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Research and Reviews for the Practicing Oncologist
COVID vaccine is safe, effective for children aged 5-11, Pfizer says
With record numbers of COVID-19 cases being reported in kids, Pfizer and its partner BioNTech have announced that their mRNA vaccine for COVID-19 is safe and appears to generate a protective immune response in children as young as 5.
The companies have been testing a lower dose of the vaccine -- just 10 milligrams -- in children between the ages of 5 and 11. That’s one-third the dose given to adults.
In a clinical trial that included more than 2,200 children, Pfizer says two doses of the vaccines given 3 weeks apart generated a high level of neutralizing antibodies, comparable to the level seen in older children who get a higher dose of the vaccine.
On the advice of its vaccine advisory committee, the Food and Drug Administration asked vaccine makers to include more children in these studies earlier this year.
Rather than testing whether the vaccines are preventing COVID-19 illness in children, as they did in adults, the pharmaceutical companies that make the COVID-19 vaccines are looking at the antibody levels generated by the vaccines instead. The FDA has approved the approach in hopes of speeding vaccines to children, who are now back in school full time in most parts of the United States.
With that in mind, Evan Anderson, MD, a doctor with Children’s Healthcare of Atlanta who is an investigator for the trial — and is therefore kept in the dark about its results — said it’s important to keep in mind that the company didn’t share any efficacy data today.
“We don’t know whether there were cases of COVID-19 among children that were enrolled in the study and how those compared in those who received placebo versus those that received vaccine,” he said.
The company says side effects seen in the trial are comparable to those seen in older children. The company said there were no cases of heart inflammation called myocarditis observed. Pfizer says they plan to send their data to the FDA as soon as possible.
The company says side effects seen in the trial are comparable to those seen in older children. Pfizer says they plan to send their data to the FDA as soon as possible.
“We are pleased to be able to submit data to regulatory authorities for this group of school-aged children before the start of the winter season,” Ugur Sahin, MD, CEO and co-founder of BioNTech, said in a news release. “The safety profile and immunogenicity data in children aged 5 to 11 years vaccinated at a lower dose are consistent with those we have observed with our vaccine in other older populations at a higher dose.”
When asked how soon the FDA might act on Pfizer’s application, Anderson said others had speculated about timelines of 4 to 6 weeks, but he also noted that the FDA could still exercise its authority to ask the company for more information, which could slow the process down.
“As a parent myself, I would love to see that timeline occurring quickly. However, I do want the FDA to fully review the data and ask the necessary questions,” he said. “It’s a little speculative to get too definitive with timelines.”
A version of this article first appeared on WebMD.com.
With record numbers of COVID-19 cases being reported in kids, Pfizer and its partner BioNTech have announced that their mRNA vaccine for COVID-19 is safe and appears to generate a protective immune response in children as young as 5.
The companies have been testing a lower dose of the vaccine -- just 10 milligrams -- in children between the ages of 5 and 11. That’s one-third the dose given to adults.
In a clinical trial that included more than 2,200 children, Pfizer says two doses of the vaccines given 3 weeks apart generated a high level of neutralizing antibodies, comparable to the level seen in older children who get a higher dose of the vaccine.
On the advice of its vaccine advisory committee, the Food and Drug Administration asked vaccine makers to include more children in these studies earlier this year.
Rather than testing whether the vaccines are preventing COVID-19 illness in children, as they did in adults, the pharmaceutical companies that make the COVID-19 vaccines are looking at the antibody levels generated by the vaccines instead. The FDA has approved the approach in hopes of speeding vaccines to children, who are now back in school full time in most parts of the United States.
With that in mind, Evan Anderson, MD, a doctor with Children’s Healthcare of Atlanta who is an investigator for the trial — and is therefore kept in the dark about its results — said it’s important to keep in mind that the company didn’t share any efficacy data today.
“We don’t know whether there were cases of COVID-19 among children that were enrolled in the study and how those compared in those who received placebo versus those that received vaccine,” he said.
The company says side effects seen in the trial are comparable to those seen in older children. The company said there were no cases of heart inflammation called myocarditis observed. Pfizer says they plan to send their data to the FDA as soon as possible.
The company says side effects seen in the trial are comparable to those seen in older children. Pfizer says they plan to send their data to the FDA as soon as possible.
“We are pleased to be able to submit data to regulatory authorities for this group of school-aged children before the start of the winter season,” Ugur Sahin, MD, CEO and co-founder of BioNTech, said in a news release. “The safety profile and immunogenicity data in children aged 5 to 11 years vaccinated at a lower dose are consistent with those we have observed with our vaccine in other older populations at a higher dose.”
When asked how soon the FDA might act on Pfizer’s application, Anderson said others had speculated about timelines of 4 to 6 weeks, but he also noted that the FDA could still exercise its authority to ask the company for more information, which could slow the process down.
“As a parent myself, I would love to see that timeline occurring quickly. However, I do want the FDA to fully review the data and ask the necessary questions,” he said. “It’s a little speculative to get too definitive with timelines.”
A version of this article first appeared on WebMD.com.
With record numbers of COVID-19 cases being reported in kids, Pfizer and its partner BioNTech have announced that their mRNA vaccine for COVID-19 is safe and appears to generate a protective immune response in children as young as 5.
The companies have been testing a lower dose of the vaccine -- just 10 milligrams -- in children between the ages of 5 and 11. That’s one-third the dose given to adults.
In a clinical trial that included more than 2,200 children, Pfizer says two doses of the vaccines given 3 weeks apart generated a high level of neutralizing antibodies, comparable to the level seen in older children who get a higher dose of the vaccine.
On the advice of its vaccine advisory committee, the Food and Drug Administration asked vaccine makers to include more children in these studies earlier this year.
Rather than testing whether the vaccines are preventing COVID-19 illness in children, as they did in adults, the pharmaceutical companies that make the COVID-19 vaccines are looking at the antibody levels generated by the vaccines instead. The FDA has approved the approach in hopes of speeding vaccines to children, who are now back in school full time in most parts of the United States.
With that in mind, Evan Anderson, MD, a doctor with Children’s Healthcare of Atlanta who is an investigator for the trial — and is therefore kept in the dark about its results — said it’s important to keep in mind that the company didn’t share any efficacy data today.
“We don’t know whether there were cases of COVID-19 among children that were enrolled in the study and how those compared in those who received placebo versus those that received vaccine,” he said.
The company says side effects seen in the trial are comparable to those seen in older children. The company said there were no cases of heart inflammation called myocarditis observed. Pfizer says they plan to send their data to the FDA as soon as possible.
The company says side effects seen in the trial are comparable to those seen in older children. Pfizer says they plan to send their data to the FDA as soon as possible.
“We are pleased to be able to submit data to regulatory authorities for this group of school-aged children before the start of the winter season,” Ugur Sahin, MD, CEO and co-founder of BioNTech, said in a news release. “The safety profile and immunogenicity data in children aged 5 to 11 years vaccinated at a lower dose are consistent with those we have observed with our vaccine in other older populations at a higher dose.”
When asked how soon the FDA might act on Pfizer’s application, Anderson said others had speculated about timelines of 4 to 6 weeks, but he also noted that the FDA could still exercise its authority to ask the company for more information, which could slow the process down.
“As a parent myself, I would love to see that timeline occurring quickly. However, I do want the FDA to fully review the data and ask the necessary questions,” he said. “It’s a little speculative to get too definitive with timelines.”
A version of this article first appeared on WebMD.com.
New angiotensin studies in COVID-19 give more reassurance
Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.
Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.
Although all the studies are observational in design and have some confounding factors, overall, However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.
Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
Was it ‘Much ado about nothing’?
Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”
But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.
In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).
In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.
In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).
The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”
“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.
A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.
A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.
In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.
“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.
[embed:render:related:node:221129]
In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.
In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.
Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.
Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.
In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.
“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.
In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.
After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
Are there different effects between ACE inhibitors and ARBs?
A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.
Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.
“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.
“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.
In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”
The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”
Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.
“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.
He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”
Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”
Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.
A version of this article originally appeared on Medscape.com.
Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.
Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.
Although all the studies are observational in design and have some confounding factors, overall, However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.
Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
Was it ‘Much ado about nothing’?
Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”
But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.
In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).
In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.
In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).
The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”
“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.
A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.
A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.
In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.
“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.
[embed:render:related:node:221129]
In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.
In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.
Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.
Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.
In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.
“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.
In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.
After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
Are there different effects between ACE inhibitors and ARBs?
A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.
Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.
“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.
“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.
In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”
The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”
Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.
“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.
He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”
Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”
Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.
A version of this article originally appeared on Medscape.com.
Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.
Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.
Although all the studies are observational in design and have some confounding factors, overall, However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.
Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
Was it ‘Much ado about nothing’?
Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”
But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.
In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).
In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.
In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).
The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”
“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.
A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.
A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.
In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.
“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.
[embed:render:related:node:221129]
In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.
In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.
Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.
Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.
In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.
“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.
In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.
After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
Are there different effects between ACE inhibitors and ARBs?
A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.
Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.
“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.
“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.
In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”
The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”
Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.
“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.
He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”
Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”
Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.
A version of this article originally appeared on Medscape.com.
Angiotensin drugs and COVID-19: More reassuring data
Initial data from one Chinese center on the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients hospitalized with COVID-19 appear to give some further reassurance about continued use of these drugs.
The report from one hospital in Wuhan found that among patients with hypertension hospitalized with the COVID-19 virus, there was no difference in disease severity or death rate in patients taking ACE inhibitors or ARBs and those not taking such medications.
The data were published online April 23 in JAMA Cardiology.
The study adds to another recent report in a larger number of COVID-19 patients from nine Chinese hospitals that suggested a beneficial effect of ACE inhibitors or ARBs on mortality.
[embed:render:related:node:221129]
Additional studies
Two other similar studies have also been recently released. Another study from China, published online March 31 in Emerging Microbes & Infections, included a small sample of 42 hospitalized patients with COVID-19 on antihypertensive therapy. Those on ACE inhibitor/ARB therapy had a lower rate of severe disease and a trend toward a lower level of IL-6 in peripheral blood. In addition, patients on ACE inhibitor/ARB therapy had increased CD3+ and CD8+ T-cell counts in peripheral blood and decreased peak viral load compared with other antihypertensive drugs.
And a preliminary study from the UK, which has not yet been peer reviewed, found that treatment with ACE inhibitors was associated with a reduced risk of rapidly deteriorating severe COVID-19 disease.
The study, available online on MedRxiv, a preprint server for health sciences, reports on 205 acute inpatients with COVID-19 at King’s College Hospital and Princess Royal University Hospital, London.
Of these, 51.2% had hypertension, 30.2% had diabetes, and 14.6% had ischemic heart disease or heart failure. Of the 37 patients on ACE inhibitors, five (14%) died or required critical care support compared with 29% (48/168) of patients not taking an ACE inhibitor.
New Wuhan study
The authors of the new article published in JAMA Cardiology, led by Juyi Li, MD, reported on a case series of 1,178 patients hospitalized with COVID-19 at the Central Hospital of Wuhan, Hubei, China, between Jan. 15 and March 15, 2020.
Patients were a median age of 55 years, and 46% were men. They had an overall in-hospital mortality rate of 11%.
Of the 1,178 patients, 362 (30.7%) had a diagnosis of hypertension. These patients were older (median age, 66 years) and had a greater prevalence of chronic diseases. Patients with hypertension also had more severe manifestations of COVID-19 compared to those without hypertension, including higher rates of acute respiratory distress syndrome and in-hospital mortality (21.3% vs. 6.5%).
Of the 362 patients with hypertension, 31.8% were taking ACE inhibitors or ARBs.
Apart from a greater prevalence of coronary artery disease, patients taking ACE inhibitors or ARBs had similar comorbidities to those not taking these medications, and also similar laboratory profile results including blood counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers, although those taking ACE inhibitors/ARBs had higher levels of alkaline phosphatase.
The most commonly used antihypertensive drugs were calcium blockers. The percentage of patients with hypertension taking any drug or drug combination did not differ between those with severe and nonsevere infections and between those who survived and those who died.
Specifically regarding ACE inhibitors/ARBs, there was no difference between those with severe versus nonsevere illness in the use of ACE inhibitors (9.2% vs. 10.1%; P = .80), ARBs (24.9% vs. 21.2%; P = .40), or the composite of ACE inhibitors or ARBs (32.9% vs. 30.7%; P = .65).
Similarly, there were no differences in nonsurvivors and survivors in the use of ACE inhibitors (9.1% vs. 9.8%; P = .85); ARBs (19.5% vs. 23.9%; P = .42), or the composite of ACE inhibitors or ARBs (27.3% vs. 33.0%; P = .34).
The frequency of severe illness and death also did not differ between those treated with and without ACE inhibitors/ARBs in patients with hypertension and other various chronic conditions including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease.
The authors noted that these data confirm previous reports showing that patients with hypertension have more severe illness and higher mortality rates associated with COVID-19 than those without hypertension.
But they added: “Our data provide some reassurance that ACE inhibitors/ARBs are not associated with the progression or outcome of COVID-19 hospitalizations in patients with hypertension.”
They also noted that these results support the recommendations from almost all major cardiovascular societies that patients do not discontinue ACE inhibitors or ARBs because of worries about COVID-19.
However, the authors did point out some limitations of their study, which included a small number of patients with hypertension taking ACE inhibitors or ARBs and the fact that a nonsevere disease course was still severe enough to require hospitalization. In addition, it was not clear whether ACE inhibitor/ARB treatment at baseline was maintained throughout hospitalization for all patients.
This was also an observational comparison and may be biased by differences in patients taking versus not taking ACE inhibitors or ARBs at the time of hospitalization, although the measured baseline characteristics were similar in both groups.
But the authors also highlighted the finding that, in this cohort, patients with hypertension had three times the mortality rate of all other patients hospitalized with COVID-19.
“Hypertension combined with cardiovascular and cerebrovascular disease, diabetes, and chronic kidney disease would predispose patients to an increased risk of severity and mortality of COVID-19. Therefore, patients with these underlying conditions who develop COVID-19 require particularly intensive surveillance and care,” they wrote.
