Pharmacology

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, the results do not suggest that continued use of ACE inhibitors and ARBs causes harm. However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.

Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
 

Was it ‘Much ado about nothing’?

Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”

But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.

In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).

In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.

In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).

The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”

“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.

A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.

A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.

In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.

“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.

In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.

In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.

Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.

Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.

In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.

“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.

In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.

After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
 

Are there different effects between ACE inhibitors and ARBs?

A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.

Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.

“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.

“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.

In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”

The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”

Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.

“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.

He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”

Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”

Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.

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

Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.

Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.

Although all the studies are observational in design and have some confounding factors, overall, the results do not suggest that continued use of ACE inhibitors and ARBs causes harm. However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.

Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
 

Was it ‘Much ado about nothing’?

Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”

But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.

In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).

In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.

In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).

The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”

“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.

A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.

A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.

In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.

“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.

In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.

In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.

Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.

Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.

In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.

“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.

In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.

After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
 

Are there different effects between ACE inhibitors and ARBs?

A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.

Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.

“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.

“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.

In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”

The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”

Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.

“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.

He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”

Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”

Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.

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

Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.

Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.

Although all the studies are observational in design and have some confounding factors, overall, the results do not suggest that continued use of ACE inhibitors and ARBs causes harm. However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.

Providing commentary, John McMurray, MD, professor of medical cardiology at the University of Glasgow, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: These are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”
 

Was it ‘Much ado about nothing’?

Franz Messerli, MD, professor of medicine at the University of Bern (Switzerland), added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 – despite all the hype in the news media – as much ado about nothing.”

But both Dr. McMurray and Dr. Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.

In one study, a team led by Mandeep Mehra, MD, of Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8,910 patients with COVID-19 admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).

In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.

In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio, 0.33), as were statins (OR, 0.35).

The authors, however, stressed that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”

“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they wrote.

A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.

A second study published in the New England Journal of Medicine had a case-control design. The authors, led by Giuseppe Mancia, MD, of the University of Milano-Bicocca (Italy), compared 6,272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.

In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.

“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors concluded.

In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.

In the third study published in the New England Journal of Medicine, a group led by Harmony R. Reynolds, MD, of New York University, analyzed data from the health records of 12,594 patients in the NYU Langone Health system who had been tested for COVID-19. They found 5,894 patients whose test results were positive. Of these patients, 1,002 had severe illness, which was defined as illness requiring admission to the ICU, need for mechanical ventilation, or death.

Using Bayesian analysis and propensity score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness among patients who tested positive.

Results showed no positive association between any of the analyzed drug classes and either a positive test result or severe illness.

In an accompanying editorial, a group led by John A. Jarcho, MD, of Harvard Medical School, Boston, and deputy editor of the New England Journal of Medicine, wrote: “Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among those infected, or the risk of in-hospital death among those with a positive test.

“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with COVID-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion,” the authors of the editorial stated.

In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, of the Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.

After overlap propensity score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.
 

Are there different effects between ACE inhibitors and ARBs?

A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.

Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.

“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.

“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.

In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”

The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”

Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.

“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.

He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”

Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”

Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.

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

Major advances in understanding the nuanced mechanisms underlying atopic dermatitis have led to a plethora of novel topical, oral, and injectable biologic agents now in advanced-stage development, Jonathan I. Silverberg, MD, PhD, said during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled due to the COVID-19 pandemic.

“In the next 2-3 years, we may have nine new treatments approved for atopic dermatitis,” said Dr. Silverberg, director of clinical research and contact dermatitis at the University.

All nine medications he discussed are either in ongoing pivotal phase 3 randomized controlled trials or have completed their phase 3 developmental programs. “This is not theoretical; these are things you’re going to be using in your toolbox imminently,” he stressed.
 

Oral JAK inhibitors

The Janus kinase (JAK) pathway is the intracellular signaling mediator that interacts with extracellular inflammatory cytokines, including interleukin-4, -13, and -31, which are familiar to dermatologists because they’re targeted by potent biologic monoclonal antibody therapies. For example, IL-4 goes through JAK1 and 3, while IL-31 signals through JAK1 and 2.

“You really need to know the key JAK and STAT pathways involved in atopic dermatitis because it will help you determine the selectivity of the agents you’re going to be using,” the dermatologist advised.

Three oral, once-daily JAK inhibitors – abrocitinib, upadacitinib, and baricitinib – are in an advanced stage of development.

“Upadacitinib and abrocitinib may be the two most potent options coming to market soon for us to be thinking about,” Dr. Silverberg said.

Abrocitinib: Three positive phase 3 studies featuring this selective JAK1 inhibitor have been completed in adults with moderate to severe atopic dermatitis (AD). The most recent, JADE COMPARE, featured a head-to-head randomized comparison of abrocitinib and the injectable IL-4/IL-13 inhibitor dupilumab. The results of this 837-patient study haven’t yet been formally presented at a conference because of the COVID-19 pandemic. However, Pfizer recently announced that abrocitinib at 200 mg/day achieved significantly greater improvements than dupilumab (Dupixent) in the coprimary endpoints of skin clearance as reflected in an Investigator’s Global Assessment (IGA) score of 0 or 1 (that is, clear or almost clear) and disease extent based upon 75% reduction from baseline in Eczema Area and Severity Index (EASI 75) at 12 weeks. The same was true at 16 weeks.

Also, a significantly larger proportion of abrocitinib-treated patients achieved at least a 4-point reduction in itch severity as measured using the Peak Pruritus Numerical Rating Scale at week 2. The company plans to file for regulatory approval later this year.

The JADE COMPARE data are exciting because of a pressing unmet need for treatment options that are even more powerful than dupilumab, Dr. Silverberg said.

Upadacitinib: This is selective JAK1 inhibitor is not as far along in the developmental pipeline as abrocitinib, but the efficacy appears to be comparable. In a phase 2 study of 126 adults with moderate to severe AD, upadacitinib at the top dose of 30 mg/day achieved efficacy results Dr. Silverberg deemed “quite extraordinary,” with a rate of IGA score of 0 or 1 of 50% at 16 weeks and an EASI 75 response rate of 69%. Those findings numerically eclipsed results seen in an earlier phase 3 pivotal trial for dupilumab, in which the IGA 0/1 rate was 37% and EASI 75 was 48%, albeit with the caveat that cross-trial comparisons must be taken with a large grain of salt.

Baricitinib: Multiple phase 3 studies of this JAK 1/2 inhibitor have reported positive results. At the top dose of 4 mg/day, baricitinib appears to be less effective than dupilumab in its earlier pivotal trials.

“This may be a good oral option for our patients. It could be similar to the Otezla [apremilast] story in psoriasis: It’s perhaps not as effective as a lot of the biologics, but patients often prefer an oral option,” Dr. Silverberg said.

Of note, in one large, placebo-controlled, phase 3 study of baricitinib on top of background low- or medium-potency topical steroids, the IGA 0/1 rate at 16 weeks with placebo plus topical steroids was a modest 14.7%, which underscores that this long-time workhorse topical therapy is objectively less effective than most physicians think. In contrast, the IGA 0/1 rate with baricitinib at 4 mg/day plus topical steroids was a more respectable 30.6%.

All three oral JAK inhibitors have rapid onset of efficacy, a key advantage over the biologic agents.

“The issue you have to keep in mind is safety. The safety in the atopic dermatitis population was overall quite good for all three drugs. However, safety concerns have come up with JAK inhibitors in rheumatoid arthritis. I think that’s the part we watch the most in this. The efficacy has become clear. Now the question is where does the safety take us,” he said.


 

Novel injectable biologics

Nemolizumab: This humanized monoclonal antibody inhibits IL-31 receptor alpha. Mounting evidence implicates IL-31 as both a proinflammatory and immunomodulatory cytokine linking the immune and neural systems.

Early on, most researchers pigeonholed IL-31 as being a key player only in the itch factor in AD. Not so. Indeed, Dr. Silverberg was the lead investigator in a recent phase 2b study of nemolizumab that demonstrated the biologic is also effective at rapidly clearing AD lesions. The study, which evaluated three different doses in 226 adults with moderate to severe AD and severe pruritus who were on background topical corticosteroids, showed that nemolizumab at 30 mg every 4 weeks trounced placebo in terms of itch reduction: The 69% drop from baseline in Peak Pruritus Numeric Rating Scale at week 16 was twice that in controls, with a significant difference apparent even at week 1.

But in addition, the 33% IGA 0/1 rate at the same time point bested the 12% rate in controls. The EASI 75 response rate was significantly higher as well – 49% versus 19% – as was the EASI 90 response of 33%, compared with 9% in controls. Moreover, nemolizumab-treated patients used close to 40% less topical steroids during the study (J Allergy Clin Immunol. 2020 Jan;145[1]:173-82).

“This is something that’s fascinating. The study gets into the idea that a subset of atopic dermatitis patients have the itch that rashes, and perhaps if you break the itch/scratch cycle you can modify the lesions. Or the effect may even be due to the direct anti-inflammatory action of IL-31 blockade,” Dr. Silverberg observed.

It appeared that a plateau hadn’t been reached for some endpoints out at week 24, when the study ended. Japanese phase 3 studies have been completed, with what he called “great results,” and others are ongoing in the United States.

Tralokinumab: This fully human monoclonal antibody binds to IL-13, but unlike dupilumab, it doesn’t also inhibit IL-4. Tralokinumab met all primary and secondary endpoints in three pivotal phase 3 clinical trials, known as ECZTRA 1-3, that assessed it as treatment for moderate to severe AD in adults and showed an overall adverse event rate comparable with placebo. Leo Pharma, the Danish company developing the biologic, has announced it will file for marketing approval before the end of 2020. Phase 3 data would have been presented at the annual meeting of the American Academy of Dermatology in Denver, had it not been canceled. Dr. Silverberg said that, based upon phase 2 results, it appears tralokinumab may not be quite as effective as dupilumab in the overall AD population, but he predicted the newcomer will still play a useful role.

