedural criteria for complex PCI, such as a total stent length in excess of 60 mm, three or more treated lesions, use of an atherectomy device, or PCI of a left main lesion, a chronic total occlusion, or a bifurcation lesion with two stents. These complex PCI patients accounted for one-third of the total study population in TWILIGHT; 36% of them met more than one criteria for complex PCI.
TWILIGHT-COMPLEX findings
In the 12 months after randomization, patients who received ticagrelor plus placebo had a 4.2% incidence of clinically significant Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding, which was significantly lower than the 7.7% rate in the group on long-term DAPT and represented a 46% relative risk reduction. Severe or fatal bleeding – that is, BARC type 3 or 5 – occurred in 1.1% of those on ticagrelor monotherapy and 2.6% of the DAPT group, for a significant 59% relative risk reduction.
The composite ischemic endpoint comprising cardiovascular death, MI, or ischemic stroke occurred in 3.6% of the ticagrelor monotherapy group and 4.8% of patients on long-term DAPT, a trend that didn’t achieve statistical significance. The all-cause mortality rate was 0.9% in the ticagrelor monotherapy group and 1.5% with extended DAPT, again a nonsignificant difference. Similarly, the rate of definite or probable stent thrombosis was numerically lower with ticagrelor monotherapy, by a margin of 0.4% versus 0.8%, a nonsignificant difference.
The results were consistent regardless of which specific criteria for complex PCI a patient had or how many of them.
Results are ‘reassuring’
At a press conference where Dr. Dangas presented the TWILIGHT-COMPLEX results, discussant Claire S. Duvernoy, MD, said she was “very impressed” with just how complex the PCIs were in the study participants.
“Really, these are the patients that in my own practice we’ve always been the most cautious about, the most worried about thrombotic risk, and the ones where we get down on our house staff when they drop an antiplatelet agent. So this study is very reassuring,” said Dr. Duvernoy, professor of medicine at the University of Michigan, Ann Arbor.
She identified two key differences between TWILIGHT-COMPLEX and earlier studies that showed a benefit for extended DAPT in higher-risk patients. In the earlier studies, it was the P2Y12 inhibitor that was dropped; TWILIGHT was the first major randomized trial to discontinue the aspirin instead. And patients in the TWILIGHT study received second-generation drug-eluting stents.
“That makes a huge difference,” Dr. Duvernoy said. “We have stents now that are much safer than the old ones were, and that’s what allows us to gain this incredible benefit of reduced bleeding.”
Dr. Dangas cautioned that since this was a secondary post hoc analysis, the TWILIGHT-COMPLEX study must be viewed as hypothesis-generating.
The TWILIGHT trial was funded by AstraZeneca. Dr. Dangas reported receiving institutional research grants from that company as well as Bayer and Daichi-Sankyo. He also served as a paid consultant to Abbott Vascular, Boston Scientific, and Biosensors.
Simultaneous with his presentation at ACC 2020, the TWILIGHT-COMPLEX results were published online (J Am Coll Cardiol. 2020 Mar 13. doi: 10.1016/j.jacc.2020.03.011).
SOURCE: Dangas GD. ACC 20, Abstract 410-09.
Patients who underwent complex PCI for acute coronary syndrome followed by 3 months of dual-antiplatelet therapy (DAPT) with ticagrelor plus aspirin fared significantly better by dropping aspirin at that point in favor of long-term ticagrelor monotherapy than with continued dual-antiplatelet therapy in the TWILIGHT-COMPLEX study.
The rate of clinically relevant bleeding was significantly lower at 12 months of follow-up in the ticagrelor monotherapy group than it was in patients randomized to continued DAPT. Moreover, this major benefit came at no cost in terms of ischemic events, which were actually numerically less frequent in the ticagrelor plus placebo group, George D. Dangas, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“We found that the aspirin just doesn’t add that much, even in complex patients – just bleeding complications, for the most part,” explained Dr. Dangas, professor of medicine and of surgery at the Icahn School of Medicine at Mount Sinai, New York.
The TWILIGHT-COMPLEX study was a secondary post hoc analysis of outcomes in 2,342 participants in the previously reported larger parent TWILIGHT randomized trial who underwent complex PCI. The main TWILIGHT trial included 7,119 patients in 11 countries who underwent PCI for acute coronary syndrome, successfully completed 3 months of DAPT with ticagrelor plus aspirin without incident, and were then randomized double blind to 12 months of ticagrelor plus placebo or to another 12 months of ticagrelor and aspirin.