Experts cautiously optimistic
Some cardiovascular experts were cautiously optimistic about these latest results.
Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, and editor-in-chief of the Journal of Clinical Hypertension, said: “This new report from Wuhan, China, gives modest reassurance that the use of ACE inhibitors or ARBs in hypertensive patients with COVID-19 disease does not increase the risk of clinical deterioration or death.
“Ongoing, more definitive studies should help resolve competing hypotheses regarding the effects of these agents: whether the increased ACE2 enzyme levels they produce can worsen outcomes by increasing access of the COVID virus to lung tissue; or whether there is a benefit linked to a protective effect of increased ACE2 on alveolar cell function,” Dr. Weber noted.
“Though the number of patients included in this new report is small, it is startling that hypertensive patients were three times as likely as nonhypertensives to have a fatal outcome, presumably reflecting vulnerability due to the cardiovascular and metabolic comorbidities associated with hypertension,” he added.
“In any case, for now, clinicians should continue treating hypertensive patients with whichever drugs, including ACE inhibitors and ARBs, best provide protection from adverse outcomes,” Dr. Weber concluded.
John McMurray, MD, professor of medical cardiology, University of Glasgow, Scotland, commented: “This study from Wuhan provides some reassurance about one of the two questions about ACEI/ARBs: Do these drugs increase susceptibility to infection? And if [the patient is] infected, do they increase the severity of infection? This study addresses the latter question and appears to suggest no increased severity.”
However, Dr. McMurray pointed out that the study had many limitations. There were only small patient numbers and the data were unadjusted, “although it looks like the ACE inhibitor/ARB treated patients were higher risk to start with.” It was an observational study, and patients were not randomized and were predominantly treated with ARBs, and not ACE inhibitors, so “we don’t know if the concerns apply equally to these two classes of drug.
“Other data published and unpublished supporting this (even showing better outcomes in patients treated with an ACE inhibitor/ARB), and, to date, any concerns about these drugs remain unsubstantiated and the guidance from medical societies to continue treatment with these agents in patients prescribed them seems wise,” Dr. McMurray added.
Franz H. Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “The study from Wuhan is not a great study. They didn’t even do a multivariable analysis. They could have done a bit more with the data, but it still gives some reassurance.”
Dr. Messerli said it was “interesting” that 30% of the patients hospitalized with COVID-19 in the sample had hypertension. “That corresponds to the general population, so does not suggest that having hypertension increases susceptibility to infection – but it does seem to increase the risk of a bad outcome.”
Dr. Messerli noted that there are two more similar studies due to be published soon, both said to suggest either a beneficial or neutral effect of ACE inhibitors/ARBs on COVID-19 outcomes in hospitalized patients.
“This does help with confidence in prescribing these agents and reinforces the recommendations for patients to stay on these drugs,” he said.
“However, none of these studies address the infectivity issue – whether their use upregulates the ACE2 receptor, which the virus uses to gain entry to cells, thereby increasing susceptibility to the infection,” Dr. Messerli cautioned. “But the similar or better outcomes on these drugs are encouraging,” he added.
The Wuhan study was supported by the Health and Family Planning Commission of Wuhan City, China. The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Initial data from one Chinese center on the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients hospitalized with COVID-19 appear to give some further reassurance about continued use of these drugs.
The report from one hospital in Wuhan found that among patients with hypertension hospitalized with the COVID-19 virus, there was no difference in disease severity or death rate in patients taking ACE inhibitors or ARBs and those not taking such medications.
The data were published online April 23 in JAMA Cardiology.
The study adds to another recent report in a larger number of COVID-19 patients from nine Chinese hospitals that suggested a beneficial effect of ACE inhibitors or ARBs on mortality.
[embed:render:related:node:221129]
Additional studies
Two other similar studies have also been recently released. Another study from China, published online March 31 in Emerging Microbes & Infections, included a small sample of 42 hospitalized patients with COVID-19 on antihypertensive therapy. Those on ACE inhibitor/ARB therapy had a lower rate of severe disease and a trend toward a lower level of IL-6 in peripheral blood. In addition, patients on ACE inhibitor/ARB therapy had increased CD3+ and CD8+ T-cell counts in peripheral blood and decreased peak viral load compared with other antihypertensive drugs.
And a preliminary study from the UK, which has not yet been peer reviewed, found that treatment with ACE inhibitors was associated with a reduced risk of rapidly deteriorating severe COVID-19 disease.
The study, available online on MedRxiv, a preprint server for health sciences, reports on 205 acute inpatients with COVID-19 at King’s College Hospital and Princess Royal University Hospital, London.
Of these, 51.2% had hypertension, 30.2% had diabetes, and 14.6% had ischemic heart disease or heart failure. Of the 37 patients on ACE inhibitors, five (14%) died or required critical care support compared with 29% (48/168) of patients not taking an ACE inhibitor.
New Wuhan study
The authors of the new article published in JAMA Cardiology, led by Juyi Li, MD, reported on a case series of 1,178 patients hospitalized with COVID-19 at the Central Hospital of Wuhan, Hubei, China, between Jan. 15 and March 15, 2020.
Patients were a median age of 55 years, and 46% were men. They had an overall in-hospital mortality rate of 11%.
Of the 1,178 patients, 362 (30.7%) had a diagnosis of hypertension. These patients were older (median age, 66 years) and had a greater prevalence of chronic diseases. Patients with hypertension also had more severe manifestations of COVID-19 compared to those without hypertension, including higher rates of acute respiratory distress syndrome and in-hospital mortality (21.3% vs. 6.5%).
Of the 362 patients with hypertension, 31.8% were taking ACE inhibitors or ARBs.
Apart from a greater prevalence of coronary artery disease, patients taking ACE inhibitors or ARBs had similar comorbidities to those not taking these medications, and also similar laboratory profile results including blood counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers, although those taking ACE inhibitors/ARBs had higher levels of alkaline phosphatase.
The most commonly used antihypertensive drugs were calcium blockers. The percentage of patients with hypertension taking any drug or drug combination did not differ between those with severe and nonsevere infections and between those who survived and those who died.
Specifically regarding ACE inhibitors/ARBs, there was no difference between those with severe versus nonsevere illness in the use of ACE inhibitors (9.2% vs. 10.1%; P = .80), ARBs (24.9% vs. 21.2%; P = .40), or the composite of ACE inhibitors or ARBs (32.9% vs. 30.7%; P = .65).
Similarly, there were no differences in nonsurvivors and survivors in the use of ACE inhibitors (9.1% vs. 9.8%; P = .85); ARBs (19.5% vs. 23.9%; P = .42), or the composite of ACE inhibitors or ARBs (27.3% vs. 33.0%; P = .34).
The frequency of severe illness and death also did not differ between those treated with and without ACE inhibitors/ARBs in patients with hypertension and other various chronic conditions including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease.
The authors noted that these data confirm previous reports showing that patients with hypertension have more severe illness and higher mortality rates associated with COVID-19 than those without hypertension.
But they added: “Our data provide some reassurance that ACE inhibitors/ARBs are not associated with the progression or outcome of COVID-19 hospitalizations in patients with hypertension.”
They also noted that these results support the recommendations from almost all major cardiovascular societies that patients do not discontinue ACE inhibitors or ARBs because of worries about COVID-19.
However, the authors did point out some limitations of their study, which included a small number of patients with hypertension taking ACE inhibitors or ARBs and the fact that a nonsevere disease course was still severe enough to require hospitalization. In addition, it was not clear whether ACE inhibitor/ARB treatment at baseline was maintained throughout hospitalization for all patients.
This was also an observational comparison and may be biased by differences in patients taking versus not taking ACE inhibitors or ARBs at the time of hospitalization, although the measured baseline characteristics were similar in both groups.
But the authors also highlighted the finding that, in this cohort, patients with hypertension had three times the mortality rate of all other patients hospitalized with COVID-19.
“Hypertension combined with cardiovascular and cerebrovascular disease, diabetes, and chronic kidney disease would predispose patients to an increased risk of severity and mortality of COVID-19. Therefore, patients with these underlying conditions who develop COVID-19 require particularly intensive surveillance and care,” they wrote.
Experts cautiously optimistic
Some cardiovascular experts were cautiously optimistic about these latest results.
Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, and editor-in-chief of the Journal of Clinical Hypertension, said: “This new report from Wuhan, China, gives modest reassurance that the use of ACE inhibitors or ARBs in hypertensive patients with COVID-19 disease does not increase the risk of clinical deterioration or death.
“Ongoing, more definitive studies should help resolve competing hypotheses regarding the effects of these agents: whether the increased ACE2 enzyme levels they produce can worsen outcomes by increasing access of the COVID virus to lung tissue; or whether there is a benefit linked to a protective effect of increased ACE2 on alveolar cell function,” Dr. Weber noted.
“Though the number of patients included in this new report is small, it is startling that hypertensive patients were three times as likely as nonhypertensives to have a fatal outcome, presumably reflecting vulnerability due to the cardiovascular and metabolic comorbidities associated with hypertension,” he added.
“In any case, for now, clinicians should continue treating hypertensive patients with whichever drugs, including ACE inhibitors and ARBs, best provide protection from adverse outcomes,” Dr. Weber concluded.
John McMurray, MD, professor of medical cardiology, University of Glasgow, Scotland, commented: “This study from Wuhan provides some reassurance about one of the two questions about ACEI/ARBs: Do these drugs increase susceptibility to infection? And if [the patient is] infected, do they increase the severity of infection? This study addresses the latter question and appears to suggest no increased severity.”
However, Dr. McMurray pointed out that the study had many limitations. There were only small patient numbers and the data were unadjusted, “although it looks like the ACE inhibitor/ARB treated patients were higher risk to start with.” It was an observational study, and patients were not randomized and were predominantly treated with ARBs, and not ACE inhibitors, so “we don’t know if the concerns apply equally to these two classes of drug.
“Other data published and unpublished supporting this (even showing better outcomes in patients treated with an ACE inhibitor/ARB), and, to date, any concerns about these drugs remain unsubstantiated and the guidance from medical societies to continue treatment with these agents in patients prescribed them seems wise,” Dr. McMurray added.
Franz H. Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “The study from Wuhan is not a great study. They didn’t even do a multivariable analysis. They could have done a bit more with the data, but it still gives some reassurance.”
Dr. Messerli said it was “interesting” that 30% of the patients hospitalized with COVID-19 in the sample had hypertension. “That corresponds to the general population, so does not suggest that having hypertension increases susceptibility to infection – but it does seem to increase the risk of a bad outcome.”
Dr. Messerli noted that there are two more similar studies due to be published soon, both said to suggest either a beneficial or neutral effect of ACE inhibitors/ARBs on COVID-19 outcomes in hospitalized patients.
“This does help with confidence in prescribing these agents and reinforces the recommendations for patients to stay on these drugs,” he said.
“However, none of these studies address the infectivity issue – whether their use upregulates the ACE2 receptor, which the virus uses to gain entry to cells, thereby increasing susceptibility to the infection,” Dr. Messerli cautioned. “But the similar or better outcomes on these drugs are encouraging,” he added.
The Wuhan study was supported by the Health and Family Planning Commission of Wuhan City, China. The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Initial data from one Chinese center on the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients hospitalized with COVID-19 appear to give some further reassurance about continued use of these drugs.
The report from one hospital in Wuhan found that among patients with hypertension hospitalized with the COVID-19 virus, there was no difference in disease severity or death rate in patients taking ACE inhibitors or ARBs and those not taking such medications.
The data were published online April 23 in JAMA Cardiology.
The study adds to another recent report in a larger number of COVID-19 patients from nine Chinese hospitals that suggested a beneficial effect of ACE inhibitors or ARBs on mortality.
[embed:render:related:node:221129]
Additional studies
Two other similar studies have also been recently released. Another study from China, published online March 31 in Emerging Microbes & Infections, included a small sample of 42 hospitalized patients with COVID-19 on antihypertensive therapy. Those on ACE inhibitor/ARB therapy had a lower rate of severe disease and a trend toward a lower level of IL-6 in peripheral blood. In addition, patients on ACE inhibitor/ARB therapy had increased CD3+ and CD8+ T-cell counts in peripheral blood and decreased peak viral load compared with other antihypertensive drugs.
And a preliminary study from the UK, which has not yet been peer reviewed, found that treatment with ACE inhibitors was associated with a reduced risk of rapidly deteriorating severe COVID-19 disease.
The study, available online on MedRxiv, a preprint server for health sciences, reports on 205 acute inpatients with COVID-19 at King’s College Hospital and Princess Royal University Hospital, London.
Of these, 51.2% had hypertension, 30.2% had diabetes, and 14.6% had ischemic heart disease or heart failure. Of the 37 patients on ACE inhibitors, five (14%) died or required critical care support compared with 29% (48/168) of patients not taking an ACE inhibitor.
New Wuhan study
The authors of the new article published in JAMA Cardiology, led by Juyi Li, MD, reported on a case series of 1,178 patients hospitalized with COVID-19 at the Central Hospital of Wuhan, Hubei, China, between Jan. 15 and March 15, 2020.
Patients were a median age of 55 years, and 46% were men. They had an overall in-hospital mortality rate of 11%.
Of the 1,178 patients, 362 (30.7%) had a diagnosis of hypertension. These patients were older (median age, 66 years) and had a greater prevalence of chronic diseases. Patients with hypertension also had more severe manifestations of COVID-19 compared to those without hypertension, including higher rates of acute respiratory distress syndrome and in-hospital mortality (21.3% vs. 6.5%).
Of the 362 patients with hypertension, 31.8% were taking ACE inhibitors or ARBs.
Apart from a greater prevalence of coronary artery disease, patients taking ACE inhibitors or ARBs had similar comorbidities to those not taking these medications, and also similar laboratory profile results including blood counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers, although those taking ACE inhibitors/ARBs had higher levels of alkaline phosphatase.