“The complexities of the immune system are such that some patients will respond better to one drug than another. I think we still have a lot to learn about who the patients are for these novel assets,” he said.

Lebrikizumab: This is another selective IL-13 inhibitor, but this one binds to IL-13 in a slightly different way than tralokinumab. The Food and Drug Administration granted it Fast Track status in December 2019. Twin placebo-controlled phase 3 studies of lebrikizumab as monotherapy for moderate to severe AD are ongoing, and another phase 3 trial of the biologic in combination with topical steroids is planned. Based upon the results of a phase 2b study, the highest dose studied – 250 mg every 2 weeks – appears to be at least as effective as dupilumab.
 

Nonsteroidal topical agents

These three late-stage topical creams – ruxolitinib, delgocitinib, and tapinarof – have previously received considerable coverage in Dermatology News. Ruxolitinib, a selective JAK1/2 inhibitor, has completed a positive phase 3 trial in adolescents and adults with mild to moderate AD. Delgocitinib, a pan-JAK1/2/3 and Tyrosine kinase 2 inhibitor, is already approved in an ointment formulation in Japan, and the cream formulation is in phase 2 studies in the United States and Europe. Tapinarof has a unique mechanism of action – it’s an aryl hydrocarbon receptor modulator – and is now in phase 3 in adolescents and adults with moderate to severe AD.

These three drugs appear to offer efficacy that’s comparable to or even better than medium-potency topical steroids, and without the notorious steroidal side effects that have caused widespread parental steroid-phobia. Potential applications for other inflammatory diseases, including vitiligo and psoriasis, are under study.

Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to those pharmaceutical companies and more than a dozen others.

[email protected]

Major advances in understanding the nuanced mechanisms underlying atopic dermatitis have led to a plethora of novel topical, oral, and injectable biologic agents now in advanced-stage development, Jonathan I. Silverberg, MD, PhD, said during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled due to the COVID-19 pandemic.

“In the next 2-3 years, we may have nine new treatments approved for atopic dermatitis,” said Dr. Silverberg, director of clinical research and contact dermatitis at the University.

All nine medications he discussed are either in ongoing pivotal phase 3 randomized controlled trials or have completed their phase 3 developmental programs. “This is not theoretical; these are things you’re going to be using in your toolbox imminently,” he stressed.
 

Oral JAK inhibitors

The Janus kinase (JAK) pathway is the intracellular signaling mediator that interacts with extracellular inflammatory cytokines, including interleukin-4, -13, and -31, which are familiar to dermatologists because they’re targeted by potent biologic monoclonal antibody therapies. For example, IL-4 goes through JAK1 and 3, while IL-31 signals through JAK1 and 2.

“You really need to know the key JAK and STAT pathways involved in atopic dermatitis because it will help you determine the selectivity of the agents you’re going to be using,” the dermatologist advised.

Three oral, once-daily JAK inhibitors – abrocitinib, upadacitinib, and baricitinib – are in an advanced stage of development.

“Upadacitinib and abrocitinib may be the two most potent options coming to market soon for us to be thinking about,” Dr. Silverberg said.

Abrocitinib: Three positive phase 3 studies featuring this selective JAK1 inhibitor have been completed in adults with moderate to severe atopic dermatitis (AD). The most recent, JADE COMPARE, featured a head-to-head randomized comparison of abrocitinib and the injectable IL-4/IL-13 inhibitor dupilumab. The results of this 837-patient study haven’t yet been formally presented at a conference because of the COVID-19 pandemic. However, Pfizer recently announced that abrocitinib at 200 mg/day achieved significantly greater improvements than dupilumab (Dupixent) in the coprimary endpoints of skin clearance as reflected in an Investigator’s Global Assessment (IGA) score of 0 or 1 (that is, clear or almost clear) and disease extent based upon 75% reduction from baseline in Eczema Area and Severity Index (EASI 75) at 12 weeks. The same was true at 16 weeks.

Also, a significantly larger proportion of abrocitinib-treated patients achieved at least a 4-point reduction in itch severity as measured using the Peak Pruritus Numerical Rating Scale at week 2. The company plans to file for regulatory approval later this year.

The JADE COMPARE data are exciting because of a pressing unmet need for treatment options that are even more powerful than dupilumab, Dr. Silverberg said.

Upadacitinib: This is selective JAK1 inhibitor is not as far along in the developmental pipeline as abrocitinib, but the efficacy appears to be comparable. In a phase 2 study of 126 adults with moderate to severe AD, upadacitinib at the top dose of 30 mg/day achieved efficacy results Dr. Silverberg deemed “quite extraordinary,” with a rate of IGA score of 0 or 1 of 50% at 16 weeks and an EASI 75 response rate of 69%. Those findings numerically eclipsed results seen in an earlier phase 3 pivotal trial for dupilumab, in which the IGA 0/1 rate was 37% and EASI 75 was 48%, albeit with the caveat that cross-trial comparisons must be taken with a large grain of salt.

Baricitinib: Multiple phase 3 studies of this JAK 1/2 inhibitor have reported positive results. At the top dose of 4 mg/day, baricitinib appears to be less effective than dupilumab in its earlier pivotal trials.

“This may be a good oral option for our patients. It could be similar to the Otezla [apremilast] story in psoriasis: It’s perhaps not as effective as a lot of the biologics, but patients often prefer an oral option,” Dr. Silverberg said.

Of note, in one large, placebo-controlled, phase 3 study of baricitinib on top of background low- or medium-potency topical steroids, the IGA 0/1 rate at 16 weeks with placebo plus topical steroids was a modest 14.7%, which underscores that this long-time workhorse topical therapy is objectively less effective than most physicians think. In contrast, the IGA 0/1 rate with baricitinib at 4 mg/day plus topical steroids was a more respectable 30.6%.

All three oral JAK inhibitors have rapid onset of efficacy, a key advantage over the biologic agents.

“The issue you have to keep in mind is safety. The safety in the atopic dermatitis population was overall quite good for all three drugs. However, safety concerns have come up with JAK inhibitors in rheumatoid arthritis. I think that’s the part we watch the most in this. The efficacy has become clear. Now the question is where does the safety take us,” he said.


 

Novel injectable biologics

Nemolizumab: This humanized monoclonal antibody inhibits IL-31 receptor alpha. Mounting evidence implicates IL-31 as both a proinflammatory and immunomodulatory cytokine linking the immune and neural systems.

Early on, most researchers pigeonholed IL-31 as being a key player only in the itch factor in AD. Not so. Indeed, Dr. Silverberg was the lead investigator in a recent phase 2b study of nemolizumab that demonstrated the biologic is also effective at rapidly clearing AD lesions. The study, which evaluated three different doses in 226 adults with moderate to severe AD and severe pruritus who were on background topical corticosteroids, showed that nemolizumab at 30 mg every 4 weeks trounced placebo in terms of itch reduction: The 69% drop from baseline in Peak Pruritus Numeric Rating Scale at week 16 was twice that in controls, with a significant difference apparent even at week 1.

But in addition, the 33% IGA 0/1 rate at the same time point bested the 12% rate in controls. The EASI 75 response rate was significantly higher as well – 49% versus 19% – as was the EASI 90 response of 33%, compared with 9% in controls. Moreover, nemolizumab-treated patients used close to 40% less topical steroids during the study (J Allergy Clin Immunol. 2020 Jan;145[1]:173-82).

“This is something that’s fascinating. The study gets into the idea that a subset of atopic dermatitis patients have the itch that rashes, and perhaps if you break the itch/scratch cycle you can modify the lesions. Or the effect may even be due to the direct anti-inflammatory action of IL-31 blockade,” Dr. Silverberg observed.

It appeared that a plateau hadn’t been reached for some endpoints out at week 24, when the study ended. Japanese phase 3 studies have been completed, with what he called “great results,” and others are ongoing in the United States.

Tralokinumab: This fully human monoclonal antibody binds to IL-13, but unlike dupilumab, it doesn’t also inhibit IL-4. Tralokinumab met all primary and secondary endpoints in three pivotal phase 3 clinical trials, known as ECZTRA 1-3, that assessed it as treatment for moderate to severe AD in adults and showed an overall adverse event rate comparable with placebo. Leo Pharma, the Danish company developing the biologic, has announced it will file for marketing approval before the end of 2020. Phase 3 data would have been presented at the annual meeting of the American Academy of Dermatology in Denver, had it not been canceled. Dr. Silverberg said that, based upon phase 2 results, it appears tralokinumab may not be quite as effective as dupilumab in the overall AD population, but he predicted the newcomer will still play a useful role.

“The complexities of the immune system are such that some patients will respond better to one drug than another. I think we still have a lot to learn about who the patients are for these novel assets,” he said.

Lebrikizumab: This is another selective IL-13 inhibitor, but this one binds to IL-13 in a slightly different way than tralokinumab. The Food and Drug Administration granted it Fast Track status in December 2019. Twin placebo-controlled phase 3 studies of lebrikizumab as monotherapy for moderate to severe AD are ongoing, and another phase 3 trial of the biologic in combination with topical steroids is planned. Based upon the results of a phase 2b study, the highest dose studied – 250 mg every 2 weeks – appears to be at least as effective as dupilumab.
 

Nonsteroidal topical agents

These three late-stage topical creams – ruxolitinib, delgocitinib, and tapinarof – have previously received considerable coverage in Dermatology News. Ruxolitinib, a selective JAK1/2 inhibitor, has completed a positive phase 3 trial in adolescents and adults with mild to moderate AD. Delgocitinib, a pan-JAK1/2/3 and Tyrosine kinase 2 inhibitor, is already approved in an ointment formulation in Japan, and the cream formulation is in phase 2 studies in the United States and Europe. Tapinarof has a unique mechanism of action – it’s an aryl hydrocarbon receptor modulator – and is now in phase 3 in adolescents and adults with moderate to severe AD.

These three drugs appear to offer efficacy that’s comparable to or even better than medium-potency topical steroids, and without the notorious steroidal side effects that have caused widespread parental steroid-phobia. Potential applications for other inflammatory diseases, including vitiligo and psoriasis, are under study.

Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to those pharmaceutical companies and more than a dozen others.

[email protected]

Major advances in understanding the nuanced mechanisms underlying atopic dermatitis have led to a plethora of novel topical, oral, and injectable biologic agents now in advanced-stage development, Jonathan I. Silverberg, MD, PhD, said during a virtual meeting held by the George Washington University department of dermatology. The virtual meeting included presentations that had been slated for the annual meeting of the American Academy of Dermatology, which was canceled due to the COVID-19 pandemic.

“In the next 2-3 years, we may have nine new treatments approved for atopic dermatitis,” said Dr. Silverberg, director of clinical research and contact dermatitis at the University.

All nine medications he discussed are either in ongoing pivotal phase 3 randomized controlled trials or have completed their phase 3 developmental programs. “This is not theoretical; these are things you’re going to be using in your toolbox imminently,” he stressed.
 

Oral JAK inhibitors

The Janus kinase (JAK) pathway is the intracellular signaling mediator that interacts with extracellular inflammatory cytokines, including interleukin-4, -13, and -31, which are familiar to dermatologists because they’re targeted by potent biologic monoclonal antibody therapies. For example, IL-4 goes through JAK1 and 3, while IL-31 signals through JAK1 and 2.

“You really need to know the key JAK and STAT pathways involved in atopic dermatitis because it will help you determine the selectivity of the agents you’re going to be using,” the dermatologist advised.

Three oral, once-daily JAK inhibitors – abrocitinib, upadacitinib, and baricitinib – are in an advanced stage of development.

“Upadacitinib and abrocitinib may be the two most potent options coming to market soon for us to be thinking about,” Dr. Silverberg said.

Abrocitinib: Three positive phase 3 studies featuring this selective JAK1 inhibitor have been completed in adults with moderate to severe atopic dermatitis (AD). The most recent, JADE COMPARE, featured a head-to-head randomized comparison of abrocitinib and the injectable IL-4/IL-13 inhibitor dupilumab. The results of this 837-patient study haven’t yet been formally presented at a conference because of the COVID-19 pandemic. However, Pfizer recently announced that abrocitinib at 200 mg/day achieved significantly greater improvements than dupilumab (Dupixent) in the coprimary endpoints of skin clearance as reflected in an Investigator’s Global Assessment (IGA) score of 0 or 1 (that is, clear or almost clear) and disease extent based upon 75% reduction from baseline in Eczema Area and Severity Index (EASI 75) at 12 weeks. The same was true at 16 weeks.

Also, a significantly larger proportion of abrocitinib-treated patients achieved at least a 4-point reduction in itch severity as measured using the Peak Pruritus Numerical Rating Scale at week 2. The company plans to file for regulatory approval later this year.

The JADE COMPARE data are exciting because of a pressing unmet need for treatment options that are even more powerful than dupilumab, Dr. Silverberg said.

Upadacitinib: This is selective JAK1 inhibitor is not as far along in the developmental pipeline as abrocitinib, but the efficacy appears to be comparable. In a phase 2 study of 126 adults with moderate to severe AD, upadacitinib at the top dose of 30 mg/day achieved efficacy results Dr. Silverberg deemed “quite extraordinary,” with a rate of IGA score of 0 or 1 of 50% at 16 weeks and an EASI 75 response rate of 69%. Those findings numerically eclipsed results seen in an earlier phase 3 pivotal trial for dupilumab, in which the IGA 0/1 rate was 37% and EASI 75 was 48%, albeit with the caveat that cross-trial comparisons must be taken with a large grain of salt.

Baricitinib: Multiple phase 3 studies of this JAK 1/2 inhibitor have reported positive results. At the top dose of 4 mg/day, baricitinib appears to be less effective than dupilumab in its earlier pivotal trials.

“This may be a good oral option for our patients. It could be similar to the Otezla [apremilast] story in psoriasis: It’s perhaps not as effective as a lot of the biologics, but patients often prefer an oral option,” Dr. Silverberg said.

Of note, in one large, placebo-controlled, phase 3 study of baricitinib on top of background low- or medium-potency topical steroids, the IGA 0/1 rate at 16 weeks with placebo plus topical steroids was a modest 14.7%, which underscores that this long-time workhorse topical therapy is objectively less effective than most physicians think. In contrast, the IGA 0/1 rate with baricitinib at 4 mg/day plus topical steroids was a more respectable 30.6%.

All three oral JAK inhibitors have rapid onset of efficacy, a key advantage over the biologic agents.

“The issue you have to keep in mind is safety. The safety in the atopic dermatitis population was overall quite good for all three drugs. However, safety concerns have come up with JAK inhibitors in rheumatoid arthritis. I think that’s the part we watch the most in this. The efficacy has become clear. Now the question is where does the safety take us,” he said.


 

Novel injectable biologics

Nemolizumab: This humanized monoclonal antibody inhibits IL-31 receptor alpha. Mounting evidence implicates IL-31 as both a proinflammatory and immunomodulatory cytokine linking the immune and neural systems.

Early on, most researchers pigeonholed IL-31 as being a key player only in the itch factor in AD. Not so. Indeed, Dr. Silverberg was the lead investigator in a recent phase 2b study of nemolizumab that demonstrated the biologic is also effective at rapidly clearing AD lesions. The study, which evaluated three different doses in 226 adults with moderate to severe AD and severe pruritus who were on background topical corticosteroids, showed that nemolizumab at 30 mg every 4 weeks trounced placebo in terms of itch reduction: The 69% drop from baseline in Peak Pruritus Numeric Rating Scale at week 16 was twice that in controls, with a significant difference apparent even at week 1.

But in addition, the 33% IGA 0/1 rate at the same time point bested the 12% rate in controls. The EASI 75 response rate was significantly higher as well – 49% versus 19% – as was the EASI 90 response of 33%, compared with 9% in controls. Moreover, nemolizumab-treated patients used close to 40% less topical steroids during the study (J Allergy Clin Immunol. 2020 Jan;145[1]:173-82).

“This is something that’s fascinating. The study gets into the idea that a subset of atopic dermatitis patients have the itch that rashes, and perhaps if you break the itch/scratch cycle you can modify the lesions. Or the effect may even be due to the direct anti-inflammatory action of IL-31 blockade,” Dr. Silverberg observed.

It appeared that a plateau hadn’t been reached for some endpoints out at week 24, when the study ended. Japanese phase 3 studies have been completed, with what he called “great results,” and others are ongoing in the United States.

Tralokinumab: This fully human monoclonal antibody binds to IL-13, but unlike dupilumab, it doesn’t also inhibit IL-4. Tralokinumab met all primary and secondary endpoints in three pivotal phase 3 clinical trials, known as ECZTRA 1-3, that assessed it as treatment for moderate to severe AD in adults and showed an overall adverse event rate comparable with placebo. Leo Pharma, the Danish company developing the biologic, has announced it will file for marketing approval before the end of 2020. Phase 3 data would have been presented at the annual meeting of the American Academy of Dermatology in Denver, had it not been canceled. Dr. Silverberg said that, based upon phase 2 results, it appears tralokinumab may not be quite as effective as dupilumab in the overall AD population, but he predicted the newcomer will still play a useful role.

“The complexities of the immune system are such that some patients will respond better to one drug than another. I think we still have a lot to learn about who the patients are for these novel assets,” he said.

Lebrikizumab: This is another selective IL-13 inhibitor, but this one binds to IL-13 in a slightly different way than tralokinumab. The Food and Drug Administration granted it Fast Track status in December 2019. Twin placebo-controlled phase 3 studies of lebrikizumab as monotherapy for moderate to severe AD are ongoing, and another phase 3 trial of the biologic in combination with topical steroids is planned. Based upon the results of a phase 2b study, the highest dose studied – 250 mg every 2 weeks – appears to be at least as effective as dupilumab.
 

Nonsteroidal topical agents

These three late-stage topical creams – ruxolitinib, delgocitinib, and tapinarof – have previously received considerable coverage in Dermatology News. Ruxolitinib, a selective JAK1/2 inhibitor, has completed a positive phase 3 trial in adolescents and adults with mild to moderate AD. Delgocitinib, a pan-JAK1/2/3 and Tyrosine kinase 2 inhibitor, is already approved in an ointment formulation in Japan, and the cream formulation is in phase 2 studies in the United States and Europe. Tapinarof has a unique mechanism of action – it’s an aryl hydrocarbon receptor modulator – and is now in phase 3 in adolescents and adults with moderate to severe AD.

These three drugs appear to offer efficacy that’s comparable to or even better than medium-potency topical steroids, and without the notorious steroidal side effects that have caused widespread parental steroid-phobia. Potential applications for other inflammatory diseases, including vitiligo and psoriasis, are under study.

Dr. Silverberg reported receiving research grants from Galderma and GlaxoSmithKline and serving as a consultant to those pharmaceutical companies and more than a dozen others.

[email protected]

The potential for serious arrhythmias from hydroxychloroquine treatment of COVID-19 patients received further documentation from a pair of studies released on May 1, casting further doubt on whether the uncertain benefit from this or related drugs to infected patients is worth the clear risks the agents pose.

A report from 90 confirmed COVID-19 patients treated with hydroxychloroquine at one Boston hospital during March-April 2020 identified a significantly prolonged, corrected QT (QTc) interval of at least 500 msec in 18 patients (20%), which included 10 patients whose QTc rose by at least 60 msec above baseline, and a total of 21 patients (23%) having a notable prolongation (JAMA Cardiol. 2020 May 4. doi: 10.1001/jamacardio.2020.1834). This series included one patient who developed torsades de pointes following treatment with hydroxychloroquine and azithromycin, “which to our knowledge has yet to be reported elsewhere in the literature,” the report said.