In the overall TWILIGHT trial, ticagrelor alone resulted in a significantly lower clinically relevant bleeding rate than did long-term ticagrelor plus aspirin, with no increase in the risk of death, MI, or stroke (N Engl J Med 2019; 381:2032-42). But the results left many interventional cardiologists wondering if a ticagrelor monotherapy strategy was really applicable to their more challenging patients undergoing complex PCI given that the risk of ischemic events is known to climb with PCI complexity. The TWILIGHT-COMPLEX study was specifically designed to address that concern.
To be eligible for TWILIGHT-COMPLEX, patients had to meet one or more prespecified angiographic or procedural criteria for complex PCI, such as a total stent length in excess of 60 mm, three or more treated lesions, use of an atherectomy device, or PCI of a left main lesion, a chronic total occlusion, or a bifurcation lesion with two stents. These complex PCI patients accounted for one-third of the total study population in TWILIGHT; 36% of them met more than one criteria for complex PCI.
TWILIGHT-COMPLEX findings
In the 12 months after randomization, patients who received ticagrelor plus placebo had a 4.2% incidence of clinically significant Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding, which was significantly lower than the 7.7% rate in the group on long-term DAPT and represented a 46% relative risk reduction. Severe or fatal bleeding – that is, BARC type 3 or 5 – occurred in 1.1% of those on ticagrelor monotherapy and 2.6% of the DAPT group, for a significant 59% relative risk reduction.
The composite ischemic endpoint comprising cardiovascular death, MI, or ischemic stroke occurred in 3.6% of the ticagrelor monotherapy group and 4.8% of patients on long-term DAPT, a trend that didn’t achieve statistical significance. The all-cause mortality rate was 0.9% in the ticagrelor monotherapy group and 1.5% with extended DAPT, again a nonsignificant difference. Similarly, the rate of definite or probable stent thrombosis was numerically lower with ticagrelor monotherapy, by a margin of 0.4% versus 0.8%, a nonsignificant difference.
The results were consistent regardless of which specific criteria for complex PCI a patient had or how many of them.
Results are ‘reassuring’
At a press conference where Dr. Dangas presented the TWILIGHT-COMPLEX results, discussant Claire S. Duvernoy, MD, said she was “very impressed” with just how complex the PCIs were in the study participants.
“Really, these are the patients that in my own practice we’ve always been the most cautious about, the most worried about thrombotic risk, and the ones where we get down on our house staff when they drop an antiplatelet agent. So this study is very reassuring,” said Dr. Duvernoy, professor of medicine at the University of Michigan, Ann Arbor.
She identified two key differences between TWILIGHT-COMPLEX and earlier studies that showed a benefit for extended DAPT in higher-risk patients. In the earlier studies, it was the P2Y12 inhibitor that was dropped; TWILIGHT was the first major randomized trial to discontinue the aspirin instead. And patients in the TWILIGHT study received second-generation drug-eluting stents.
“That makes a huge difference,” Dr. Duvernoy said. “We have stents now that are much safer than the old ones were, and that’s what allows us to gain this incredible benefit of reduced bleeding.”
Dr. Dangas cautioned that since this was a secondary post hoc analysis, the TWILIGHT-COMPLEX study must be viewed as hypothesis-generating.
The TWILIGHT trial was funded by AstraZeneca. Dr. Dangas reported receiving institutional research grants from that company as well as Bayer and Daichi-Sankyo. He also served as a paid consultant to Abbott Vascular, Boston Scientific, and Biosensors.
Simultaneous with his presentation at ACC 2020, the TWILIGHT-COMPLEX results were published online (J Am Coll Cardiol. 2020 Mar 13. doi: 10.1016/j.jacc.2020.03.011).
SOURCE: Dangas GD. ACC 20, Abstract 410-09.
Patients who underwent complex PCI for acute coronary syndrome followed by 3 months of dual-antiplatelet therapy (DAPT) with ticagrelor plus aspirin fared significantly better by dropping aspirin at that point in favor of long-term ticagrelor monotherapy than with continued dual-antiplatelet therapy in the TWILIGHT-COMPLEX study.
The rate of clinically relevant bleeding was significantly lower at 12 months of follow-up in the ticagrelor monotherapy group than it was in patients randomized to continued DAPT. Moreover, this major benefit came at no cost in terms of ischemic events, which were actually numerically less frequent in the ticagrelor plus placebo group, George D. Dangas, MD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.
“We found that the aspirin just doesn’t add that much, even in complex patients – just bleeding complications, for the most part,” explained Dr. Dangas, professor of medicine and of surgery at the Icahn School of Medicine at Mount Sinai, New York.