The most commonly used antihypertensive drugs were calcium blockers. The percentage of patients with hypertension taking any drug or drug combination did not differ between those with severe and nonsevere infections and between those who survived and those who died.
Specifically regarding ACE inhibitors/ARBs, there was no difference between those with severe versus nonsevere illness in the use of ACE inhibitors (9.2% vs. 10.1%; P = .80), ARBs (24.9% vs. 21.2%; P = .40), or the composite of ACE inhibitors or ARBs (32.9% vs. 30.7%; P = .65).
Similarly, there were no differences in nonsurvivors and survivors in the use of ACE inhibitors (9.1% vs. 9.8%; P = .85); ARBs (19.5% vs. 23.9%; P = .42), or the composite of ACE inhibitors or ARBs (27.3% vs. 33.0%; P = .34).
The frequency of severe illness and death also did not differ between those treated with and without ACE inhibitors/ARBs in patients with hypertension and other various chronic conditions including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease.
The authors noted that these data confirm previous reports showing that patients with hypertension have more severe illness and higher mortality rates associated with COVID-19 than those without hypertension.
But they added: “Our data provide some reassurance that ACE inhibitors/ARBs are not associated with the progression or outcome of COVID-19 hospitalizations in patients with hypertension.”
They also noted that these results support the recommendations from almost all major cardiovascular societies that patients do not discontinue ACE inhibitors or ARBs because of worries about COVID-19.
However, the authors did point out some limitations of their study, which included a small number of patients with hypertension taking ACE inhibitors or ARBs and the fact that a nonsevere disease course was still severe enough to require hospitalization. In addition, it was not clear whether ACE inhibitor/ARB treatment at baseline was maintained throughout hospitalization for all patients.
This was also an observational comparison and may be biased by differences in patients taking versus not taking ACE inhibitors or ARBs at the time of hospitalization, although the measured baseline characteristics were similar in both groups.
But the authors also highlighted the finding that, in this cohort, patients with hypertension had three times the mortality rate of all other patients hospitalized with COVID-19.
“Hypertension combined with cardiovascular and cerebrovascular disease, diabetes, and chronic kidney disease would predispose patients to an increased risk of severity and mortality of COVID-19. Therefore, patients with these underlying conditions who develop COVID-19 require particularly intensive surveillance and care,” they wrote.
Experts cautiously optimistic
Some cardiovascular experts were cautiously optimistic about these latest results.
Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, and editor-in-chief of the Journal of Clinical Hypertension, said: “This new report from Wuhan, China, gives modest reassurance that the use of ACE inhibitors or ARBs in hypertensive patients with COVID-19 disease does not increase the risk of clinical deterioration or death.
“Ongoing, more definitive studies should help resolve competing hypotheses regarding the effects of these agents: whether the increased ACE2 enzyme levels they produce can worsen outcomes by increasing access of the COVID virus to lung tissue; or whether there is a benefit linked to a protective effect of increased ACE2 on alveolar cell function,” Dr. Weber noted.
“Though the number of patients included in this new report is small, it is startling that hypertensive patients were three times as likely as nonhypertensives to have a fatal outcome, presumably reflecting vulnerability due to the cardiovascular and metabolic comorbidities associated with hypertension,” he added.
“In any case, for now, clinicians should continue treating hypertensive patients with whichever drugs, including ACE inhibitors and ARBs, best provide protection from adverse outcomes,” Dr. Weber concluded.
John McMurray, MD, professor of medical cardiology, University of Glasgow, Scotland, commented: “This study from Wuhan provides some reassurance about one of the two questions about ACEI/ARBs: Do these drugs increase susceptibility to infection? And if [the patient is] infected, do they increase the severity of infection? This study addresses the latter question and appears to suggest no increased severity.”
However, Dr. McMurray pointed out that the study had many limitations. There were only small patient numbers and the data were unadjusted, “although it looks like the ACE inhibitor/ARB treated patients were higher risk to start with.” It was an observational study, and patients were not randomized and were predominantly treated with ARBs, and not ACE inhibitors, so “we don’t know if the concerns apply equally to these two classes of drug.
“Other data published and unpublished supporting this (even showing better outcomes in patients treated with an ACE inhibitor/ARB), and, to date, any concerns about these drugs remain unsubstantiated and the guidance from medical societies to continue treatment with these agents in patients prescribed them seems wise,” Dr. McMurray added.
Franz H. Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “The study from Wuhan is not a great study. They didn’t even do a multivariable analysis. They could have done a bit more with the data, but it still gives some reassurance.”
Dr. Messerli said it was “interesting” that 30% of the patients hospitalized with COVID-19 in the sample had hypertension. “That corresponds to the general population, so does not suggest that having hypertension increases susceptibility to infection – but it does seem to increase the risk of a bad outcome.”
Dr. Messerli noted that there are two more similar studies due to be published soon, both said to suggest either a beneficial or neutral effect of ACE inhibitors/ARBs on COVID-19 outcomes in hospitalized patients.
“This does help with confidence in prescribing these agents and reinforces the recommendations for patients to stay on these drugs,” he said.
“However, none of these studies address the infectivity issue – whether their use upregulates the ACE2 receptor, which the virus uses to gain entry to cells, thereby increasing susceptibility to the infection,” Dr. Messerli cautioned. “But the similar or better outcomes on these drugs are encouraging,” he added.
The Wuhan study was supported by the Health and Family Planning Commission of Wuhan City, China. The authors have reported no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Hydroxychloroquine ineffective for COVID-19, VA study suggests
Hydroxychloroquine (HCQ) with or without azithromycin (AZ) is not associated with a lower risk of requiring mechanical ventilation, according to a retrospective study of Veterans Affairs patients hospitalized with COVID-19.
The study, which was posted on a preprint server April 21 and has not been peer reviewed, also showed an increased risk of death associated with COVID-19 patients treated with HCQ alone.
“These findings highlight the importance of awaiting the results of ongoing prospective, randomized controlled studies before widespread adoption of these drugs,” write Joseph Magagnoli with Dorn Research Institute at the Columbia (S.C.) VA Health Care System and the department of clinical pharmacy & outcomes sciences, University of South Carolina, and colleagues.
A spokesperson with the University of Virginia, Charlottesville, where several of coauthors practice, said that the authors declined to comment for this article before peer review is completed.
The new data are not the first to suggest no benefit with HCQ among patients with COVID-19. A randomized trial showed no benefit and more side effects among 75 patients in China treated with HCQ, compared with 75 who received standard of care alone, according to a preprint posted online April 14.
No benefit in ventilation, death rates
The current analysis included data from all 368 male patients hospitalized with confirmed COVID-19 and treated at Veterans Health Administration medical centers in the United States through April 11.
Patients were categorized into three groups: those treated with HCQ in addition to standard of care (n = 97); those treated with HCQ and the antibiotic azithromycin plus standard of care (n = 113); and those who received standard supportive care only (n = 158).
Compared with the no HCQ group, the risk of death from any cause was higher in the HCQ group (adjusted hazard ratio, 2.61; 95% confidence interval, 1.10-6.17; P = .03) but not in the HCQ+AZ group (aHR, 1.14; 95% CI, 0.56-2.32; P = .72).
The risk of ventilation was similar in the HCQ group (aHR, 1.43; 95% CI, 0.53-3.79; P = .48) and in the HCQ+AZ group (aHR, 0.43; 95% CI, 0.16-1.12; P = .09), compared with the no-HCQ group.
This study provides another counterbalance to claims of HCQ efficacy, David R. Wessner, PhD, professor of biology and chair of the department of health and human values at Davidson (N.C.) College, said in an interview.
Interest in HCQ spiked after an open-label, nonrandomized, single-center study of COVID-19 patients in France suggested that hydroxychloroquine helped clear the virus and had a potential enhanced effect when combined with azithromycin.
But the 36-patient trial has since been called into question.
Wait for convincing data
Dr. Wessner, whose research focuses on viral pathogenesis, says that, although the current data don’t definitively answer the question of whether HCQ is effective in treating COVID-19, taking a “let’s try it and see” approach is not reasonable.
“Until we have good, prospective randomized trials, it’s hard to know what to make of this. But this is more evidence that there’s not a good reason to use [HCQ],” Dr. Wessner said. He points out that the small randomized trial from China shows that HCQ comes with potential harms.
Anecdotal evidence is often cited by those who promote HCQ as a potential treatment, but “those are one-off examples,” Wessner continued. “That doesn’t really tell us anything.”
Some HCQ proponents have said that trials finding no benefit are flawed in that the drug is given too late. However, Dr. Wessner says, there’s no way to prove or disprove that claim without randomized controlled trials.
Conflicting messages
Despite lack of clear evidence of benefit for patients with COVID-19, HCQ is recommended off-label by the Chinese National guideline, and the U.S. Food and Drug Administration has issued an emergency-use authorization for the treatment of adult patients with COVID-19.
Conversely, the Infectious Diseases Society of America and a guideline panel convened by the National Institutes of Health each concluded recently that because of insufficient data, they could not recommend any specific treatments for patients with COVID-19.
The VA data for the current study came from the Veterans Affairs Informatics and Computing Infrastructure, which includes inpatient, outpatient and laboratory data and pharmacy claims.
The authors acknowledge some limitations, “including those inherent to all retrospective analyses such as nonrandomization of treatments.”
However, they note that they did adjust for potential confounders, including comorbidities, medications, and clinical and laboratory factors.
A coauthor, Jayakrishna Ambati, MD, is a cofounder of iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics, and has received consultancy fees from Allergan, Biogen, Boehringer Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences, all unrelated to this work. Dr. Ambati is named as an inventor on a patent application filed by the University of Virginia relating to COVID-19 but unrelated to this work. Another coauthor has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics, all unrelated to this work. The other authors and Dr. Wessner have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Hydroxychloroquine (HCQ) with or without azithromycin (AZ) is not associated with a lower risk of requiring mechanical ventilation, according to a retrospective study of Veterans Affairs patients hospitalized with COVID-19.
The study, which was posted on a preprint server April 21 and has not been peer reviewed, also showed an increased risk of death associated with COVID-19 patients treated with HCQ alone.
“These findings highlight the importance of awaiting the results of ongoing prospective, randomized controlled studies before widespread adoption of these drugs,” write Joseph Magagnoli with Dorn Research Institute at the Columbia (S.C.) VA Health Care System and the department of clinical pharmacy & outcomes sciences, University of South Carolina, and colleagues.
A spokesperson with the University of Virginia, Charlottesville, where several of coauthors practice, said that the authors declined to comment for this article before peer review is completed.
The new data are not the first to suggest no benefit with HCQ among patients with COVID-19. A randomized trial showed no benefit and more side effects among 75 patients in China treated with HCQ, compared with 75 who received standard of care alone, according to a preprint posted online April 14.
No benefit in ventilation, death rates
The current analysis included data from all 368 male patients hospitalized with confirmed COVID-19 and treated at Veterans Health Administration medical centers in the United States through April 11.
Patients were categorized into three groups: those treated with HCQ in addition to standard of care (n = 97); those treated with HCQ and the antibiotic azithromycin plus standard of care (n = 113); and those who received standard supportive care only (n = 158).
Compared with the no HCQ group, the risk of death from any cause was higher in the HCQ group (adjusted hazard ratio, 2.61; 95% confidence interval, 1.10-6.17; P = .03) but not in the HCQ+AZ group (aHR, 1.14; 95% CI, 0.56-2.32; P = .72).
The risk of ventilation was similar in the HCQ group (aHR, 1.43; 95% CI, 0.53-3.79; P = .48) and in the HCQ+AZ group (aHR, 0.43; 95% CI, 0.16-1.12; P = .09), compared with the no-HCQ group.
This study provides another counterbalance to claims of HCQ efficacy, David R. Wessner, PhD, professor of biology and chair of the department of health and human values at Davidson (N.C.) College, said in an interview.
Interest in HCQ spiked after an open-label, nonrandomized, single-center study of COVID-19 patients in France suggested that hydroxychloroquine helped clear the virus and had a potential enhanced effect when combined with azithromycin.
But the 36-patient trial has since been called into question.
Wait for convincing data
Dr. Wessner, whose research focuses on viral pathogenesis, says that, although the current data don’t definitively answer the question of whether HCQ is effective in treating COVID-19, taking a “let’s try it and see” approach is not reasonable.
“Until we have good, prospective randomized trials, it’s hard to know what to make of this. But this is more evidence that there’s not a good reason to use [HCQ],” Dr. Wessner said. He points out that the small randomized trial from China shows that HCQ comes with potential harms.
Anecdotal evidence is often cited by those who promote HCQ as a potential treatment, but “those are one-off examples,” Wessner continued. “That doesn’t really tell us anything.”
Some HCQ proponents have said that trials finding no benefit are flawed in that the drug is given too late. However, Dr. Wessner says, there’s no way to prove or disprove that claim without randomized controlled trials.
Conflicting messages
Despite lack of clear evidence of benefit for patients with COVID-19, HCQ is recommended off-label by the Chinese National guideline, and the U.S. Food and Drug Administration has issued an emergency-use authorization for the treatment of adult patients with COVID-19.
Conversely, the Infectious Diseases Society of America and a guideline panel convened by the National Institutes of Health each concluded recently that because of insufficient data, they could not recommend any specific treatments for patients with COVID-19.
The VA data for the current study came from the Veterans Affairs Informatics and Computing Infrastructure, which includes inpatient, outpatient and laboratory data and pharmacy claims.
The authors acknowledge some limitations, “including those inherent to all retrospective analyses such as nonrandomization of treatments.”
However, they note that they did adjust for potential confounders, including comorbidities, medications, and clinical and laboratory factors.
A coauthor, Jayakrishna Ambati, MD, is a cofounder of iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics, and has received consultancy fees from Allergan, Biogen, Boehringer Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences, all unrelated to this work. Dr. Ambati is named as an inventor on a patent application filed by the University of Virginia relating to COVID-19 but unrelated to this work. Another coauthor has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics, all unrelated to this work. The other authors and Dr. Wessner have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Hydroxychloroquine (HCQ) with or without azithromycin (AZ) is not associated with a lower risk of requiring mechanical ventilation, according to a retrospective study of Veterans Affairs patients hospitalized with COVID-19.