The second report, from a single center in Lyon, France, included 40 confirmed COVID-19 patients treated with hydroxychloroquine during 2 weeks in late March, and found that 37 (93%) had some increase in the QTc interval, including 14 patients (36%) with an increase of at least 60 msec, and 7 patients (18%) whose QTc rose to at least 500 msec (JAMA Cardiol. 2020 May. doi: 10.1001/jamacardio.2020.1787). However, none of the 40 patients in this series developed an identified ventricular arrhythmia. All patients in both studies received hydroxychloroquine for at least 1 day, and roughly half the patients in each series also received concurrent azithromycin, another drug that can prolong the QTc interval and that has been frequently used in combination with hydroxychloroquine as an unproven COVID-19 treatment cocktail.

These two reports, as well as prior report from Brazil on COVID-19 patients treated with chloroquine diphosphate (JAMA Netw Open. 2020;3[4]:e208857), “underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed,” wrote Robert O. Bonow, MD, a professor of medicine at Northwestern University in Chicago, and coauthors in an editorial that accompanied the two reports (JAMA Cardiol. 2020 May 4;doi: 10.1001/jamacardio.2020.1782). The editorial cited two recently-begun prospective trials, ORCHID and RECOVERY, that are more systematically assessing the safety and efficacy of hydroxychloroquine treatment in COVID-19 patients.

The findings lend further support to a Safety Communication from the U.S. Food and Drug Administration on April 24 that reminded clinicians that the Emergency Use Authorization for hydroxychloroquine and chloroquine in COVID-19 patients that the FDA issued on March 28 applied to only certain hospitalized patients or those enrolled in clinical trials. The Safety Communication also said that agency was aware of reports of adverse arrhythmia events when COVID-19 patients received these drugs outside a hospital setting as well as uninfected people who had received one of these drugs for preventing infection.

In addition, leaders of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society on April 10 issued a summary of considerations when using hydroxychloroquine and azithromycin to treat COVID-19 patients, and noted that a way to minimized the risk from these drugs is to withhold them from patients with a QTc interval of 500 msec or greater at baseline (J Am Coll Cardiol. 2020 Apr 10. doi: 10.1016/j.jacc.2020.04.016). The summary also highlighted the need for regular ECG monitoring of COVID-19 patients who receive drugs that can prolong the QTc interval, and recommended withdrawing treatment from patients when their QTc exceeds the 500 msec threshold.

None of the authors of the two reports and editorial had relevant commercial disclosures.

[email protected]

The potential for serious arrhythmias from hydroxychloroquine treatment of COVID-19 patients received further documentation from a pair of studies released on May 1, casting further doubt on whether the uncertain benefit from this or related drugs to infected patients is worth the clear risks the agents pose.

A report from 90 confirmed COVID-19 patients treated with hydroxychloroquine at one Boston hospital during March-April 2020 identified a significantly prolonged, corrected QT (QTc) interval of at least 500 msec in 18 patients (20%), which included 10 patients whose QTc rose by at least 60 msec above baseline, and a total of 21 patients (23%) having a notable prolongation (JAMA Cardiol. 2020 May 4. doi: 10.1001/jamacardio.2020.1834). This series included one patient who developed torsades de pointes following treatment with hydroxychloroquine and azithromycin, “which to our knowledge has yet to be reported elsewhere in the literature,” the report said.

The second report, from a single center in Lyon, France, included 40 confirmed COVID-19 patients treated with hydroxychloroquine during 2 weeks in late March, and found that 37 (93%) had some increase in the QTc interval, including 14 patients (36%) with an increase of at least 60 msec, and 7 patients (18%) whose QTc rose to at least 500 msec (JAMA Cardiol. 2020 May. doi: 10.1001/jamacardio.2020.1787). However, none of the 40 patients in this series developed an identified ventricular arrhythmia. All patients in both studies received hydroxychloroquine for at least 1 day, and roughly half the patients in each series also received concurrent azithromycin, another drug that can prolong the QTc interval and that has been frequently used in combination with hydroxychloroquine as an unproven COVID-19 treatment cocktail.

These two reports, as well as prior report from Brazil on COVID-19 patients treated with chloroquine diphosphate (JAMA Netw Open. 2020;3[4]:e208857), “underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed,” wrote Robert O. Bonow, MD, a professor of medicine at Northwestern University in Chicago, and coauthors in an editorial that accompanied the two reports (JAMA Cardiol. 2020 May 4;doi: 10.1001/jamacardio.2020.1782). The editorial cited two recently-begun prospective trials, ORCHID and RECOVERY, that are more systematically assessing the safety and efficacy of hydroxychloroquine treatment in COVID-19 patients.

The findings lend further support to a Safety Communication from the U.S. Food and Drug Administration on April 24 that reminded clinicians that the Emergency Use Authorization for hydroxychloroquine and chloroquine in COVID-19 patients that the FDA issued on March 28 applied to only certain hospitalized patients or those enrolled in clinical trials. The Safety Communication also said that agency was aware of reports of adverse arrhythmia events when COVID-19 patients received these drugs outside a hospital setting as well as uninfected people who had received one of these drugs for preventing infection.

In addition, leaders of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society on April 10 issued a summary of considerations when using hydroxychloroquine and azithromycin to treat COVID-19 patients, and noted that a way to minimized the risk from these drugs is to withhold them from patients with a QTc interval of 500 msec or greater at baseline (J Am Coll Cardiol. 2020 Apr 10. doi: 10.1016/j.jacc.2020.04.016). The summary also highlighted the need for regular ECG monitoring of COVID-19 patients who receive drugs that can prolong the QTc interval, and recommended withdrawing treatment from patients when their QTc exceeds the 500 msec threshold.

None of the authors of the two reports and editorial had relevant commercial disclosures.

[email protected]

The potential for serious arrhythmias from hydroxychloroquine treatment of COVID-19 patients received further documentation from a pair of studies released on May 1, casting further doubt on whether the uncertain benefit from this or related drugs to infected patients is worth the clear risks the agents pose.

A report from 90 confirmed COVID-19 patients treated with hydroxychloroquine at one Boston hospital during March-April 2020 identified a significantly prolonged, corrected QT (QTc) interval of at least 500 msec in 18 patients (20%), which included 10 patients whose QTc rose by at least 60 msec above baseline, and a total of 21 patients (23%) having a notable prolongation (JAMA Cardiol. 2020 May 4. doi: 10.1001/jamacardio.2020.1834). This series included one patient who developed torsades de pointes following treatment with hydroxychloroquine and azithromycin, “which to our knowledge has yet to be reported elsewhere in the literature,” the report said.

The second report, from a single center in Lyon, France, included 40 confirmed COVID-19 patients treated with hydroxychloroquine during 2 weeks in late March, and found that 37 (93%) had some increase in the QTc interval, including 14 patients (36%) with an increase of at least 60 msec, and 7 patients (18%) whose QTc rose to at least 500 msec (JAMA Cardiol. 2020 May. doi: 10.1001/jamacardio.2020.1787). However, none of the 40 patients in this series developed an identified ventricular arrhythmia. All patients in both studies received hydroxychloroquine for at least 1 day, and roughly half the patients in each series also received concurrent azithromycin, another drug that can prolong the QTc interval and that has been frequently used in combination with hydroxychloroquine as an unproven COVID-19 treatment cocktail.

These two reports, as well as prior report from Brazil on COVID-19 patients treated with chloroquine diphosphate (JAMA Netw Open. 2020;3[4]:e208857), “underscore the potential risk associated with widespread use of hydroxychloroquine and the combination of hydroxychloroquine and azithromycin in ambulatory patients with known or suspected COVID-19. Understanding whether this risk is worth taking in the absence of evidence of therapeutic efficacy creates a knowledge gap that needs to be addressed,” wrote Robert O. Bonow, MD, a professor of medicine at Northwestern University in Chicago, and coauthors in an editorial that accompanied the two reports (JAMA Cardiol. 2020 May 4;doi: 10.1001/jamacardio.2020.1782). The editorial cited two recently-begun prospective trials, ORCHID and RECOVERY, that are more systematically assessing the safety and efficacy of hydroxychloroquine treatment in COVID-19 patients.

The findings lend further support to a Safety Communication from the U.S. Food and Drug Administration on April 24 that reminded clinicians that the Emergency Use Authorization for hydroxychloroquine and chloroquine in COVID-19 patients that the FDA issued on March 28 applied to only certain hospitalized patients or those enrolled in clinical trials. The Safety Communication also said that agency was aware of reports of adverse arrhythmia events when COVID-19 patients received these drugs outside a hospital setting as well as uninfected people who had received one of these drugs for preventing infection.

In addition, leaders of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society on April 10 issued a summary of considerations when using hydroxychloroquine and azithromycin to treat COVID-19 patients, and noted that a way to minimized the risk from these drugs is to withhold them from patients with a QTc interval of 500 msec or greater at baseline (J Am Coll Cardiol. 2020 Apr 10. doi: 10.1016/j.jacc.2020.04.016). The summary also highlighted the need for regular ECG monitoring of COVID-19 patients who receive drugs that can prolong the QTc interval, and recommended withdrawing treatment from patients when their QTc exceeds the 500 msec threshold.

None of the authors of the two reports and editorial had relevant commercial disclosures.

[email protected]

The US Food and Drug Administration (FDA) issued an emergency use authorization on May 1 for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

The investigational antiviral drug, manufactured by Gilead Sciences Inc., was shown in a preliminary analysis of a National Institutes of Health (NIH) clinical trial to shorten recovery time in some patients, according to information presented during a White House press conference earlier this week. However, the results of the trial have not been published and little is known about how safe and effective it is in treating people in the hospital with COVID-19.

The emergency use authorization (EUA) designation means remdesivir can be distributed in the United States and administered intravenously by healthcare providers, as appropriate to treat severe disease. Those with severe disease, the FDA said in a press release, are patients with low blood oxygen levels or those who need oxygen therapy or more intensive support such as a mechanical ventilator.

“There’s tremendous interest among all parties to identify and arm ourselves with medicines to combat COVID-19, and through our Coronavirus Treatment Acceleration Program, the FDA is working around-the-clock and using every tool at our disposal to speed these efforts,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

The FDA writes, “Based on evaluation of the emergency use authorization criteria and the scientific evidence available, it was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use.”