The TWILIGHT-COMPLEX study was a secondary post hoc analysis of outcomes in 2,342 participants in the previously reported larger parent TWILIGHT randomized trial who underwent complex PCI. The main TWILIGHT trial included 7,119 patients in 11 countries who underwent PCI for acute coronary syndrome, successfully completed 3 months of DAPT with ticagrelor plus aspirin without incident, and were then randomized double blind to 12 months of ticagrelor plus placebo or to another 12 months of ticagrelor and aspirin.
In the overall TWILIGHT trial, ticagrelor alone resulted in a significantly lower clinically relevant bleeding rate than did long-term ticagrelor plus aspirin, with no increase in the risk of death, MI, or stroke (N Engl J Med 2019; 381:2032-42). But the results left many interventional cardiologists wondering if a ticagrelor monotherapy strategy was really applicable to their more challenging patients undergoing complex PCI given that the risk of ischemic events is known to climb with PCI complexity. The TWILIGHT-COMPLEX study was specifically designed to address that concern.
To be eligible for TWILIGHT-COMPLEX, patients had to meet one or more prespecified angiographic or procedural criteria for complex PCI, such as a total stent length in excess of 60 mm, three or more treated lesions, use of an atherectomy device, or PCI of a left main lesion, a chronic total occlusion, or a bifurcation lesion with two stents. These complex PCI patients accounted for one-third of the total study population in TWILIGHT; 36% of them met more than one criteria for complex PCI.
TWILIGHT-COMPLEX findings
In the 12 months after randomization, patients who received ticagrelor plus placebo had a 4.2% incidence of clinically significant Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding, which was significantly lower than the 7.7% rate in the group on long-term DAPT and represented a 46% relative risk reduction. Severe or fatal bleeding – that is, BARC type 3 or 5 – occurred in 1.1% of those on ticagrelor monotherapy and 2.6% of the DAPT group, for a significant 59% relative risk reduction.
The composite ischemic endpoint comprising cardiovascular death, MI, or ischemic stroke occurred in 3.6% of the ticagrelor monotherapy group and 4.8% of patients on long-term DAPT, a trend that didn’t achieve statistical significance. The all-cause mortality rate was 0.9% in the ticagrelor monotherapy group and 1.5% with extended DAPT, again a nonsignificant difference. Similarly, the rate of definite or probable stent thrombosis was numerically lower with ticagrelor monotherapy, by a margin of 0.4% versus 0.8%, a nonsignificant difference.
The results were consistent regardless of which specific criteria for complex PCI a patient had or how many of them.
Results are ‘reassuring’
At a press conference where Dr. Dangas presented the TWILIGHT-COMPLEX results, discussant Claire S. Duvernoy, MD, said she was “very impressed” with just how complex the PCIs were in the study participants.
“Really, these are the patients that in my own practice we’ve always been the most cautious about, the most worried about thrombotic risk, and the ones where we get down on our house staff when they drop an antiplatelet agent. So this study is very reassuring,” said Dr. Duvernoy, professor of medicine at the University of Michigan, Ann Arbor.
She identified two key differences between TWILIGHT-COMPLEX and earlier studies that showed a benefit for extended DAPT in higher-risk patients. In the earlier studies, it was the P2Y12 inhibitor that was dropped; TWILIGHT was the first major randomized trial to discontinue the aspirin instead. And patients in the TWILIGHT study received second-generation drug-eluting stents.
“That makes a huge difference,” Dr. Duvernoy said. “We have stents now that are much safer than the old ones were, and that’s what allows us to gain this incredible benefit of reduced bleeding.”
Dr. Dangas cautioned that since this was a secondary post hoc analysis, the TWILIGHT-COMPLEX study must be viewed as hypothesis-generating.
The TWILIGHT trial was funded by AstraZeneca. Dr. Dangas reported receiving institutional research grants from that company as well as Bayer and Daichi-Sankyo. He also served as a paid consultant to Abbott Vascular, Boston Scientific, and Biosensors.
Simultaneous with his presentation at ACC 2020, the TWILIGHT-COMPLEX results were published online (J Am Coll Cardiol. 2020 Mar 13. doi: 10.1016/j.jacc.2020.03.011).
SOURCE: Dangas GD. ACC 20, Abstract 410-09.
FROM ACC 2020
Hypertension goes unmedicated in 40% of adults
Roughly 30% of adults in the United States had hypertension in 2017, and just under 60% of those adults reported using antihypertensive medication, according to the Centers for Disease Control and Prevention.
There is, however, quite a bit of variation from those age-standardized national figures when state-level data are considered.
In Alabama and West Virginia, the prevalence of hypertension in 2017 was 38.6%, the highest in the country, with Arkansas (38.5%) and Mississippi (38.2%) not far behind. Meanwhile, Minnesota came in with a lowest-in-the-nation rate of 24.3%, which was nearly matched by Colorado at 24.8%, Claudine M. Samanic, PhD, and associates wrote in the MMWR.