The study, which was posted on a preprint server April 21 and has not been peer reviewed, also showed an increased risk of death associated with COVID-19 patients treated with HCQ alone.
“These findings highlight the importance of awaiting the results of ongoing prospective, randomized controlled studies before widespread adoption of these drugs,” write Joseph Magagnoli with Dorn Research Institute at the Columbia (S.C.) VA Health Care System and the department of clinical pharmacy & outcomes sciences, University of South Carolina, and colleagues.
A spokesperson with the University of Virginia, Charlottesville, where several of coauthors practice, said that the authors declined to comment for this article before peer review is completed.
The new data are not the first to suggest no benefit with HCQ among patients with COVID-19. A randomized trial showed no benefit and more side effects among 75 patients in China treated with HCQ, compared with 75 who received standard of care alone, according to a preprint posted online April 14.
No benefit in ventilation, death rates
The current analysis included data from all 368 male patients hospitalized with confirmed COVID-19 and treated at Veterans Health Administration medical centers in the United States through April 11.
Patients were categorized into three groups: those treated with HCQ in addition to standard of care (n = 97); those treated with HCQ and the antibiotic azithromycin plus standard of care (n = 113); and those who received standard supportive care only (n = 158).
Compared with the no HCQ group, the risk of death from any cause was higher in the HCQ group (adjusted hazard ratio, 2.61; 95% confidence interval, 1.10-6.17; P = .03) but not in the HCQ+AZ group (aHR, 1.14; 95% CI, 0.56-2.32; P = .72).
The risk of ventilation was similar in the HCQ group (aHR, 1.43; 95% CI, 0.53-3.79; P = .48) and in the HCQ+AZ group (aHR, 0.43; 95% CI, 0.16-1.12; P = .09), compared with the no-HCQ group.
This study provides another counterbalance to claims of HCQ efficacy, David R. Wessner, PhD, professor of biology and chair of the department of health and human values at Davidson (N.C.) College, said in an interview.
Interest in HCQ spiked after an open-label, nonrandomized, single-center study of COVID-19 patients in France suggested that hydroxychloroquine helped clear the virus and had a potential enhanced effect when combined with azithromycin.
But the 36-patient trial has since been called into question.
Wait for convincing data
Dr. Wessner, whose research focuses on viral pathogenesis, says that, although the current data don’t definitively answer the question of whether HCQ is effective in treating COVID-19, taking a “let’s try it and see” approach is not reasonable.
“Until we have good, prospective randomized trials, it’s hard to know what to make of this. But this is more evidence that there’s not a good reason to use [HCQ],” Dr. Wessner said. He points out that the small randomized trial from China shows that HCQ comes with potential harms.
Anecdotal evidence is often cited by those who promote HCQ as a potential treatment, but “those are one-off examples,” Wessner continued. “That doesn’t really tell us anything.”
Some HCQ proponents have said that trials finding no benefit are flawed in that the drug is given too late. However, Dr. Wessner says, there’s no way to prove or disprove that claim without randomized controlled trials.
Conflicting messages
Despite lack of clear evidence of benefit for patients with COVID-19, HCQ is recommended off-label by the Chinese National guideline, and the U.S. Food and Drug Administration has issued an emergency-use authorization for the treatment of adult patients with COVID-19.
Conversely, the Infectious Diseases Society of America and a guideline panel convened by the National Institutes of Health each concluded recently that because of insufficient data, they could not recommend any specific treatments for patients with COVID-19.
The VA data for the current study came from the Veterans Affairs Informatics and Computing Infrastructure, which includes inpatient, outpatient and laboratory data and pharmacy claims.
The authors acknowledge some limitations, “including those inherent to all retrospective analyses such as nonrandomization of treatments.”
However, they note that they did adjust for potential confounders, including comorbidities, medications, and clinical and laboratory factors.
A coauthor, Jayakrishna Ambati, MD, is a cofounder of iVeena Holdings, iVeena Delivery Systems and Inflammasome Therapeutics, and has received consultancy fees from Allergan, Biogen, Boehringer Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences, all unrelated to this work. Dr. Ambati is named as an inventor on a patent application filed by the University of Virginia relating to COVID-19 but unrelated to this work. Another coauthor has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics, all unrelated to this work. The other authors and Dr. Wessner have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
New guidance on management of acute CVD during COVID-19
The Chinese Society of Cardiology (CSC) has issued a consensus statement on the management of cardiac emergencies during the COVID-19 pandemic.
The document first appeared in the Chinese Journal of Cardiology, and a translated version was published in Circulation. The consensus statement was developed by 125 medical experts in the fields of cardiovascular disease and infectious disease. This included 23 experts currently working in Wuhan, China.
Three overarching principles guided their recommendations.
- The highest priority is prevention and control of transmission (including protecting staff).
- Patients should be assessed both for COVID-19 and for cardiovascular issues.
- At all times, all interventions and therapies provided should be in concordance with directives of infection control authorities.
“Considering that some asymptomatic patients may be a source of infection and transmission, all patients with severe emergent cardiovascular diseases should be managed as suspected cases of COVID-19 in Hubei Province,” noted writing chair and cardiologist Yaling Han, MD, of the General Hospital of Northern Theater Command in Shenyang, China.
In areas outside Hubei Province, where COVID-19 was less prevalent, this “infected until proven otherwise” approach was also recommended, although not as strictly.
Diagnosing CVD and COVID-19 simultaneously
In patients with emergent cardiovascular needs in whom COVID-19 has not been ruled out, quarantine in a single-bed room is needed, they wrote. The patient should be monitored for clinical manifestations of the disease, and undergo COVID-19 nucleic acid testing as soon as possible.
After infection control is considered, including limiting risk for infection to health care workers, risk assessment that weighs the relative advantages and disadvantages of treating the cardiovascular disease while preventing transmission can be considered, the investigators wrote.
At all times, transfers to different areas of the hospital and between hospitals should be minimized to reduce the risk for infection transmission.
The authors also recommended the use of “select laboratory tests with definitive sensitivity and specificity for disease diagnosis or assessment.”
For patients with acute aortic syndrome or acute pulmonary embolism, this means CT angiography. When acute pulmonary embolism is suspected, D-dimer testing and deep vein ultrasound can be employed, and for patients with acute coronary syndrome, ordinary electrocardiography and standard biomarkers for cardiac injury are preferred.
In addition, “all patients should undergo lung CT examination to evaluate for imaging features typical of COVID-19. ... Chest x-ray is not recommended because of a high rate of false negative diagnosis,” the authors wrote.
Intervene with caution
Medical therapy should be optimized in patients with emergent cardiovascular issues, with invasive strategies for diagnosis and therapy used “with caution,” according to the Chinese experts.
Conditions for which conservative medical treatment is recommended during COVID-19 pandemic include ST-segment elevation MI (STEMI) where thrombolytic therapy is indicated, STEMI when the optimal window for revascularization has passed, high-risk non-STEMI (NSTEMI), patients with uncomplicated Stanford type B aortic dissection, acute pulmonary embolism, acute exacerbation of heart failure, and hypertensive emergency.
“Vigilance should be paid to avoid misdiagnosing patients with pulmonary infarction as COVID-19 pneumonia,” they noted.
Diagnoses warranting invasive intervention are limited to STEMI with hemodynamic instability, life-threatening NSTEMI, Stanford type A or complex type B acute aortic dissection, bradyarrhythmia complicated by syncope or unstable hemodynamics mandating implantation of a device, and pulmonary embolism with hemodynamic instability for whom intravenous thrombolytics are too risky.
Interventions should be done in a cath lab or operating room with negative-pressure ventilation, with strict periprocedural disinfection. Personal protective equipment should also be of the strictest level.
In patients for whom COVID-19 cannot be ruled out presenting in a region with low incidence of COVID-19, interventions should only be considered for more severe cases and undertaken in a cath lab, electrophysiology lab, or operating room “with more than standard disinfection procedures that fulfill regulatory mandates for infection control.”
If negative-pressure ventilation is not available, air conditioning (for example, laminar flow and ventilation) should be stopped.
Establish plans now
“We operationalized all of these strategies at Beth Israel Deaconess Medical Center several weeks ago, since Boston had that early outbreak with the Biogen conference, but I suspect many institutions nationally are still formulating plans,” said Dhruv Kazi, MD, MSc, in an interview.
Although COVID-19 is “primarily a single-organ disease – it destroys the lungs” – transmission of infection to cardiology providers was an early problem that needed to be addressed, said Dr. Kazi. “We now know that a cardiologist seeing a patient who reports shortness of breath and then leans in to carefully auscultate the lungs and heart can get exposed if not provided adequate personal protective equipment; hence the cancellation of elective procedures, conversion of most elective visits to telemedicine, if possible, and the use of surgical/N95 masks in clinic and on rounds.”
Regarding the CSC recommendation to consider medical over invasive management, Dr. Kazi noteed that this works better in a setting where rapid testing is available. “Where that is not the case – as in the U.S. – resorting to conservative therapy for all COVID suspect cases will result in suboptimal care, particularly when nine out of every 10 COVID suspects will eventually rule out.”
One of his biggest worries now is that patients simply won’t come. Afraid of being exposed to COVID-19, patients with MIs and strokes may avoid or delay coming to the hospital.
“There is some evidence that this occurred in Wuhan, and I’m starting to see anecdotal evidence of this in Boston,” said Dr. Kazi. “We need to remind our patients that, if they experience symptoms of a heart attack or stroke, they deserve the same lifesaving treatment we offered before this pandemic set in. They should not try and sit it out.”
A version of this article originally appeared on Medscape.com.
The Chinese Society of Cardiology (CSC) has issued a consensus statement on the management of cardiac emergencies during the COVID-19 pandemic.
The document first appeared in the Chinese Journal of Cardiology, and a translated version was published in Circulation. The consensus statement was developed by 125 medical experts in the fields of cardiovascular disease and infectious disease. This included 23 experts currently working in Wuhan, China.
Three overarching principles guided their recommendations.
- The highest priority is prevention and control of transmission (including protecting staff).
- Patients should be assessed both for COVID-19 and for cardiovascular issues.
- At all times, all interventions and therapies provided should be in concordance with directives of infection control authorities.
“Considering that some asymptomatic patients may be a source of infection and transmission, all patients with severe emergent cardiovascular diseases should be managed as suspected cases of COVID-19 in Hubei Province,” noted writing chair and cardiologist Yaling Han, MD, of the General Hospital of Northern Theater Command in Shenyang, China.
In areas outside Hubei Province, where COVID-19 was less prevalent, this “infected until proven otherwise” approach was also recommended, although not as strictly.
Diagnosing CVD and COVID-19 simultaneously
In patients with emergent cardiovascular needs in whom COVID-19 has not been ruled out, quarantine in a single-bed room is needed, they wrote. The patient should be monitored for clinical manifestations of the disease, and undergo COVID-19 nucleic acid testing as soon as possible.
After infection control is considered, including limiting risk for infection to health care workers, risk assessment that weighs the relative advantages and disadvantages of treating the cardiovascular disease while preventing transmission can be considered, the investigators wrote.
At all times, transfers to different areas of the hospital and between hospitals should be minimized to reduce the risk for infection transmission.
The authors also recommended the use of “select laboratory tests with definitive sensitivity and specificity for disease diagnosis or assessment.”
For patients with acute aortic syndrome or acute pulmonary embolism, this means CT angiography. When acute pulmonary embolism is suspected, D-dimer testing and deep vein ultrasound can be employed, and for patients with acute coronary syndrome, ordinary electrocardiography and standard biomarkers for cardiac injury are preferred.
In addition, “all patients should undergo lung CT examination to evaluate for imaging features typical of COVID-19. ... Chest x-ray is not recommended because of a high rate of false negative diagnosis,” the authors wrote.
Intervene with caution
Medical therapy should be optimized in patients with emergent cardiovascular issues, with invasive strategies for diagnosis and therapy used “with caution,” according to the Chinese experts.
Conditions for which conservative medical treatment is recommended during COVID-19 pandemic include ST-segment elevation MI (STEMI) where thrombolytic therapy is indicated, STEMI when the optimal window for revascularization has passed, high-risk non-STEMI (NSTEMI), patients with uncomplicated Stanford type B aortic dissection, acute pulmonary embolism, acute exacerbation of heart failure, and hypertensive emergency.
“Vigilance should be paid to avoid misdiagnosing patients with pulmonary infarction as COVID-19 pneumonia,” they noted.
Diagnoses warranting invasive intervention are limited to STEMI with hemodynamic instability, life-threatening NSTEMI, Stanford type A or complex type B acute aortic dissection, bradyarrhythmia complicated by syncope or unstable hemodynamics mandating implantation of a device, and pulmonary embolism with hemodynamic instability for whom intravenous thrombolytics are too risky.
Interventions should be done in a cath lab or operating room with negative-pressure ventilation, with strict periprocedural disinfection. Personal protective equipment should also be of the strictest level.
In patients for whom COVID-19 cannot be ruled out presenting in a region with low incidence of COVID-19, interventions should only be considered for more severe cases and undertaken in a cath lab, electrophysiology lab, or operating room “with more than standard disinfection procedures that fulfill regulatory mandates for infection control.”
If negative-pressure ventilation is not available, air conditioning (for example, laminar flow and ventilation) should be stopped.
Establish plans now
“We operationalized all of these strategies at Beth Israel Deaconess Medical Center several weeks ago, since Boston had that early outbreak with the Biogen conference, but I suspect many institutions nationally are still formulating plans,” said Dhruv Kazi, MD, MSc, in an interview.
Although COVID-19 is “primarily a single-organ disease – it destroys the lungs” – transmission of infection to cardiology providers was an early problem that needed to be addressed, said Dr. Kazi. “We now know that a cardiologist seeing a patient who reports shortness of breath and then leans in to carefully auscultate the lungs and heart can get exposed if not provided adequate personal protective equipment; hence the cancellation of elective procedures, conversion of most elective visits to telemedicine, if possible, and the use of surgical/N95 masks in clinic and on rounds.”