The drug must be administered intravenously and the optimal dosing and duration are not yet known, the company said in a press release issued May 1.

In addition, Gilead advises that infusion-related reactions and liver transaminase elevations have been seen in patients treated with the drug.

“If signs and symptoms of a clinically significant infusion reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. Monitor renal and hepatic function prior to initiating and daily during therapy with remdesivir; additionally monitor serum chemistries and hematology daily during therapy,” the company said.

Before granting the emergency use authorization, the FDA had allowed for study of the drug in clinical trials, as well as expanded access use for individual patients and through a multipatient expanded access program coordinated by Gilead.

“The EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biologics for prevention and treatment of COVID-19 is terminated and may be revised or revoked if it is determined the EUA no longer meets the statutory criteria for issuance,” the FDA said.


This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) issued an emergency use authorization on May 1 for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

The investigational antiviral drug, manufactured by Gilead Sciences Inc., was shown in a preliminary analysis of a National Institutes of Health (NIH) clinical trial to shorten recovery time in some patients, according to information presented during a White House press conference earlier this week. However, the results of the trial have not been published and little is known about how safe and effective it is in treating people in the hospital with COVID-19.

The emergency use authorization (EUA) designation means remdesivir can be distributed in the United States and administered intravenously by healthcare providers, as appropriate to treat severe disease. Those with severe disease, the FDA said in a press release, are patients with low blood oxygen levels or those who need oxygen therapy or more intensive support such as a mechanical ventilator.

“There’s tremendous interest among all parties to identify and arm ourselves with medicines to combat COVID-19, and through our Coronavirus Treatment Acceleration Program, the FDA is working around-the-clock and using every tool at our disposal to speed these efforts,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

The FDA writes, “Based on evaluation of the emergency use authorization criteria and the scientific evidence available, it was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use.”

The drug must be administered intravenously and the optimal dosing and duration are not yet known, the company said in a press release issued May 1.

In addition, Gilead advises that infusion-related reactions and liver transaminase elevations have been seen in patients treated with the drug.

“If signs and symptoms of a clinically significant infusion reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. Monitor renal and hepatic function prior to initiating and daily during therapy with remdesivir; additionally monitor serum chemistries and hematology daily during therapy,” the company said.

Before granting the emergency use authorization, the FDA had allowed for study of the drug in clinical trials, as well as expanded access use for individual patients and through a multipatient expanded access program coordinated by Gilead.

“The EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biologics for prevention and treatment of COVID-19 is terminated and may be revised or revoked if it is determined the EUA no longer meets the statutory criteria for issuance,” the FDA said.


This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) issued an emergency use authorization on May 1 for remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in adults and children hospitalized with severe disease.

The investigational antiviral drug, manufactured by Gilead Sciences Inc., was shown in a preliminary analysis of a National Institutes of Health (NIH) clinical trial to shorten recovery time in some patients, according to information presented during a White House press conference earlier this week. However, the results of the trial have not been published and little is known about how safe and effective it is in treating people in the hospital with COVID-19.

The emergency use authorization (EUA) designation means remdesivir can be distributed in the United States and administered intravenously by healthcare providers, as appropriate to treat severe disease. Those with severe disease, the FDA said in a press release, are patients with low blood oxygen levels or those who need oxygen therapy or more intensive support such as a mechanical ventilator.

“There’s tremendous interest among all parties to identify and arm ourselves with medicines to combat COVID-19, and through our Coronavirus Treatment Acceleration Program, the FDA is working around-the-clock and using every tool at our disposal to speed these efforts,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

The FDA writes, “Based on evaluation of the emergency use authorization criteria and the scientific evidence available, it was determined that it is reasonable to believe that remdesivir may be effective in treating COVID-19, and that, given there are no adequate, approved, or available alternative treatments, the known and potential benefits to treat this serious or life-threatening virus currently outweigh the known and potential risks of the drug’s use.”

The drug must be administered intravenously and the optimal dosing and duration are not yet known, the company said in a press release issued May 1.

In addition, Gilead advises that infusion-related reactions and liver transaminase elevations have been seen in patients treated with the drug.

“If signs and symptoms of a clinically significant infusion reaction occur, immediately discontinue administration of remdesivir and initiate appropriate treatment. Patients should have appropriate clinical and laboratory monitoring to aid in early detection of any potential adverse events. Monitor renal and hepatic function prior to initiating and daily during therapy with remdesivir; additionally monitor serum chemistries and hematology daily during therapy,” the company said.

Before granting the emergency use authorization, the FDA had allowed for study of the drug in clinical trials, as well as expanded access use for individual patients and through a multipatient expanded access program coordinated by Gilead.

“The EUA will be effective until the declaration that circumstances exist justifying the authorization of the emergency use of drugs and biologics for prevention and treatment of COVID-19 is terminated and may be revised or revoked if it is determined the EUA no longer meets the statutory criteria for issuance,” the FDA said.


This article first appeared on Medscape.com.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Ustekinumab or a tumor necrosis factor inhibitor (TNFi) are better used alone than with methotrexate in the treatment of psoriatic arthritis suggest the results of PsABio (A Study on Assessment of STELARA and Tumor Necrosis Factor Alpha Inhibitor Therapies in Participants With Psoriatic Arthritis), a large, ongoing, prospective observational study.

The percentages of patients achieving multiple psoriatic arthritis disease activity outcome measures at 6 months were higher if biologic monotherapy was used rather than a biologic in combination with methotrexate.

For example, minimal disease activity (MDA) was achieved by 27.5% of patients taking ustekinumab as monotherapy and by 32.1% of those taking a TNFi alone. When methotrexate was used in combination, the respective percentages of patients achieving MDA were 23.7% and 27.8%.

A similar pattern was seen for very-low disease activity (VLDA), with 9.8% of patients in the ustekinumab monotherapy arm and 12% of those in the TNFi monotherapy arm achieving this target, compared with 5.7% and 5.4% when these drugs were combined with methotrexate.

MDA is defined as meeting five or more cutoffs for seven domains of disease activity, and VLDA for all seven: 0-1 tender joints, 0-1 swollen joints, Psoriasis Area Severity Index 1 or less or body surface area involved 3% or less, 0-1 tender entheseal points, Health Assessment Questionnaire score of 0.5 or less, patient global disease activity visual analog scale score of 20 or lower, and patient pain visual analog scale score of 15 or lower.

Other outcome measures used that showed no advantage of adding methotrexate to these biologics were the Clinical Disease Activity in Psoriatic Arthritis low disease activity and remission scores, the patient acceptable symptoms rate of the 12-item Psoriatic Arthritis Impact of Disease Questionnaire, and improvement in skin involvement.

“Patients were no more likely to achieve lower disease activity or a remission target having received methotrexate than they did just on the biologic drug on its own,” Stefan Siebert, MBBCh, PhD, one of the PsABio investigators, said in an interview.

Dr. Siebert, who is clinical senior lecturer in inflammation and rheumatology at the University of Glasgow (Scotland), was scheduled to present the findings at the British Society for Rheumatology annual conference. The meeting was canceled because of the ongoing COVID-19 crisis. Abstracts and ePosters from the meeting have since been released in a supplement to Rheumatology and via the BSR’s conference app.
 

First data for ustekinumab

“There certainly doesn’t appear to be any added benefit from using methotrexate on a group level in patients getting ustekinumab and TNF inhibitors,” Dr. Siebert said. “We’ve looked at everything,” he emphasized, and “none of the single domains or composite measures were improved by the addition of methotrexate. I think we knew that for TNF inhibitors, but the key thing is we’ve never known that for ustekinumab, and this is the first study to show that.”

Indeed, the findings match up with those from the SEAM-PsA (Etanercept and Methotrexate in Subjects with Psoriatic Arthritis) study in which patients who were treated with the TNFi etanercept as monotherapy did much better than those given the TNFi in combination with methotrexate or methotrexate alone. While not a randomized trial, PsABio now shows that the same is true for ustekinumab.

Obviously, there are some clear differences between a clinical trial and an observational study such as PsABio. For one thing, there was no randomization and patients taking methotrexate were presumably doing so for good reason, Dr. Siebert said. Secondly, there was no methotrexate-only arm.

PsABio recruited patients who were starting treatment with either ustekinumab or a new TNFi as first-, second-, or third-line biologic disease-modifying antirheumatic therapy (DMARD). “These are all people starting on a biologic, so they’ve already got severe disease and have failed methotrexate on some level. So everything we’ve done is biologic without methotrexate or biologic with methotrexate,” Dr. Siebert explained. Patients may not have been taking methotrexate for a variety of reasons, such as inefficacy or side effects, so PsABio “doesn’t tell us anything about methotrexate on its own.”

Time to rethink ingrained methotrexate use

The rationale for using methotrexate in combination with biologics in psoriatic arthritis comes from its long-standing use in rheumatoid arthritis. Much of what is advocated in guidelines comes from experience in RA, Dr. Siebert said.

“In rheumatoid arthritis, we know that the TNF inhibitors work much better if you use methotrexate, that’s a given,” he noted. “We’ve been trained that you have to have methotrexate to have a biologic. However, PsABio, together with other studies, show that you don’t have to, and you should have a good reason to add methotrexate.”

Individual patients may still benefit from methotrexate use, but the decision to treat all patients the same is not supported by the current evidence. “It’s good that it shows that, actually, once you get someone on a decent biologic, it’s working: It’s doing what it ‘says on the tin’ for a lot of patients. I really think that is the key message, here, that you don’t have to; this reassures clinicians and actually makes them think ‘should this patient be on methotrexate?’ ” Dr. Siebert said.

The PsABio study was funded by Janssen. Dr. Siebert has acted as a consultant to and received research funding from Janssen, UCB, Pfizer, Boehringer Ingelheim, Novartis, and Celgene. He has also acted as a consultant for AbbVie and received research support from Bristol-Myers Squibb.