There was also a considerable gap between the states in hypertensive adults’ self-reported use of antihypertensive drugs, which was generally higher in the states with a greater prevalence of disease, they noted.
Adults in Mississippi were the most likely (71.2%) to be taking medication, along with those in Alabama (70.5%) and Arkansas (69.3%). Idaho occupied the other end of the scale with a rate of 50.2%, while Montana and Vermont were slightly better at 51.7%, based on survey data from the Behavioral Risk Factor Surveillance System.
“Prevalence of antihypertensive medication use was higher in older age groups, highest among blacks, and higher among women [64.0%] than men [56.7%]. This overall gender difference has been reported previously, but the reasons are unclear,” wrote Dr. Samanic and associates at the CDC’s National Center for Chronic Disease Prevention and Health Promotion.
The BRFSS data for 2017 are based on based on interviews with 450,016 adults. Respondents were asked, “Have you ever been told by a doctor, nurse, or other health professional that you have high blood pressure?” and were considered to have hypertension if they answered yes.
SOURCE: Samanic CM et al. MMWR. 2020 Apr 10;69(14):393-8.
Roughly 30% of adults in the United States had hypertension in 2017, and just under 60% of those adults reported using antihypertensive medication, according to the Centers for Disease Control and Prevention.
There is, however, quite a bit of variation from those age-standardized national figures when state-level data are considered.
In Alabama and West Virginia, the prevalence of hypertension in 2017 was 38.6%, the highest in the country, with Arkansas (38.5%) and Mississippi (38.2%) not far behind. Meanwhile, Minnesota came in with a lowest-in-the-nation rate of 24.3%, which was nearly matched by Colorado at 24.8%, Claudine M. Samanic, PhD, and associates wrote in the MMWR.
There was also a considerable gap between the states in hypertensive adults’ self-reported use of antihypertensive drugs, which was generally higher in the states with a greater prevalence of disease, they noted.
Adults in Mississippi were the most likely (71.2%) to be taking medication, along with those in Alabama (70.5%) and Arkansas (69.3%). Idaho occupied the other end of the scale with a rate of 50.2%, while Montana and Vermont were slightly better at 51.7%, based on survey data from the Behavioral Risk Factor Surveillance System.
“Prevalence of antihypertensive medication use was higher in older age groups, highest among blacks, and higher among women [64.0%] than men [56.7%]. This overall gender difference has been reported previously, but the reasons are unclear,” wrote Dr. Samanic and associates at the CDC’s National Center for Chronic Disease Prevention and Health Promotion.
The BRFSS data for 2017 are based on based on interviews with 450,016 adults. Respondents were asked, “Have you ever been told by a doctor, nurse, or other health professional that you have high blood pressure?” and were considered to have hypertension if they answered yes.
SOURCE: Samanic CM et al. MMWR. 2020 Apr 10;69(14):393-8.
Roughly 30% of adults in the United States had hypertension in 2017, and just under 60% of those adults reported using antihypertensive medication, according to the Centers for Disease Control and Prevention.
There is, however, quite a bit of variation from those age-standardized national figures when state-level data are considered.
In Alabama and West Virginia, the prevalence of hypertension in 2017 was 38.6%, the highest in the country, with Arkansas (38.5%) and Mississippi (38.2%) not far behind. Meanwhile, Minnesota came in with a lowest-in-the-nation rate of 24.3%, which was nearly matched by Colorado at 24.8%, Claudine M. Samanic, PhD, and associates wrote in the MMWR.
There was also a considerable gap between the states in hypertensive adults’ self-reported use of antihypertensive drugs, which was generally higher in the states with a greater prevalence of disease, they noted.
Adults in Mississippi were the most likely (71.2%) to be taking medication, along with those in Alabama (70.5%) and Arkansas (69.3%). Idaho occupied the other end of the scale with a rate of 50.2%, while Montana and Vermont were slightly better at 51.7%, based on survey data from the Behavioral Risk Factor Surveillance System.
“Prevalence of antihypertensive medication use was higher in older age groups, highest among blacks, and higher among women [64.0%] than men [56.7%]. This overall gender difference has been reported previously, but the reasons are unclear,” wrote Dr. Samanic and associates at the CDC’s National Center for Chronic Disease Prevention and Health Promotion.
The BRFSS data for 2017 are based on based on interviews with 450,016 adults. Respondents were asked, “Have you ever been told by a doctor, nurse, or other health professional that you have high blood pressure?” and were considered to have hypertension if they answered yes.
SOURCE: Samanic CM et al. MMWR. 2020 Apr 10;69(14):393-8.
FROM THE MMWR