Regarding the CSC recommendation to consider medical over invasive management, Dr. Kazi noteed that this works better in a setting where rapid testing is available. “Where that is not the case – as in the U.S. – resorting to conservative therapy for all COVID suspect cases will result in suboptimal care, particularly when nine out of every 10 COVID suspects will eventually rule out.”
One of his biggest worries now is that patients simply won’t come. Afraid of being exposed to COVID-19, patients with MIs and strokes may avoid or delay coming to the hospital.
“There is some evidence that this occurred in Wuhan, and I’m starting to see anecdotal evidence of this in Boston,” said Dr. Kazi. “We need to remind our patients that, if they experience symptoms of a heart attack or stroke, they deserve the same lifesaving treatment we offered before this pandemic set in. They should not try and sit it out.”
A version of this article originally appeared on Medscape.com.
The Chinese Society of Cardiology (CSC) has issued a consensus statement on the management of cardiac emergencies during the COVID-19 pandemic.
The document first appeared in the Chinese Journal of Cardiology, and a translated version was published in Circulation. The consensus statement was developed by 125 medical experts in the fields of cardiovascular disease and infectious disease. This included 23 experts currently working in Wuhan, China.
Three overarching principles guided their recommendations.
- The highest priority is prevention and control of transmission (including protecting staff).
- Patients should be assessed both for COVID-19 and for cardiovascular issues.
- At all times, all interventions and therapies provided should be in concordance with directives of infection control authorities.
“Considering that some asymptomatic patients may be a source of infection and transmission, all patients with severe emergent cardiovascular diseases should be managed as suspected cases of COVID-19 in Hubei Province,” noted writing chair and cardiologist Yaling Han, MD, of the General Hospital of Northern Theater Command in Shenyang, China.
In areas outside Hubei Province, where COVID-19 was less prevalent, this “infected until proven otherwise” approach was also recommended, although not as strictly.
Diagnosing CVD and COVID-19 simultaneously
In patients with emergent cardiovascular needs in whom COVID-19 has not been ruled out, quarantine in a single-bed room is needed, they wrote. The patient should be monitored for clinical manifestations of the disease, and undergo COVID-19 nucleic acid testing as soon as possible.
After infection control is considered, including limiting risk for infection to health care workers, risk assessment that weighs the relative advantages and disadvantages of treating the cardiovascular disease while preventing transmission can be considered, the investigators wrote.
At all times, transfers to different areas of the hospital and between hospitals should be minimized to reduce the risk for infection transmission.
The authors also recommended the use of “select laboratory tests with definitive sensitivity and specificity for disease diagnosis or assessment.”
For patients with acute aortic syndrome or acute pulmonary embolism, this means CT angiography. When acute pulmonary embolism is suspected, D-dimer testing and deep vein ultrasound can be employed, and for patients with acute coronary syndrome, ordinary electrocardiography and standard biomarkers for cardiac injury are preferred.
In addition, “all patients should undergo lung CT examination to evaluate for imaging features typical of COVID-19. ... Chest x-ray is not recommended because of a high rate of false negative diagnosis,” the authors wrote.
Intervene with caution
Medical therapy should be optimized in patients with emergent cardiovascular issues, with invasive strategies for diagnosis and therapy used “with caution,” according to the Chinese experts.
Conditions for which conservative medical treatment is recommended during COVID-19 pandemic include ST-segment elevation MI (STEMI) where thrombolytic therapy is indicated, STEMI when the optimal window for revascularization has passed, high-risk non-STEMI (NSTEMI), patients with uncomplicated Stanford type B aortic dissection, acute pulmonary embolism, acute exacerbation of heart failure, and hypertensive emergency.
“Vigilance should be paid to avoid misdiagnosing patients with pulmonary infarction as COVID-19 pneumonia,” they noted.
Diagnoses warranting invasive intervention are limited to STEMI with hemodynamic instability, life-threatening NSTEMI, Stanford type A or complex type B acute aortic dissection, bradyarrhythmia complicated by syncope or unstable hemodynamics mandating implantation of a device, and pulmonary embolism with hemodynamic instability for whom intravenous thrombolytics are too risky.
Interventions should be done in a cath lab or operating room with negative-pressure ventilation, with strict periprocedural disinfection. Personal protective equipment should also be of the strictest level.
In patients for whom COVID-19 cannot be ruled out presenting in a region with low incidence of COVID-19, interventions should only be considered for more severe cases and undertaken in a cath lab, electrophysiology lab, or operating room “with more than standard disinfection procedures that fulfill regulatory mandates for infection control.”
If negative-pressure ventilation is not available, air conditioning (for example, laminar flow and ventilation) should be stopped.
Establish plans now
“We operationalized all of these strategies at Beth Israel Deaconess Medical Center several weeks ago, since Boston had that early outbreak with the Biogen conference, but I suspect many institutions nationally are still formulating plans,” said Dhruv Kazi, MD, MSc, in an interview.
Although COVID-19 is “primarily a single-organ disease – it destroys the lungs” – transmission of infection to cardiology providers was an early problem that needed to be addressed, said Dr. Kazi. “We now know that a cardiologist seeing a patient who reports shortness of breath and then leans in to carefully auscultate the lungs and heart can get exposed if not provided adequate personal protective equipment; hence the cancellation of elective procedures, conversion of most elective visits to telemedicine, if possible, and the use of surgical/N95 masks in clinic and on rounds.”
Regarding the CSC recommendation to consider medical over invasive management, Dr. Kazi noteed that this works better in a setting where rapid testing is available. “Where that is not the case – as in the U.S. – resorting to conservative therapy for all COVID suspect cases will result in suboptimal care, particularly when nine out of every 10 COVID suspects will eventually rule out.”
One of his biggest worries now is that patients simply won’t come. Afraid of being exposed to COVID-19, patients with MIs and strokes may avoid or delay coming to the hospital.
“There is some evidence that this occurred in Wuhan, and I’m starting to see anecdotal evidence of this in Boston,” said Dr. Kazi. “We need to remind our patients that, if they experience symptoms of a heart attack or stroke, they deserve the same lifesaving treatment we offered before this pandemic set in. They should not try and sit it out.”
A version of this article originally appeared on Medscape.com.
Preventable diseases could gain a foothold because of COVID-19
There is a highly infectious virus spreading around the world and it is targeting the most vulnerable among us. It is among the most contagious of human diseases, spreading through the air unseen. No, it isn’t the novel coronavirus, COVID-19. It’s measles.
Remember measles? Outbreaks in recent years have brought the disease, which once was declared eliminated in the United States, back into the news and public awareness, but measles never has really gone away. Every year there are millions of cases worldwide – in 2018 alone there were nearly 10 million estimated cases and 142,300 deaths, according to the World Health Organization. The good news is that measles vaccination is highly effective, at about 97% after the recommended two doses. According to the Centers for Disease Control and Prevention, “because of vaccination, more than 21 million lives have been saved and measles deaths have been reduced by 80% since 2000.” This is a tremendous public health success and a cause for celebration. But our work is not done. The recent increases in vaccine hesitancy and refusal in many countries has contributed to the resurgence of measles worldwide.
Influenza still is in full swing with the CDC reporting high activity in 1 states for the week ending April 4th. Seasonal influenza, according to currently available data, has a lower fatality rate than COVID-19, but that doesn’t mean it is harmless. Thus far in the 2019-2020 flu season, there have been at least 24,000 deaths because of influenza in the United States alone, 166 of which were among pediatric patients.*
Like many pediatricians, I have seen firsthand the impact of vaccine-preventable illnesses like influenza, pertussis, and varicella. I have personally cared for an infant with pertussis who had to be intubated and on a ventilator for nearly a week. I have told the family of a child with cancer that they would have to be admitted to the hospital yet again for intravenous antiviral medication because that little rash turned out to be varicella. I have performed CPR on a previously healthy teenager with the flu whose heart was failing despite maximum ventilator support. All these illnesses might have been prevented had these patients or those around them been appropriately vaccinated.
Right now, the United States and governments around the world are taking unprecedented public health measures to prevent the spread of COVID-19, directing the public to stay home, avoid unnecessary contact with other people, practice good hand-washing and infection-control techniques. In order to promote social distancing, many primary care clinics are canceling nonurgent appointments or converting them to virtual visits, including some visits for routine vaccinations for older children, teens, and adults. This is a responsible choice to keep potentially asymptomatic people from spreading COVID-19, but once restrictions begin to lift, we all will need to act to help our patients catch up on these missing vaccinations.
This pandemic has made it more apparent than ever that we all rely upon each other to stay healthy. While this pandemic has disrupted nearly every aspect of daily life, we can’t let it disrupt one of the great successes in health care today: the prevention of serious illnesses. As soon as it is safe to do so, we must help and encourage patients to catch up on missing vaccinations. It’s rare that preventative public health measures and vaccine developments are in the nightly news, so we should use this increased public awareness to ensure patients are well educated and protected from every disease. As part of this, we must continue our efforts to share accurate information on the safety and efficacy of routine vaccination. And when there is a vaccine for COVID-19? Let’s make sure everyone gets that too.
Dr. Leighton is a pediatrician in the ED at Children’s National Hospital and currently is completing her MPH in health policy at George Washington University, both in Washington. She had no relevant financial disclosures.*
* This article was updated 4/10/2020.
There is a highly infectious virus spreading around the world and it is targeting the most vulnerable among us. It is among the most contagious of human diseases, spreading through the air unseen. No, it isn’t the novel coronavirus, COVID-19. It’s measles.
Remember measles? Outbreaks in recent years have brought the disease, which once was declared eliminated in the United States, back into the news and public awareness, but measles never has really gone away. Every year there are millions of cases worldwide – in 2018 alone there were nearly 10 million estimated cases and 142,300 deaths, according to the World Health Organization. The good news is that measles vaccination is highly effective, at about 97% after the recommended two doses. According to the Centers for Disease Control and Prevention, “because of vaccination, more than 21 million lives have been saved and measles deaths have been reduced by 80% since 2000.” This is a tremendous public health success and a cause for celebration. But our work is not done. The recent increases in vaccine hesitancy and refusal in many countries has contributed to the resurgence of measles worldwide.
Influenza still is in full swing with the CDC reporting high activity in 1 states for the week ending April 4th. Seasonal influenza, according to currently available data, has a lower fatality rate than COVID-19, but that doesn’t mean it is harmless. Thus far in the 2019-2020 flu season, there have been at least 24,000 deaths because of influenza in the United States alone, 166 of which were among pediatric patients.*
Like many pediatricians, I have seen firsthand the impact of vaccine-preventable illnesses like influenza, pertussis, and varicella. I have personally cared for an infant with pertussis who had to be intubated and on a ventilator for nearly a week. I have told the family of a child with cancer that they would have to be admitted to the hospital yet again for intravenous antiviral medication because that little rash turned out to be varicella. I have performed CPR on a previously healthy teenager with the flu whose heart was failing despite maximum ventilator support. All these illnesses might have been prevented had these patients or those around them been appropriately vaccinated.
Right now, the United States and governments around the world are taking unprecedented public health measures to prevent the spread of COVID-19, directing the public to stay home, avoid unnecessary contact with other people, practice good hand-washing and infection-control techniques. In order to promote social distancing, many primary care clinics are canceling nonurgent appointments or converting them to virtual visits, including some visits for routine vaccinations for older children, teens, and adults. This is a responsible choice to keep potentially asymptomatic people from spreading COVID-19, but once restrictions begin to lift, we all will need to act to help our patients catch up on these missing vaccinations.
This pandemic has made it more apparent than ever that we all rely upon each other to stay healthy. While this pandemic has disrupted nearly every aspect of daily life, we can’t let it disrupt one of the great successes in health care today: the prevention of serious illnesses. As soon as it is safe to do so, we must help and encourage patients to catch up on missing vaccinations. It’s rare that preventative public health measures and vaccine developments are in the nightly news, so we should use this increased public awareness to ensure patients are well educated and protected from every disease. As part of this, we must continue our efforts to share accurate information on the safety and efficacy of routine vaccination. And when there is a vaccine for COVID-19? Let’s make sure everyone gets that too.
Dr. Leighton is a pediatrician in the ED at Children’s National Hospital and currently is completing her MPH in health policy at George Washington University, both in Washington. She had no relevant financial disclosures.*
* This article was updated 4/10/2020.
There is a highly infectious virus spreading around the world and it is targeting the most vulnerable among us. It is among the most contagious of human diseases, spreading through the air unseen. No, it isn’t the novel coronavirus, COVID-19. It’s measles.
Remember measles? Outbreaks in recent years have brought the disease, which once was declared eliminated in the United States, back into the news and public awareness, but measles never has really gone away. Every year there are millions of cases worldwide – in 2018 alone there were nearly 10 million estimated cases and 142,300 deaths, according to the World Health Organization. The good news is that measles vaccination is highly effective, at about 97% after the recommended two doses. According to the Centers for Disease Control and Prevention, “because of vaccination, more than 21 million lives have been saved and measles deaths have been reduced by 80% since 2000.” This is a tremendous public health success and a cause for celebration. But our work is not done. The recent increases in vaccine hesitancy and refusal in many countries has contributed to the resurgence of measles worldwide.
Influenza still is in full swing with the CDC reporting high activity in 1 states for the week ending April 4th. Seasonal influenza, according to currently available data, has a lower fatality rate than COVID-19, but that doesn’t mean it is harmless. Thus far in the 2019-2020 flu season, there have been at least 24,000 deaths because of influenza in the United States alone, 166 of which were among pediatric patients.*
Like many pediatricians, I have seen firsthand the impact of vaccine-preventable illnesses like influenza, pertussis, and varicella. I have personally cared for an infant with pertussis who had to be intubated and on a ventilator for nearly a week. I have told the family of a child with cancer that they would have to be admitted to the hospital yet again for intravenous antiviral medication because that little rash turned out to be varicella. I have performed CPR on a previously healthy teenager with the flu whose heart was failing despite maximum ventilator support. All these illnesses might have been prevented had these patients or those around them been appropriately vaccinated.