SOURCE: Siebert S et al. Rheumatology. 2020;59(Suppl 2). doi: 10.1093/rheumatology/keaa110.023, Abstract O24.

Initial data from one Chinese center on the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients hospitalized with COVID-19 appear to give some further reassurance about continued use of these drugs.

The report from one hospital in Wuhan found that among patients with hypertension hospitalized with the COVID-19 virus, there was no difference in disease severity or death rate in patients taking ACE inhibitors or ARBs and those not taking such medications.

The data were published online April 23 in JAMA Cardiology.

The study adds to another recent report in a larger number of COVID-19 patients from nine Chinese hospitals that suggested a beneficial effect of ACE inhibitors or ARBs on mortality.

Additional studies

Two other similar studies have also been recently released. Another study from China, published online March 31 in Emerging Microbes & Infections, included a small sample of 42 hospitalized patients with COVID-19 on antihypertensive therapy. Those on ACE inhibitor/ARB therapy had a lower rate of severe disease and a trend toward a lower level of IL-6 in peripheral blood. In addition, patients on ACE inhibitor/ARB therapy had increased CD3+ and CD8+ T-cell counts in peripheral blood and decreased peak viral load compared with other antihypertensive drugs.

And a preliminary study from the UK, which has not yet been peer reviewed, found that treatment with ACE inhibitors was associated with a reduced risk of rapidly deteriorating severe COVID-19 disease.

The study, available online on MedRxiv, a preprint server for health sciences, reports on 205 acute inpatients with COVID-19 at King’s College Hospital and Princess Royal University Hospital, London.

Of these, 51.2% had hypertension, 30.2% had diabetes, and 14.6% had ischemic heart disease or heart failure. Of the 37 patients on ACE inhibitors, five (14%) died or required critical care support compared with 29% (48/168) of patients not taking an ACE inhibitor.
 

New Wuhan study

The authors of the new article published in JAMA Cardiology, led by Juyi Li, MD, reported on a case series of 1,178 patients hospitalized with COVID-19 at the Central Hospital of Wuhan, Hubei, China, between Jan. 15 and March 15, 2020.

Patients were a median age of 55 years, and 46% were men. They had an overall in-hospital mortality rate of 11%.

Of the 1,178 patients, 362 (30.7%) had a diagnosis of hypertension. These patients were older (median age, 66 years) and had a greater prevalence of chronic diseases. Patients with hypertension also had more severe manifestations of COVID-19 compared to those without hypertension, including higher rates of acute respiratory distress syndrome and in-hospital mortality (21.3% vs. 6.5%).

Of the 362 patients with hypertension, 31.8% were taking ACE inhibitors or ARBs.

Apart from a greater prevalence of coronary artery disease, patients taking ACE inhibitors or ARBs had similar comorbidities to those not taking these medications, and also similar laboratory profile results including blood counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers, although those taking ACE inhibitors/ARBs had higher levels of alkaline phosphatase.

The most commonly used antihypertensive drugs were calcium blockers. The percentage of patients with hypertension taking any drug or drug combination did not differ between those with severe and nonsevere infections and between those who survived and those who died.

Specifically regarding ACE inhibitors/ARBs, there was no difference between those with severe versus nonsevere illness in the use of ACE inhibitors (9.2% vs. 10.1%; P = .80), ARBs (24.9% vs. 21.2%; P = .40), or the composite of ACE inhibitors or ARBs (32.9% vs. 30.7%; P = .65).

Similarly, there were no differences in nonsurvivors and survivors in the use of ACE inhibitors (9.1% vs. 9.8%; P = .85); ARBs (19.5% vs. 23.9%; P = .42), or the composite of ACE inhibitors or ARBs (27.3% vs. 33.0%; P = .34).

The frequency of severe illness and death also did not differ between those treated with and without ACE inhibitors/ARBs in patients with hypertension and other various chronic conditions including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease.

The authors noted that these data confirm previous reports showing that patients with hypertension have more severe illness and higher mortality rates associated with COVID-19 than those without hypertension.

But they added: “Our data provide some reassurance that ACE inhibitors/ARBs are not associated with the progression or outcome of COVID-19 hospitalizations in patients with hypertension.”

They also noted that these results support the recommendations from almost all major cardiovascular societies that patients do not discontinue ACE inhibitors or ARBs because of worries about COVID-19.

However, the authors did point out some limitations of their study, which included a small number of patients with hypertension taking ACE inhibitors or ARBs and the fact that a nonsevere disease course was still severe enough to require hospitalization. In addition, it was not clear whether ACE inhibitor/ARB treatment at baseline was maintained throughout hospitalization for all patients.

This was also an observational comparison and may be biased by differences in patients taking versus not taking ACE inhibitors or ARBs at the time of hospitalization, although the measured baseline characteristics were similar in both groups.

But the authors also highlighted the finding that, in this cohort, patients with hypertension had three times the mortality rate of all other patients hospitalized with COVID-19.

“Hypertension combined with cardiovascular and cerebrovascular disease, diabetes, and chronic kidney disease would predispose patients to an increased risk of severity and mortality of COVID-19. Therefore, patients with these underlying conditions who develop COVID-19 require particularly intensive surveillance and care,” they wrote.
 

Experts cautiously optimistic

Some cardiovascular experts were cautiously optimistic about these latest results.

Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, and editor-in-chief of the Journal of Clinical Hypertension, said: “This new report from Wuhan, China, gives modest reassurance that the use of ACE inhibitors or ARBs in hypertensive patients with COVID-19 disease does not increase the risk of clinical deterioration or death.

“Ongoing, more definitive studies should help resolve competing hypotheses regarding the effects of these agents: whether the increased ACE2 enzyme levels they produce can worsen outcomes by increasing access of the COVID virus to lung tissue; or whether there is a benefit linked to a protective effect of increased ACE2 on alveolar cell function,” Dr. Weber noted.

“Though the number of patients included in this new report is small, it is startling that hypertensive patients were three times as likely as nonhypertensives to have a fatal outcome, presumably reflecting vulnerability due to the cardiovascular and metabolic comorbidities associated with hypertension,” he added.

“In any case, for now, clinicians should continue treating hypertensive patients with whichever drugs, including ACE inhibitors and ARBs, best provide protection from adverse outcomes,” Dr. Weber concluded.

John McMurray, MD, professor of medical cardiology, University of Glasgow, Scotland, commented: “This study from Wuhan provides some reassurance about one of the two questions about ACEI/ARBs: Do these drugs increase susceptibility to infection? And if [the patient is] infected, do they increase the severity of infection? This study addresses the latter question and appears to suggest no increased severity.”

However, Dr. McMurray pointed out that the study had many limitations. There were only small patient numbers and the data were unadjusted, “although it looks like the ACE inhibitor/ARB treated patients were higher risk to start with.” It was an observational study, and patients were not randomized and were predominantly treated with ARBs, and not ACE inhibitors, so “we don’t know if the concerns apply equally to these two classes of drug.

“Other data published and unpublished supporting this (even showing better outcomes in patients treated with an ACE inhibitor/ARB), and, to date, any concerns about these drugs remain unsubstantiated and the guidance from medical societies to continue treatment with these agents in patients prescribed them seems wise,” Dr. McMurray added.

Franz H. Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “The study from Wuhan is not a great study. They didn’t even do a multivariable analysis. They could have done a bit more with the data, but it still gives some reassurance.”

Dr. Messerli said it was “interesting” that 30% of the patients hospitalized with COVID-19 in the sample had hypertension. “That corresponds to the general population, so does not suggest that having hypertension increases susceptibility to infection – but it does seem to increase the risk of a bad outcome.”

Dr. Messerli noted that there are two more similar studies due to be published soon, both said to suggest either a beneficial or neutral effect of ACE inhibitors/ARBs on COVID-19 outcomes in hospitalized patients.

“This does help with confidence in prescribing these agents and reinforces the recommendations for patients to stay on these drugs,” he said.

“However, none of these studies address the infectivity issue – whether their use upregulates the ACE2 receptor, which the virus uses to gain entry to cells, thereby increasing susceptibility to the infection,” Dr. Messerli cautioned. “But the similar or better outcomes on these drugs are encouraging,” he added.

The Wuhan study was supported by the Health and Family Planning Commission of Wuhan City, China. The authors have reported no relevant financial relationships.

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

Initial data from one Chinese center on the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients hospitalized with COVID-19 appear to give some further reassurance about continued use of these drugs.

The report from one hospital in Wuhan found that among patients with hypertension hospitalized with the COVID-19 virus, there was no difference in disease severity or death rate in patients taking ACE inhibitors or ARBs and those not taking such medications.

The data were published online April 23 in JAMA Cardiology.

The study adds to another recent report in a larger number of COVID-19 patients from nine Chinese hospitals that suggested a beneficial effect of ACE inhibitors or ARBs on mortality.

Additional studies

Two other similar studies have also been recently released. Another study from China, published online March 31 in Emerging Microbes & Infections, included a small sample of 42 hospitalized patients with COVID-19 on antihypertensive therapy. Those on ACE inhibitor/ARB therapy had a lower rate of severe disease and a trend toward a lower level of IL-6 in peripheral blood. In addition, patients on ACE inhibitor/ARB therapy had increased CD3+ and CD8+ T-cell counts in peripheral blood and decreased peak viral load compared with other antihypertensive drugs.

And a preliminary study from the UK, which has not yet been peer reviewed, found that treatment with ACE inhibitors was associated with a reduced risk of rapidly deteriorating severe COVID-19 disease.

The study, available online on MedRxiv, a preprint server for health sciences, reports on 205 acute inpatients with COVID-19 at King’s College Hospital and Princess Royal University Hospital, London.

Of these, 51.2% had hypertension, 30.2% had diabetes, and 14.6% had ischemic heart disease or heart failure. Of the 37 patients on ACE inhibitors, five (14%) died or required critical care support compared with 29% (48/168) of patients not taking an ACE inhibitor.
 