Right now, the United States and governments around the world are taking unprecedented public health measures to prevent the spread of COVID-19, directing the public to stay home, avoid unnecessary contact with other people, practice good hand-washing and infection-control techniques. In order to promote social distancing, many primary care clinics are canceling nonurgent appointments or converting them to virtual visits, including some visits for routine vaccinations for older children, teens, and adults. This is a responsible choice to keep potentially asymptomatic people from spreading COVID-19, but once restrictions begin to lift, we all will need to act to help our patients catch up on these missing vaccinations.
This pandemic has made it more apparent than ever that we all rely upon each other to stay healthy. While this pandemic has disrupted nearly every aspect of daily life, we can’t let it disrupt one of the great successes in health care today: the prevention of serious illnesses. As soon as it is safe to do so, we must help and encourage patients to catch up on missing vaccinations. It’s rare that preventative public health measures and vaccine developments are in the nightly news, so we should use this increased public awareness to ensure patients are well educated and protected from every disease. As part of this, we must continue our efforts to share accurate information on the safety and efficacy of routine vaccination. And when there is a vaccine for COVID-19? Let’s make sure everyone gets that too.
Dr. Leighton is a pediatrician in the ED at Children’s National Hospital and currently is completing her MPH in health policy at George Washington University, both in Washington. She had no relevant financial disclosures.*
* This article was updated 4/10/2020.
Clinicians petition government for national quarantine
Clinicians across the United States are petitioning the federal government to follow the lead of South Korea, China, and other nations by imposing an immediate nationwide quarantine to slow the inevitable spread of COVID-19. Without federal action, the creators say, their lives and the lives of their colleagues, patients, and families are being put at increased risk.
In addition to the quarantine, the petition, posted on the website Change.org, calls on U.S. leaders to institute emergency production and distribution of personal protective equipment for healthcare workers and to rapidly increase access to testing.
The petition – which garnered more than 40,000 signatures in just 12 hours and as of this writing was approaching 94,000 – was started by an apolitical Facebook group to focus attention on what members see as the most critical issues for clinicians: slowing the spread of the virus through a coast-to-coast quarantine, protection of medical personnel with adequate supplies of essential equipment, and widespread testing.
“We started this group last Friday out of the realization that clinicians needed information about the outbreak and weren’t getting it,” said coadministrator Jessica McIntyre, MD, a pediatric hospitalist at Elliot Hospital in Manchester, N.H.
“We wanted to get ahead of it and connect with people before we were in the trenches experiencing it and to see what other programs were doing. From a local perspective, it has been really hard to see what people are doing in other states, especially when the protocols in our own states are changing every single day as we collect more information,” she said in an interview.
The Horse Has Bolted
A family medicine physician in Illinois helped launch the Facebook group. She asked that her name not be used but said in an interview that earlier actions may have prevented or at least delayed the need for the more draconian measures that her group is recommending.
“Clearly South Korea is one of the superstars as far as response has gone, but the concern we have in the United States is that we’re well beyond that point – we needed to be testing people over a month ago, in the hope of preventing a quarantine,” she said in an interview.
According to National Public Radio, as of March 13, South Korea had conducted 3,600 tests per million population, compared with five per million in the United States.
“I think the most concerning part is to see where Italy is now and where we are in comparison. Our ICUs have not yet overflowed, but I think we’re definitely looking at that in the next few weeks – hopefully longer, but I suspect that it will happen shortly,” she continued.
She cited work by Harvard University biostatistician Xihong Lin, PhD, that shows that when health authorities in Wuhan, China – widely cited as the epicenter of the global pandemic – cordoned off the city, the infection rate dropped from one person infecting 3.8 others to one infecting 1.25, thereby significantly slowing the rate of transmission.
“This is absolutely what we need to be doing,” she said.
Real News
Within 3 days of its creation, the online group had accrued more than 80,000 members with advanced medical training, including MDs, DOs, physician assistants, nurse practitioners, and certified registered nurse anesthetists.
“A lot of us were already very busy with our day-to-day work outside of COVID-19, and I think a lot of us felt unsure about where to get the best information,” said coadministrator David Janssen, MD, a family medicine physician in group practice in Sioux Center, Iowa,
“If you turn on the TV, there’s a lot of politicizing of the issue, and there’s a lot of good information, but also a lot of bad information. When health care providers talk to other health care providers, that’s often how we get our information and how we learn,” he said in an interview.
The COVID-19 U.S. Physicians/APP Facebook group includes 20 volunteer moderators who handle hundreds of posts per hour from persons seeking information on the novel coronavirus, what to tell patients, and how to protect themselves.
“It’s been wonderful to see how providers have been helping other providers sort through issues. Teaching hospitals have their hands on the latest research, but a lot of people like myself are at small community hospitals, critical-access hospitals, where we may have a lot of questions but don’t necessarily have the answers readily available to us,” Dr. Janssen said.
Dr. Janssen said that his community of about 8,000 residents initially had only four COVID-19 testing kits, or one for every 2,000 people. The situation has since improved, and more tests are now available, he added.
Dr. McIntyre, Dr. Janssen, and the Illinois family physician have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Clinicians across the United States are petitioning the federal government to follow the lead of South Korea, China, and other nations by imposing an immediate nationwide quarantine to slow the inevitable spread of COVID-19. Without federal action, the creators say, their lives and the lives of their colleagues, patients, and families are being put at increased risk.
In addition to the quarantine, the petition, posted on the website Change.org, calls on U.S. leaders to institute emergency production and distribution of personal protective equipment for healthcare workers and to rapidly increase access to testing.
The petition – which garnered more than 40,000 signatures in just 12 hours and as of this writing was approaching 94,000 – was started by an apolitical Facebook group to focus attention on what members see as the most critical issues for clinicians: slowing the spread of the virus through a coast-to-coast quarantine, protection of medical personnel with adequate supplies of essential equipment, and widespread testing.
“We started this group last Friday out of the realization that clinicians needed information about the outbreak and weren’t getting it,” said coadministrator Jessica McIntyre, MD, a pediatric hospitalist at Elliot Hospital in Manchester, N.H.
“We wanted to get ahead of it and connect with people before we were in the trenches experiencing it and to see what other programs were doing. From a local perspective, it has been really hard to see what people are doing in other states, especially when the protocols in our own states are changing every single day as we collect more information,” she said in an interview.
The Horse Has Bolted
A family medicine physician in Illinois helped launch the Facebook group. She asked that her name not be used but said in an interview that earlier actions may have prevented or at least delayed the need for the more draconian measures that her group is recommending.
“Clearly South Korea is one of the superstars as far as response has gone, but the concern we have in the United States is that we’re well beyond that point – we needed to be testing people over a month ago, in the hope of preventing a quarantine,” she said in an interview.
According to National Public Radio, as of March 13, South Korea had conducted 3,600 tests per million population, compared with five per million in the United States.
“I think the most concerning part is to see where Italy is now and where we are in comparison. Our ICUs have not yet overflowed, but I think we’re definitely looking at that in the next few weeks – hopefully longer, but I suspect that it will happen shortly,” she continued.
She cited work by Harvard University biostatistician Xihong Lin, PhD, that shows that when health authorities in Wuhan, China – widely cited as the epicenter of the global pandemic – cordoned off the city, the infection rate dropped from one person infecting 3.8 others to one infecting 1.25, thereby significantly slowing the rate of transmission.
“This is absolutely what we need to be doing,” she said.
Real News
Within 3 days of its creation, the online group had accrued more than 80,000 members with advanced medical training, including MDs, DOs, physician assistants, nurse practitioners, and certified registered nurse anesthetists.
“A lot of us were already very busy with our day-to-day work outside of COVID-19, and I think a lot of us felt unsure about where to get the best information,” said coadministrator David Janssen, MD, a family medicine physician in group practice in Sioux Center, Iowa,
“If you turn on the TV, there’s a lot of politicizing of the issue, and there’s a lot of good information, but also a lot of bad information. When health care providers talk to other health care providers, that’s often how we get our information and how we learn,” he said in an interview.
The COVID-19 U.S. Physicians/APP Facebook group includes 20 volunteer moderators who handle hundreds of posts per hour from persons seeking information on the novel coronavirus, what to tell patients, and how to protect themselves.
“It’s been wonderful to see how providers have been helping other providers sort through issues. Teaching hospitals have their hands on the latest research, but a lot of people like myself are at small community hospitals, critical-access hospitals, where we may have a lot of questions but don’t necessarily have the answers readily available to us,” Dr. Janssen said.
Dr. Janssen said that his community of about 8,000 residents initially had only four COVID-19 testing kits, or one for every 2,000 people. The situation has since improved, and more tests are now available, he added.
Dr. McIntyre, Dr. Janssen, and the Illinois family physician have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
Clinicians across the United States are petitioning the federal government to follow the lead of South Korea, China, and other nations by imposing an immediate nationwide quarantine to slow the inevitable spread of COVID-19. Without federal action, the creators say, their lives and the lives of their colleagues, patients, and families are being put at increased risk.
In addition to the quarantine, the petition, posted on the website Change.org, calls on U.S. leaders to institute emergency production and distribution of personal protective equipment for healthcare workers and to rapidly increase access to testing.
The petition – which garnered more than 40,000 signatures in just 12 hours and as of this writing was approaching 94,000 – was started by an apolitical Facebook group to focus attention on what members see as the most critical issues for clinicians: slowing the spread of the virus through a coast-to-coast quarantine, protection of medical personnel with adequate supplies of essential equipment, and widespread testing.
“We started this group last Friday out of the realization that clinicians needed information about the outbreak and weren’t getting it,” said coadministrator Jessica McIntyre, MD, a pediatric hospitalist at Elliot Hospital in Manchester, N.H.
“We wanted to get ahead of it and connect with people before we were in the trenches experiencing it and to see what other programs were doing. From a local perspective, it has been really hard to see what people are doing in other states, especially when the protocols in our own states are changing every single day as we collect more information,” she said in an interview.
The Horse Has Bolted
A family medicine physician in Illinois helped launch the Facebook group. She asked that her name not be used but said in an interview that earlier actions may have prevented or at least delayed the need for the more draconian measures that her group is recommending.
“Clearly South Korea is one of the superstars as far as response has gone, but the concern we have in the United States is that we’re well beyond that point – we needed to be testing people over a month ago, in the hope of preventing a quarantine,” she said in an interview.
According to National Public Radio, as of March 13, South Korea had conducted 3,600 tests per million population, compared with five per million in the United States.
“I think the most concerning part is to see where Italy is now and where we are in comparison. Our ICUs have not yet overflowed, but I think we’re definitely looking at that in the next few weeks – hopefully longer, but I suspect that it will happen shortly,” she continued.
She cited work by Harvard University biostatistician Xihong Lin, PhD, that shows that when health authorities in Wuhan, China – widely cited as the epicenter of the global pandemic – cordoned off the city, the infection rate dropped from one person infecting 3.8 others to one infecting 1.25, thereby significantly slowing the rate of transmission.
“This is absolutely what we need to be doing,” she said.
Real News
Within 3 days of its creation, the online group had accrued more than 80,000 members with advanced medical training, including MDs, DOs, physician assistants, nurse practitioners, and certified registered nurse anesthetists.
“A lot of us were already very busy with our day-to-day work outside of COVID-19, and I think a lot of us felt unsure about where to get the best information,” said coadministrator David Janssen, MD, a family medicine physician in group practice in Sioux Center, Iowa,
“If you turn on the TV, there’s a lot of politicizing of the issue, and there’s a lot of good information, but also a lot of bad information. When health care providers talk to other health care providers, that’s often how we get our information and how we learn,” he said in an interview.
The COVID-19 U.S. Physicians/APP Facebook group includes 20 volunteer moderators who handle hundreds of posts per hour from persons seeking information on the novel coronavirus, what to tell patients, and how to protect themselves.
“It’s been wonderful to see how providers have been helping other providers sort through issues. Teaching hospitals have their hands on the latest research, but a lot of people like myself are at small community hospitals, critical-access hospitals, where we may have a lot of questions but don’t necessarily have the answers readily available to us,” Dr. Janssen said.
Dr. Janssen said that his community of about 8,000 residents initially had only four COVID-19 testing kits, or one for every 2,000 people. The situation has since improved, and more tests are now available, he added.
Dr. McIntyre, Dr. Janssen, and the Illinois family physician have disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
2018 REVIEWER APPRECIATION
The JCSO Editors and editorial staff thank all those who generously contributed to the peer-review process this past year. We are mindful of the many demands on you and value the time and expertise you put in to reviewing submissions.
Click on the PDF icon at the top of this introduction for a complete list of the names of all the reviewers.
The JCSO Editors and editorial staff thank all those who generously contributed to the peer-review process this past year. We are mindful of the many demands on you and value the time and expertise you put in to reviewing submissions.
Click on the PDF icon at the top of this introduction for a complete list of the names of all the reviewers.
The JCSO Editors and editorial staff thank all those who generously contributed to the peer-review process this past year. We are mindful of the many demands on you and value the time and expertise you put in to reviewing submissions.
Click on the PDF icon at the top of this introduction for a complete list of the names of all the reviewers.
With this year’s close, the end of an era
This is the final issue of
JCSO was one of the few publications to span clinical and supportive care and to reach out to the entire oncology care team – oncologists, supportive care specialists, advanced practice providers, and pharmacists. Patients – their needs, concerns, and well-being – were always at the forefront of our thinking when we planned our issues. In the 2016 survey, our readers told us that they read the journal mainly to learn about clinical and supportive developments (72% and 57% of respondents, respectively), and almost 60% indicated that they routinely used information presented in our articles in their practice. To achieve those goals, we drew on the expertise and steady guidance of many over the course of our lifetime and we owe a deep gratitude to our editors emeriti, Lee Schwartzberg, MD, (Community Oncology) and Michael Fisch, MD, and Jamie von Roenn, MD (JSO), as well as the associate editors, members of the editorial advisory board, reviewers, authors, and of course, you, the reader.
I’d like specifically to thank the incumbent editors, Jame Abraham, MD; Howard Burris, MD; David Cella, PhD; Kevin Knopf, MD; and Thomas Strouse, MD for their support and invaluable contributions in recent years. Thank you too, to past associate editors Linda Bosserman, MD, (
Looking ahead
From January 2019, JCSO’s sister publications,
In this issue
We end with a bumper crop of articles, beginning with a report by Hedden and colleagues on page e234 describing how they developed, implemented, and evaluated a supportive care program for patients with prostate cancer. That is followed by a literature-based review article by Ibrahim colleagues detailing the effectiveness of duloxetine in the treatment of painful chemotherapy-induced peripheral neuropathy (p. e243). In the original research section, on page e250, Palmisiano and colleagues report on mortality outcomes in hospitalized patients with cancer after rapid response team activation; Jeurkar and colleagues compare risk models guiding growth factor use in chemotherapy (p. e256); and Chao and colleagues describe the symptom burdens associated with chemotherapy-induced anemia in patients with late-stage cancer (e260).
Challenging and elusive are the key words in this issue's Case Reports in which Pollock and colleagues describe the difficulties in managing a cetuximab rash (p. e272), Roberts and colleagues write about elevated liver function tests in a patient on palbociclib and fulvestrant (p. e277), and Mukherjee and colleagues describe a patient with intravascular large B-cell lymphoma, who presented both a diagnostic and management challenge for the care team (p. e280). Turn to page e283, where our regular contributor, Jane de Lartigue, has written an in-depth review on everything you need to know about biosimilars. Susan London follows up on page e290 with an article on findings from studies on biosimilars for 3 oncology drugs that were reported at this year’s annual meeting of the American Society of Clinical Oncology. Dr de Lartigue also reports on the approval of dabrafenib and trametinib for BRAF-mutant melanoma (e228) and osimertinib for advanced non–small-cell lung cancer (p. e231).
And finally…
I wish you and your colleagues and families all good things for the coming year. Thank you and goodbye – and stay in touch by downloading my podcast!
This is the final issue of
JCSO was one of the few publications to span clinical and supportive care and to reach out to the entire oncology care team – oncologists, supportive care specialists, advanced practice providers, and pharmacists. Patients – their needs, concerns, and well-being – were always at the forefront of our thinking when we planned our issues. In the 2016 survey, our readers told us that they read the journal mainly to learn about clinical and supportive developments (72% and 57% of respondents, respectively), and almost 60% indicated that they routinely used information presented in our articles in their practice. To achieve those goals, we drew on the expertise and steady guidance of many over the course of our lifetime and we owe a deep gratitude to our editors emeriti, Lee Schwartzberg, MD, (Community Oncology) and Michael Fisch, MD, and Jamie von Roenn, MD (JSO), as well as the associate editors, members of the editorial advisory board, reviewers, authors, and of course, you, the reader.
I’d like specifically to thank the incumbent editors, Jame Abraham, MD; Howard Burris, MD; David Cella, PhD; Kevin Knopf, MD; and Thomas Strouse, MD for their support and invaluable contributions in recent years. Thank you too, to past associate editors Linda Bosserman, MD, (
Looking ahead
From January 2019, JCSO’s sister publications,
In this issue
We end with a bumper crop of articles, beginning with a report by Hedden and colleagues on page e234 describing how they developed, implemented, and evaluated a supportive care program for patients with prostate cancer. That is followed by a literature-based review article by Ibrahim colleagues detailing the effectiveness of duloxetine in the treatment of painful chemotherapy-induced peripheral neuropathy (p. e243). In the original research section, on page e250, Palmisiano and colleagues report on mortality outcomes in hospitalized patients with cancer after rapid response team activation; Jeurkar and colleagues compare risk models guiding growth factor use in chemotherapy (p. e256); and Chao and colleagues describe the symptom burdens associated with chemotherapy-induced anemia in patients with late-stage cancer (e260).
Challenging and elusive are the key words in this issue's Case Reports in which Pollock and colleagues describe the difficulties in managing a cetuximab rash (p. e272), Roberts and colleagues write about elevated liver function tests in a patient on palbociclib and fulvestrant (p. e277), and Mukherjee and colleagues describe a patient with intravascular large B-cell lymphoma, who presented both a diagnostic and management challenge for the care team (p. e280). Turn to page e283, where our regular contributor, Jane de Lartigue, has written an in-depth review on everything you need to know about biosimilars. Susan London follows up on page e290 with an article on findings from studies on biosimilars for 3 oncology drugs that were reported at this year’s annual meeting of the American Society of Clinical Oncology. Dr de Lartigue also reports on the approval of dabrafenib and trametinib for BRAF-mutant melanoma (e228) and osimertinib for advanced non–small-cell lung cancer (p. e231).
And finally…
I wish you and your colleagues and families all good things for the coming year. Thank you and goodbye – and stay in touch by downloading my podcast!
This is the final issue of
JCSO was one of the few publications to span clinical and supportive care and to reach out to the entire oncology care team – oncologists, supportive care specialists, advanced practice providers, and pharmacists. Patients – their needs, concerns, and well-being – were always at the forefront of our thinking when we planned our issues. In the 2016 survey, our readers told us that they read the journal mainly to learn about clinical and supportive developments (72% and 57% of respondents, respectively), and almost 60% indicated that they routinely used information presented in our articles in their practice. To achieve those goals, we drew on the expertise and steady guidance of many over the course of our lifetime and we owe a deep gratitude to our editors emeriti, Lee Schwartzberg, MD, (Community Oncology) and Michael Fisch, MD, and Jamie von Roenn, MD (JSO), as well as the associate editors, members of the editorial advisory board, reviewers, authors, and of course, you, the reader.
I’d like specifically to thank the incumbent editors, Jame Abraham, MD; Howard Burris, MD; David Cella, PhD; Kevin Knopf, MD; and Thomas Strouse, MD for their support and invaluable contributions in recent years. Thank you too, to past associate editors Linda Bosserman, MD, (
Looking ahead
From January 2019, JCSO’s sister publications,
In this issue
We end with a bumper crop of articles, beginning with a report by Hedden and colleagues on page e234 describing how they developed, implemented, and evaluated a supportive care program for patients with prostate cancer. That is followed by a literature-based review article by Ibrahim colleagues detailing the effectiveness of duloxetine in the treatment of painful chemotherapy-induced peripheral neuropathy (p. e243). In the original research section, on page e250, Palmisiano and colleagues report on mortality outcomes in hospitalized patients with cancer after rapid response team activation; Jeurkar and colleagues compare risk models guiding growth factor use in chemotherapy (p. e256); and Chao and colleagues describe the symptom burdens associated with chemotherapy-induced anemia in patients with late-stage cancer (e260).
Challenging and elusive are the key words in this issue's Case Reports in which Pollock and colleagues describe the difficulties in managing a cetuximab rash (p. e272), Roberts and colleagues write about elevated liver function tests in a patient on palbociclib and fulvestrant (p. e277), and Mukherjee and colleagues describe a patient with intravascular large B-cell lymphoma, who presented both a diagnostic and management challenge for the care team (p. e280). Turn to page e283, where our regular contributor, Jane de Lartigue, has written an in-depth review on everything you need to know about biosimilars. Susan London follows up on page e290 with an article on findings from studies on biosimilars for 3 oncology drugs that were reported at this year’s annual meeting of the American Society of Clinical Oncology. Dr de Lartigue also reports on the approval of dabrafenib and trametinib for BRAF-mutant melanoma (e228) and osimertinib for advanced non–small-cell lung cancer (p. e231).
And finally…
I wish you and your colleagues and families all good things for the coming year. Thank you and goodbye – and stay in touch by downloading my podcast!
Trio of biosimilars have good showing
Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, according to findings reported at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.
Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual ASCO meeting. The findings advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
“Biosimilars are here,” said Michael A Thompson, MD, PhD, of Aurora Health Care in Milwaukee, Wisconsin, “[although] issues remain, including clinical decision support and pathway adoption, naming differences across the world, competition and lower prices versus the illusion of a free market, and adoption to decrease costs and increase value to our patients.” Dr Thompson was commenting during an invited discussion at the meeting. He is the medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health (also see Commentary at end of article).
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The overall response rate by week 19, confirmed by week 25 – the trial’s primary endpoint – was 45.3% with the biosimilar and 44.6% with bevacizumab, reported lead author Mark A Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando. The confidence interval (CI) for the risk difference fell within the equivalence margins set by European Union regulators (-13% and +13% for the 95% CI). And the confidence interval for the risk ratio fell within the equivalence margins set by the US Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival (PFS) was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio [HR], 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, respectively, Dr Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the 2 agents. Patients also had similar rates of grade 3 or higher serious adverse events (AEs) and of fatal (grade 5) serious AEs with the biosimilar and bevacizumab (5.3% and 5.9%, respectively).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr Socinski summarized. “These results confirm the similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU.”
Funding Pfizer sponsored the REFLECTIONS trial. Disclosures Dr Socinski disclosed that his institution receives research funding from Pfizer. Source Socinski MA et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer. ASCO 2018, Abstract 109. https://meetinglibrary.asco.org/record/161702/abstract. Clinical trial registry number NCT02364999 https://clinicaltrials.gov/ct2/show/NCT02364999
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer. The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various AEs were essentially the same.
The 48-week results showed a median PFS of 11.1 months with trastuzumab-dkst and 11.1 months with trastuzumab (HR, 0.95; P = .842), reported senior investigator Hope S Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The overall survival is immature but is impressive at over 80% at 52 weeks,” she noted.
Presence of overall response at 24 weeks correlated with duration of PFS at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr Rugo commented.
Common AEs through week 48 were much the same as those seen at week 24, with few additional [events] occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell to a very low number and was identical between the 2 arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of AEs of special interest – respiratory events, cardiac disorders, and infusion-related AEs – and of serious AEs were similar for the 2 agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.”
Dr Rugo emphasized that trastuzumab-dkst provides “an additional high-quality treatment option for patients with HER2+ breast cancers in any setting. This study shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Funding Mylan sponsored the HERITAGE trial. Disclosures Dr Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan. Source Manikhas A et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. ASCO 2018, Abstract 110. https://meetinglibrary.asco.org/record/161572/abstract. Clinical trial registry number NCT02472964 https://clinicaltrials.gov/ct2/show/NCT02472964
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of OB&GYN at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony-stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Data for the former came from PIONEER, a phase 3, randomized, controlled trial among patients with nonmetastatic breast cancer undergoing docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy in the neoadjuvant or adjuvant setting (Ann Oncol. 2015;26[9]:1948-53). Data for the latter came from MONITOR-GCSF, a postmarketing, open-label, observational cohort study among patients from 12 European countries receiving chemotherapy for various solid and hematologic malignancies (Support Care Cancer. 2016;24[2]:911-25).
Dr Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial/biosimilar population. Findings were similar for temperature exceeding 38.5°C in any cycle: 3.4% and 5.6%, respectively. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% and 74.3%) and higher rates of infection (15.5% and 7.9%) and hospitalization caused by febrile neutropenia (3.9% and 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 and 261 events, respectively) and skin/subcutaneous tissue disorders (5 and 258 events). “Seeing these data, you have to keep in mind that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr Harbeck commented. “Having seen the discrepancies in the data, I think it’s important to have randomized controlled trials to assess and monitor AEs for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Funding Sandoz sponsored the PIONEER and MONITOR-GCSF trials. Disclosures Dr Harbeck disclosed that she has a consulting or advisory role with Sandoz. Source Harbeck N et al. Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF). ASCO 2018, Abstract 111. https://meetinglibrary.asco.org/record/161688/abstract. Clinical trial registry number NCT01519700 https://clinicaltrials.gov/ct2/show/NCT01519700
Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, according to findings reported at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.
Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual ASCO meeting. The findings advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
“Biosimilars are here,” said Michael A Thompson, MD, PhD, of Aurora Health Care in Milwaukee, Wisconsin, “[although] issues remain, including clinical decision support and pathway adoption, naming differences across the world, competition and lower prices versus the illusion of a free market, and adoption to decrease costs and increase value to our patients.” Dr Thompson was commenting during an invited discussion at the meeting. He is the medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health (also see Commentary at end of article).
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The overall response rate by week 19, confirmed by week 25 – the trial’s primary endpoint – was 45.3% with the biosimilar and 44.6% with bevacizumab, reported lead author Mark A Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando. The confidence interval (CI) for the risk difference fell within the equivalence margins set by European Union regulators (-13% and +13% for the 95% CI). And the confidence interval for the risk ratio fell within the equivalence margins set by the US Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival (PFS) was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio [HR], 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, respectively, Dr Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the 2 agents. Patients also had similar rates of grade 3 or higher serious adverse events (AEs) and of fatal (grade 5) serious AEs with the biosimilar and bevacizumab (5.3% and 5.9%, respectively).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr Socinski summarized. “These results confirm the similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU.”
Funding Pfizer sponsored the REFLECTIONS trial. Disclosures Dr Socinski disclosed that his institution receives research funding from Pfizer. Source Socinski MA et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer. ASCO 2018, Abstract 109. https://meetinglibrary.asco.org/record/161702/abstract. Clinical trial registry number NCT02364999 https://clinicaltrials.gov/ct2/show/NCT02364999
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer. The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various AEs were essentially the same.
The 48-week results showed a median PFS of 11.1 months with trastuzumab-dkst and 11.1 months with trastuzumab (HR, 0.95; P = .842), reported senior investigator Hope S Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The overall survival is immature but is impressive at over 80% at 52 weeks,” she noted.
Presence of overall response at 24 weeks correlated with duration of PFS at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr Rugo commented.
Common AEs through week 48 were much the same as those seen at week 24, with few additional [events] occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell to a very low number and was identical between the 2 arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of AEs of special interest – respiratory events, cardiac disorders, and infusion-related AEs – and of serious AEs were similar for the 2 agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.”