New Wuhan study

The authors of the new article published in JAMA Cardiology, led by Juyi Li, MD, reported on a case series of 1,178 patients hospitalized with COVID-19 at the Central Hospital of Wuhan, Hubei, China, between Jan. 15 and March 15, 2020.

Patients were a median age of 55 years, and 46% were men. They had an overall in-hospital mortality rate of 11%.

Of the 1,178 patients, 362 (30.7%) had a diagnosis of hypertension. These patients were older (median age, 66 years) and had a greater prevalence of chronic diseases. Patients with hypertension also had more severe manifestations of COVID-19 compared to those without hypertension, including higher rates of acute respiratory distress syndrome and in-hospital mortality (21.3% vs. 6.5%).

Of the 362 patients with hypertension, 31.8% were taking ACE inhibitors or ARBs.

Apart from a greater prevalence of coronary artery disease, patients taking ACE inhibitors or ARBs had similar comorbidities to those not taking these medications, and also similar laboratory profile results including blood counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers, although those taking ACE inhibitors/ARBs had higher levels of alkaline phosphatase.

The most commonly used antihypertensive drugs were calcium blockers. The percentage of patients with hypertension taking any drug or drug combination did not differ between those with severe and nonsevere infections and between those who survived and those who died.

Specifically regarding ACE inhibitors/ARBs, there was no difference between those with severe versus nonsevere illness in the use of ACE inhibitors (9.2% vs. 10.1%; P = .80), ARBs (24.9% vs. 21.2%; P = .40), or the composite of ACE inhibitors or ARBs (32.9% vs. 30.7%; P = .65).

Similarly, there were no differences in nonsurvivors and survivors in the use of ACE inhibitors (9.1% vs. 9.8%; P = .85); ARBs (19.5% vs. 23.9%; P = .42), or the composite of ACE inhibitors or ARBs (27.3% vs. 33.0%; P = .34).

The frequency of severe illness and death also did not differ between those treated with and without ACE inhibitors/ARBs in patients with hypertension and other various chronic conditions including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease.

The authors noted that these data confirm previous reports showing that patients with hypertension have more severe illness and higher mortality rates associated with COVID-19 than those without hypertension.

But they added: “Our data provide some reassurance that ACE inhibitors/ARBs are not associated with the progression or outcome of COVID-19 hospitalizations in patients with hypertension.”

They also noted that these results support the recommendations from almost all major cardiovascular societies that patients do not discontinue ACE inhibitors or ARBs because of worries about COVID-19.

However, the authors did point out some limitations of their study, which included a small number of patients with hypertension taking ACE inhibitors or ARBs and the fact that a nonsevere disease course was still severe enough to require hospitalization. In addition, it was not clear whether ACE inhibitor/ARB treatment at baseline was maintained throughout hospitalization for all patients.

This was also an observational comparison and may be biased by differences in patients taking versus not taking ACE inhibitors or ARBs at the time of hospitalization, although the measured baseline characteristics were similar in both groups.

But the authors also highlighted the finding that, in this cohort, patients with hypertension had three times the mortality rate of all other patients hospitalized with COVID-19.

“Hypertension combined with cardiovascular and cerebrovascular disease, diabetes, and chronic kidney disease would predispose patients to an increased risk of severity and mortality of COVID-19. Therefore, patients with these underlying conditions who develop COVID-19 require particularly intensive surveillance and care,” they wrote.
 

Experts cautiously optimistic

Some cardiovascular experts were cautiously optimistic about these latest results.

Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, and editor-in-chief of the Journal of Clinical Hypertension, said: “This new report from Wuhan, China, gives modest reassurance that the use of ACE inhibitors or ARBs in hypertensive patients with COVID-19 disease does not increase the risk of clinical deterioration or death.

“Ongoing, more definitive studies should help resolve competing hypotheses regarding the effects of these agents: whether the increased ACE2 enzyme levels they produce can worsen outcomes by increasing access of the COVID virus to lung tissue; or whether there is a benefit linked to a protective effect of increased ACE2 on alveolar cell function,” Dr. Weber noted.

“Though the number of patients included in this new report is small, it is startling that hypertensive patients were three times as likely as nonhypertensives to have a fatal outcome, presumably reflecting vulnerability due to the cardiovascular and metabolic comorbidities associated with hypertension,” he added.

“In any case, for now, clinicians should continue treating hypertensive patients with whichever drugs, including ACE inhibitors and ARBs, best provide protection from adverse outcomes,” Dr. Weber concluded.

John McMurray, MD, professor of medical cardiology, University of Glasgow, Scotland, commented: “This study from Wuhan provides some reassurance about one of the two questions about ACEI/ARBs: Do these drugs increase susceptibility to infection? And if [the patient is] infected, do they increase the severity of infection? This study addresses the latter question and appears to suggest no increased severity.”

However, Dr. McMurray pointed out that the study had many limitations. There were only small patient numbers and the data were unadjusted, “although it looks like the ACE inhibitor/ARB treated patients were higher risk to start with.” It was an observational study, and patients were not randomized and were predominantly treated with ARBs, and not ACE inhibitors, so “we don’t know if the concerns apply equally to these two classes of drug.

“Other data published and unpublished supporting this (even showing better outcomes in patients treated with an ACE inhibitor/ARB), and, to date, any concerns about these drugs remain unsubstantiated and the guidance from medical societies to continue treatment with these agents in patients prescribed them seems wise,” Dr. McMurray added.

Franz H. Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “The study from Wuhan is not a great study. They didn’t even do a multivariable analysis. They could have done a bit more with the data, but it still gives some reassurance.”

Dr. Messerli said it was “interesting” that 30% of the patients hospitalized with COVID-19 in the sample had hypertension. “That corresponds to the general population, so does not suggest that having hypertension increases susceptibility to infection – but it does seem to increase the risk of a bad outcome.”

Dr. Messerli noted that there are two more similar studies due to be published soon, both said to suggest either a beneficial or neutral effect of ACE inhibitors/ARBs on COVID-19 outcomes in hospitalized patients.

“This does help with confidence in prescribing these agents and reinforces the recommendations for patients to stay on these drugs,” he said.

“However, none of these studies address the infectivity issue – whether their use upregulates the ACE2 receptor, which the virus uses to gain entry to cells, thereby increasing susceptibility to the infection,” Dr. Messerli cautioned. “But the similar or better outcomes on these drugs are encouraging,” he added.

The Wuhan study was supported by the Health and Family Planning Commission of Wuhan City, China. The authors have reported no relevant financial relationships.

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

Initial data from one Chinese center on the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in patients hospitalized with COVID-19 appear to give some further reassurance about continued use of these drugs.

The report from one hospital in Wuhan found that among patients with hypertension hospitalized with the COVID-19 virus, there was no difference in disease severity or death rate in patients taking ACE inhibitors or ARBs and those not taking such medications.

The data were published online April 23 in JAMA Cardiology.

The study adds to another recent report in a larger number of COVID-19 patients from nine Chinese hospitals that suggested a beneficial effect of ACE inhibitors or ARBs on mortality.

Additional studies

Two other similar studies have also been recently released. Another study from China, published online March 31 in Emerging Microbes & Infections, included a small sample of 42 hospitalized patients with COVID-19 on antihypertensive therapy. Those on ACE inhibitor/ARB therapy had a lower rate of severe disease and a trend toward a lower level of IL-6 in peripheral blood. In addition, patients on ACE inhibitor/ARB therapy had increased CD3+ and CD8+ T-cell counts in peripheral blood and decreased peak viral load compared with other antihypertensive drugs.

And a preliminary study from the UK, which has not yet been peer reviewed, found that treatment with ACE inhibitors was associated with a reduced risk of rapidly deteriorating severe COVID-19 disease.

The study, available online on MedRxiv, a preprint server for health sciences, reports on 205 acute inpatients with COVID-19 at King’s College Hospital and Princess Royal University Hospital, London.

Of these, 51.2% had hypertension, 30.2% had diabetes, and 14.6% had ischemic heart disease or heart failure. Of the 37 patients on ACE inhibitors, five (14%) died or required critical care support compared with 29% (48/168) of patients not taking an ACE inhibitor.
 

New Wuhan study

The authors of the new article published in JAMA Cardiology, led by Juyi Li, MD, reported on a case series of 1,178 patients hospitalized with COVID-19 at the Central Hospital of Wuhan, Hubei, China, between Jan. 15 and March 15, 2020.

Patients were a median age of 55 years, and 46% were men. They had an overall in-hospital mortality rate of 11%.

Of the 1,178 patients, 362 (30.7%) had a diagnosis of hypertension. These patients were older (median age, 66 years) and had a greater prevalence of chronic diseases. Patients with hypertension also had more severe manifestations of COVID-19 compared to those without hypertension, including higher rates of acute respiratory distress syndrome and in-hospital mortality (21.3% vs. 6.5%).

Of the 362 patients with hypertension, 31.8% were taking ACE inhibitors or ARBs.

Apart from a greater prevalence of coronary artery disease, patients taking ACE inhibitors or ARBs had similar comorbidities to those not taking these medications, and also similar laboratory profile results including blood counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers, although those taking ACE inhibitors/ARBs had higher levels of alkaline phosphatase.

The most commonly used antihypertensive drugs were calcium blockers. The percentage of patients with hypertension taking any drug or drug combination did not differ between those with severe and nonsevere infections and between those who survived and those who died.

Specifically regarding ACE inhibitors/ARBs, there was no difference between those with severe versus nonsevere illness in the use of ACE inhibitors (9.2% vs. 10.1%; P = .80), ARBs (24.9% vs. 21.2%; P = .40), or the composite of ACE inhibitors or ARBs (32.9% vs. 30.7%; P = .65).

Similarly, there were no differences in nonsurvivors and survivors in the use of ACE inhibitors (9.1% vs. 9.8%; P = .85); ARBs (19.5% vs. 23.9%; P = .42), or the composite of ACE inhibitors or ARBs (27.3% vs. 33.0%; P = .34).