Dr Rugo emphasized that trastuzumab-dkst provides “an additional high-quality treatment option for patients with HER2+ breast cancers in any setting. This study shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Funding Mylan sponsored the HERITAGE trial. Disclosures Dr Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan. Source Manikhas A et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. ASCO 2018, Abstract 110. https://meetinglibrary.asco.org/record/161572/abstract. Clinical trial registry number NCT02472964 https://clinicaltrials.gov/ct2/show/NCT02472964
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of OB&GYN at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony-stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Data for the former came from PIONEER, a phase 3, randomized, controlled trial among patients with nonmetastatic breast cancer undergoing docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy in the neoadjuvant or adjuvant setting (Ann Oncol. 2015;26[9]:1948-53). Data for the latter came from MONITOR-GCSF, a postmarketing, open-label, observational cohort study among patients from 12 European countries receiving chemotherapy for various solid and hematologic malignancies (Support Care Cancer. 2016;24[2]:911-25).
Dr Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial/biosimilar population. Findings were similar for temperature exceeding 38.5°C in any cycle: 3.4% and 5.6%, respectively. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% and 74.3%) and higher rates of infection (15.5% and 7.9%) and hospitalization caused by febrile neutropenia (3.9% and 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 and 261 events, respectively) and skin/subcutaneous tissue disorders (5 and 258 events). “Seeing these data, you have to keep in mind that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr Harbeck commented. “Having seen the discrepancies in the data, I think it’s important to have randomized controlled trials to assess and monitor AEs for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Funding Sandoz sponsored the PIONEER and MONITOR-GCSF trials. Disclosures Dr Harbeck disclosed that she has a consulting or advisory role with Sandoz. Source Harbeck N et al. Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF). ASCO 2018, Abstract 111. https://meetinglibrary.asco.org/record/161688/abstract. Clinical trial registry number NCT01519700 https://clinicaltrials.gov/ct2/show/NCT01519700
Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, according to findings reported at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.
Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual ASCO meeting. The findings advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.
“Biosimilars are here,” said Michael A Thompson, MD, PhD, of Aurora Health Care in Milwaukee, Wisconsin, “[although] issues remain, including clinical decision support and pathway adoption, naming differences across the world, competition and lower prices versus the illusion of a free market, and adoption to decrease costs and increase value to our patients.” Dr Thompson was commenting during an invited discussion at the meeting. He is the medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health (also see Commentary at end of article).
Bevacizumab biosimilar
The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.
The overall response rate by week 19, confirmed by week 25 – the trial’s primary endpoint – was 45.3% with the biosimilar and 44.6% with bevacizumab, reported lead author Mark A Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando. The confidence interval (CI) for the risk difference fell within the equivalence margins set by European Union regulators (-13% and +13% for the 95% CI). And the confidence interval for the risk ratio fell within the equivalence margins set by the US Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).
Median progression-free survival (PFS) was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio [HR], 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, respectively, Dr Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.
Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the 2 agents. Patients also had similar rates of grade 3 or higher serious adverse events (AEs) and of fatal (grade 5) serious AEs with the biosimilar and bevacizumab (5.3% and 5.9%, respectively).
“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr Socinski summarized. “These results confirm the similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU.”
Funding Pfizer sponsored the REFLECTIONS trial. Disclosures Dr Socinski disclosed that his institution receives research funding from Pfizer. Source Socinski MA et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer. ASCO 2018, Abstract 109. https://meetinglibrary.asco.org/record/161702/abstract. Clinical trial registry number NCT02364999 https://clinicaltrials.gov/ct2/show/NCT02364999
Trastuzumab biosimilar
The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer. The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various AEs were essentially the same.
The 48-week results showed a median PFS of 11.1 months with trastuzumab-dkst and 11.1 months with trastuzumab (HR, 0.95; P = .842), reported senior investigator Hope S Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The overall survival is immature but is impressive at over 80% at 52 weeks,” she noted.
Presence of overall response at 24 weeks correlated with duration of PFS at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr Rugo commented.
Common AEs through week 48 were much the same as those seen at week 24, with few additional [events] occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell to a very low number and was identical between the 2 arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”
The 48-week rates of AEs of special interest – respiratory events, cardiac disorders, and infusion-related AEs – and of serious AEs were similar for the 2 agents.
“We didn’t see any additional serious cardiac events during monotherapy,” Dr Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.
“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.”
Dr Rugo emphasized that trastuzumab-dkst provides “an additional high-quality treatment option for patients with HER2+ breast cancers in any setting. This study shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”
Funding Mylan sponsored the HERITAGE trial. Disclosures Dr Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan. Source Manikhas A et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. ASCO 2018, Abstract 110. https://meetinglibrary.asco.org/record/161572/abstract. Clinical trial registry number NCT02472964 https://clinicaltrials.gov/ct2/show/NCT02472964
Filgrastim biosimilar
Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of OB&GYN at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony-stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.
Data for the former came from PIONEER, a phase 3, randomized, controlled trial among patients with nonmetastatic breast cancer undergoing docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy in the neoadjuvant or adjuvant setting (Ann Oncol. 2015;26[9]:1948-53). Data for the latter came from MONITOR-GCSF, a postmarketing, open-label, observational cohort study among patients from 12 European countries receiving chemotherapy for various solid and hematologic malignancies (Support Care Cancer. 2016;24[2]:911-25).
Dr Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.
Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial/biosimilar population. Findings were similar for temperature exceeding 38.5°C in any cycle: 3.4% and 5.6%, respectively. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% and 74.3%) and higher rates of infection (15.5% and 7.9%) and hospitalization caused by febrile neutropenia (3.9% and 1.8%). Findings were essentially the same in cycle-level analyses.
The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 and 261 events, respectively) and skin/subcutaneous tissue disorders (5 and 258 events). “Seeing these data, you have to keep in mind that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”
Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.
“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr Harbeck commented. “Having seen the discrepancies in the data, I think it’s important to have randomized controlled trials to assess and monitor AEs for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
Funding Sandoz sponsored the PIONEER and MONITOR-GCSF trials. Disclosures Dr Harbeck disclosed that she has a consulting or advisory role with Sandoz. Source Harbeck N et al. Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF). ASCO 2018, Abstract 111. https://meetinglibrary.asco.org/record/161688/abstract. Clinical trial registry number NCT01519700 https://clinicaltrials.gov/ct2/show/NCT01519700
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All rights reserved. This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, accordi</metaDescription> <articlePDF/> <teaserImage/> <title>Trio of biosimilars have good showing</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear>2018</pubPubdateYear> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume>16</pubVolume> <pubNumber>6</pubNumber> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>jcso</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term canonical="true">29</term> </publications> <sections> <term canonical="true">27980</term> </sections> <topics> <term canonical="true">270</term> <term>192</term> <term>240</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Trio of biosimilars have good showing</title> <deck/> </itemMeta> <itemContent> <p>Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, according to findings reported at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.</p> <p>Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual ASCO meeting. The findings advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost. </p> <p>“Biosimilars are here,” said Michael A Thompson, MD, PhD, of Aurora Health Care in Milwaukee, Wisconsin, “[although] issues remain, including clinical decision support and pathway adoption, naming differences across the world, competition and lower prices versus the illusion of a free market, and adoption to decrease costs and increase value to our patients.” Dr Thompson was commenting during an invited discussion at the meeting. He is the medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health (also see Commentary, p. e292).</p> <h2>Bevacizumab biosimilar </h2> <p>The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent. </p> <p>The overall response rate by week 19, confirmed by week 25 – the trial’s primary endpoint – was 45.3% with the biosimilar and 44.6% with bevacizumab, reported lead author Mark A Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando. The confidence interval (CI) for the risk difference fell within the equivalence margins set by European Union regulators (-13% and +13% for the 95% CI). And the confidence interval for the risk ratio fell within the equivalence margins set by the US Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI). <br/><br/>Median progression-free survival (PFS) was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio [HR], 0.974; <i>P</i> = .814), and corresponding 1-year rates were 30.8% and 29.3%, respectively, Dr Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; <i>P</i> = .991), and corresponding 1-year rates were 66.4% and 68.8%. <br/><br/>Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the 2 agents. Patients also had similar rates of grade 3 or higher serious adverse events (AEs) and of fatal (grade 5) serious AEs with the biosimilar and bevacizumab (5.3% and 5.9%, respectively). <br/><br/>“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr Socinski summarized. “These results confirm the similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU.” </p> <p><b>Funding </b>Pfizer sponsored the REFLECTIONS trial. <b>Disclosures</b> Dr Socinski disclosed that his institution receives research funding from Pfizer. <b>Source</b> Socinski MA et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer. ASCO 2018, Abstract 109. https://meetinglibrary.asco.org/record/161702/abstract. <b>Clinical trial registry number</b> NCT02364999 https://clinicaltrials.gov/ct2/show/NCT02364999</p> <h2><br/><br/>Trastuzumab biosimilar </h2> <p>The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer. The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various AEs were essentially the same. </p> <p>The 48-week results showed a median PFS of 11.1 months with trastuzumab-dkst and 11.1 months with trastuzumab (HR, 0.95; <i>P</i> = .842), reported senior investigator Hope S Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The overall survival is immature but is impressive at over 80% at 52 weeks,” she noted. <br/><br/>Presence of overall response at 24 weeks correlated with duration of PFS at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr Rugo commented. <br/><br/>Common AEs through week 48 were much the same as those seen at week 24, with few additional [events] occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell to a very low number and was identical between the 2 arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.” <br/><br/>The 48-week rates of AEs of special interest – respiratory events, cardiac disorders, and infusion-related AEs – and of serious AEs were similar for the 2 agents. <br/><br/>“We didn’t see any additional serious cardiac events during monotherapy,” Dr Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups. <br/><br/>“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.” <br/><br/>Dr Rugo emphasized that trastuzumab-dkst provides “an additional high-quality treatment option for patients with HER2+ breast cancers in any setting. This study shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”</p> <p><b>Funding</b> Mylan sponsored the HERITAGE trial. <b>Disclosures</b> Dr Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan. <b>Source</b> Manikhas A et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. ASCO 2018, Abstract 110. https://meetinglibrary.asco.org/record/161572/abstract. <b>Clinical trial registry number</b> NCT02472964 https://clinicaltrials.gov/ct2/show/NCT02472964 <br/><br/></p> <h2>Filgrastim biosimilar </h2> <p>Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of OB&GYN at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony-stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer. </p> <p>Data for the former came from PIONEER, a phase 3, randomized, controlled trial among patients with nonmetastatic breast cancer undergoing docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy in the neoadjuvant or adjuvant setting (Ann Oncol. 2015;26[9]:1948-53). Data for the latter came from MONITOR-GCSF, a postmarketing, open-label, observational cohort study among patients from 12 European countries receiving chemotherapy for various solid and hematologic malignancies (Support Care Cancer. 2016;24[2]:911-25). <br/><br/>Dr Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort. <br/><br/>Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial/biosimilar population. Findings were similar for temperature exceeding 38.5°C in any cycle: 3.4% and 5.6%, respectively. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% and 74.3%) and higher rates of infection (15.5% and 7.9%) and hospitalization caused by febrile neutropenia (3.9% and 1.8%). Findings were essentially the same in cycle-level analyses. <br/><br/>The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 and 261 events, respectively) and skin/subcutaneous tissue disorders (5 and 258 events). “Seeing these data, you have to keep in mind that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.” <br/><br/>Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF. <br/><br/>“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr Harbeck commented. “Having seen the discrepancies in the data, I think it’s important to have randomized controlled trials to assess and monitor AEs for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.<br/><br/> </p> <p> <b>Funding</b> Sandoz sponsored the PIONEER and MONITOR-GCSF trials. <b>Disclosures</b> Dr Harbeck disclosed that she has a consulting or advisory role with Sandoz. <b>Source</b> Harbeck N et al. Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF). ASCO 2018, Abstract 111. https://meetinglibrary.asco.org/record/161688/abstract. <b>Clinical trial registry number</b> NCT01519700 https://clinicaltrials.gov/ct2/show/NCT01519700 </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>bio</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p class="author">Susan London</p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>ref</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> <p class="reference">1. Ann Oncol. 2015;26:1948-53 https://academic.oup.com/annonc/article/26/9/1948/189814 <br/><br/>2. Support Care Cancer. 2016;24:911-25 https://link.springer.com/article/10.1007%2Fs00520-015-2861-z <br/><br/>3. JAMA. 2017;317:37-47 https://jamanetwork.com/journals/jama/fullarticle/2590051 <br/><br/>4. J Clin Oncol. 2018;36 (suppl; abstr 112) https://meetinglibrary.asco.org/record/161569/abstract <br/><br/>5. J Clin Oncol. 2018;36:1260-65. http://ascopubs.org/doi/full/10.1200/JCO.2017.77.4893</p> </itemContent> </newsItem> </itemSet></root>
Key clinical points Biosimilars for bevacizumab, trastuzumab, and filgrastim showed similar efficacy and safety compared with their reference drugs.
Major findings Bevacizumab In patients with advanced nonsquamous NSCLC, the ORR was 45.3% with a candidate bevacizumab biosimilar and 44.6% with bevacizumab. Trastuzumab In patients with HER2+ advanced breast cancer, 48-week median PFS was 11.1 months for both trastuzumab-dkst and trastuzumab. Filgrastim The rate of chemotherapy-induced febrile neutropenia among breast cancer patients given a biosimilar for filgrastim was 5.1% in a trial population and 6.2% in a real-world population.
Study details Randomized, controlled trials of first-line therapy among 719 patients with advanced nonsquamous NSCLC (REFLECTIONS trial with bevacizumab) and among 458 patients with HER2+ advanced breast cancer (HERITAGE trial with trastuzumab). Comparison of outcomes in a randomized, controlled trial among 217 patients with nonmetastatic breast cancer (PIONEER trial with filgrastim) and a real-world cohort study of 466 patients with any-stage breast cancer (MONITOR-GCSF with filgrastim).
Disclosures and sources See article text.