The frequency of severe illness and death also did not differ between those treated with and without ACE inhibitors/ARBs in patients with hypertension and other various chronic conditions including coronary heart disease, cerebrovascular disease, diabetes, neurological disease, and chronic renal disease.

The authors noted that these data confirm previous reports showing that patients with hypertension have more severe illness and higher mortality rates associated with COVID-19 than those without hypertension.

But they added: “Our data provide some reassurance that ACE inhibitors/ARBs are not associated with the progression or outcome of COVID-19 hospitalizations in patients with hypertension.”

They also noted that these results support the recommendations from almost all major cardiovascular societies that patients do not discontinue ACE inhibitors or ARBs because of worries about COVID-19.

However, the authors did point out some limitations of their study, which included a small number of patients with hypertension taking ACE inhibitors or ARBs and the fact that a nonsevere disease course was still severe enough to require hospitalization. In addition, it was not clear whether ACE inhibitor/ARB treatment at baseline was maintained throughout hospitalization for all patients.

This was also an observational comparison and may be biased by differences in patients taking versus not taking ACE inhibitors or ARBs at the time of hospitalization, although the measured baseline characteristics were similar in both groups.

But the authors also highlighted the finding that, in this cohort, patients with hypertension had three times the mortality rate of all other patients hospitalized with COVID-19.

“Hypertension combined with cardiovascular and cerebrovascular disease, diabetes, and chronic kidney disease would predispose patients to an increased risk of severity and mortality of COVID-19. Therefore, patients with these underlying conditions who develop COVID-19 require particularly intensive surveillance and care,” they wrote.
 

Experts cautiously optimistic

Some cardiovascular experts were cautiously optimistic about these latest results.

Michael A. Weber, MD, professor of medicine at the State University of New York, Brooklyn, and editor-in-chief of the Journal of Clinical Hypertension, said: “This new report from Wuhan, China, gives modest reassurance that the use of ACE inhibitors or ARBs in hypertensive patients with COVID-19 disease does not increase the risk of clinical deterioration or death.

“Ongoing, more definitive studies should help resolve competing hypotheses regarding the effects of these agents: whether the increased ACE2 enzyme levels they produce can worsen outcomes by increasing access of the COVID virus to lung tissue; or whether there is a benefit linked to a protective effect of increased ACE2 on alveolar cell function,” Dr. Weber noted.

“Though the number of patients included in this new report is small, it is startling that hypertensive patients were three times as likely as nonhypertensives to have a fatal outcome, presumably reflecting vulnerability due to the cardiovascular and metabolic comorbidities associated with hypertension,” he added.

“In any case, for now, clinicians should continue treating hypertensive patients with whichever drugs, including ACE inhibitors and ARBs, best provide protection from adverse outcomes,” Dr. Weber concluded.

John McMurray, MD, professor of medical cardiology, University of Glasgow, Scotland, commented: “This study from Wuhan provides some reassurance about one of the two questions about ACEI/ARBs: Do these drugs increase susceptibility to infection? And if [the patient is] infected, do they increase the severity of infection? This study addresses the latter question and appears to suggest no increased severity.”

However, Dr. McMurray pointed out that the study had many limitations. There were only small patient numbers and the data were unadjusted, “although it looks like the ACE inhibitor/ARB treated patients were higher risk to start with.” It was an observational study, and patients were not randomized and were predominantly treated with ARBs, and not ACE inhibitors, so “we don’t know if the concerns apply equally to these two classes of drug.

“Other data published and unpublished supporting this (even showing better outcomes in patients treated with an ACE inhibitor/ARB), and, to date, any concerns about these drugs remain unsubstantiated and the guidance from medical societies to continue treatment with these agents in patients prescribed them seems wise,” Dr. McMurray added.

Franz H. Messerli, MD, professor of medicine at the University of Bern, Switzerland, commented: “The study from Wuhan is not a great study. They didn’t even do a multivariable analysis. They could have done a bit more with the data, but it still gives some reassurance.”

Dr. Messerli said it was “interesting” that 30% of the patients hospitalized with COVID-19 in the sample had hypertension. “That corresponds to the general population, so does not suggest that having hypertension increases susceptibility to infection – but it does seem to increase the risk of a bad outcome.”

Dr. Messerli noted that there are two more similar studies due to be published soon, both said to suggest either a beneficial or neutral effect of ACE inhibitors/ARBs on COVID-19 outcomes in hospitalized patients.

“This does help with confidence in prescribing these agents and reinforces the recommendations for patients to stay on these drugs,” he said.

“However, none of these studies address the infectivity issue – whether their use upregulates the ACE2 receptor, which the virus uses to gain entry to cells, thereby increasing susceptibility to the infection,” Dr. Messerli cautioned. “But the similar or better outcomes on these drugs are encouraging,” he added.

The Wuhan study was supported by the Health and Family Planning Commission of Wuhan City, China. The authors have reported no relevant financial relationships.

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

International Laboratories has initiated a voluntary recall to the consumer level in the United States of a single lot of the antiplatelet clopidogrel because it is mislabeled and may contain simvastatin, a cholesterol-lowering drug, instead of clopidogrel.

The recalled product ― lot number 117099A of clopidogrel tablets (USP 75 mg) packaged in bottles of 30 tablets ― may contain clopidogrel 75 mg tablets or it could contain simvastatin tablets (USP 10 mg), according to a company announcement posted on the US Food and Drug Administration (FDA) website.

“Missed doses of clopidogrel increases the risk of heart attack and stroke which can be life threatening. Additionally, unintentional consumption of simvastatin could include the common side effects associated with its use and may cause fetal harm when administered to a pregnant woman,” the company cautions.

To date, the company has not received any reports of harm arising from the problem that prompted the recall.

The recalled product was distributed nationwide and was delivered to distribution centers in Arkansas, Georgia, Indiana, California, and Maryland and to retail stores in all US states.

International Laboratories is notifying distributors and customers by letter and is arranging for the return of all recalled products.

For questions regarding this recall, contact Inmar by phone 855-258-7280 (weekdays between 9:00 AM and 5:00 PM EST) or by email at [email protected].

Adverse reactions or quality problems experienced with the use of this product should be reported to the FDA’s MedWatch adverse event reporting program.
 

This article first appeared on Medscape.com.

International Laboratories has initiated a voluntary recall to the consumer level in the United States of a single lot of the antiplatelet clopidogrel because it is mislabeled and may contain simvastatin, a cholesterol-lowering drug, instead of clopidogrel.

The recalled product ― lot number 117099A of clopidogrel tablets (USP 75 mg) packaged in bottles of 30 tablets ― may contain clopidogrel 75 mg tablets or it could contain simvastatin tablets (USP 10 mg), according to a company announcement posted on the US Food and Drug Administration (FDA) website.

“Missed doses of clopidogrel increases the risk of heart attack and stroke which can be life threatening. Additionally, unintentional consumption of simvastatin could include the common side effects associated with its use and may cause fetal harm when administered to a pregnant woman,” the company cautions.

To date, the company has not received any reports of harm arising from the problem that prompted the recall.

The recalled product was distributed nationwide and was delivered to distribution centers in Arkansas, Georgia, Indiana, California, and Maryland and to retail stores in all US states.

International Laboratories is notifying distributors and customers by letter and is arranging for the return of all recalled products.

For questions regarding this recall, contact Inmar by phone 855-258-7280 (weekdays between 9:00 AM and 5:00 PM EST) or by email at [email protected].

Adverse reactions or quality problems experienced with the use of this product should be reported to the FDA’s MedWatch adverse event reporting program.
 

This article first appeared on Medscape.com.

International Laboratories has initiated a voluntary recall to the consumer level in the United States of a single lot of the antiplatelet clopidogrel because it is mislabeled and may contain simvastatin, a cholesterol-lowering drug, instead of clopidogrel.

The recalled product ― lot number 117099A of clopidogrel tablets (USP 75 mg) packaged in bottles of 30 tablets ― may contain clopidogrel 75 mg tablets or it could contain simvastatin tablets (USP 10 mg), according to a company announcement posted on the US Food and Drug Administration (FDA) website.

“Missed doses of clopidogrel increases the risk of heart attack and stroke which can be life threatening. Additionally, unintentional consumption of simvastatin could include the common side effects associated with its use and may cause fetal harm when administered to a pregnant woman,” the company cautions.

To date, the company has not received any reports of harm arising from the problem that prompted the recall.

The recalled product was distributed nationwide and was delivered to distribution centers in Arkansas, Georgia, Indiana, California, and Maryland and to retail stores in all US states.

International Laboratories is notifying distributors and customers by letter and is arranging for the return of all recalled products.

For questions regarding this recall, contact Inmar by phone 855-258-7280 (weekdays between 9:00 AM and 5:00 PM EST) or by email at [email protected].

Adverse reactions or quality problems experienced with the use of this product should be reported to the FDA’s MedWatch adverse event reporting program.
 

This article first appeared on Medscape.com.

The nation’s leading cardiology associations urged caution with hydroxychloroquine and azithromycin for COVID-19 in patients with cardiovascular disease.

Thinkstock

“Hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for COVID-19; both drugs are listed as definite causes of torsade de pointes” and increase in the risk of other arrhythmias and sudden death, the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society said in a joint statement April 8 in Circulation.

The statement came amid ongoing promotion by the Trump administration of hydroxychloroquine, in particular, for COVID-19 despite lack of strong data.

In addition to underlying cardiovascular disease, “seriously ill patients often have comorbidities that can increase risk of serious arrhythmias,” including hypokalemia, hypomagnesemia, fever, and systemic inflammation, the groups said.

They recommended withholding the drugs in patients with baseline QT prolongation (e.g., QTc of at least 500 msec) or with known congenital long QT syndrome; monitoring cardiac rhythm and QT interval and withdrawing hydroxychloroquine and azithromycin if QTc exceeds 500 msec; correcting hypokalemia to levels greater than 4 mEq/L and hypomagnesemia to more than 2 mg/dL; and avoiding other QTc-prolonging agents when possible.

The groups noted that, “in patients critically ill with COVID-19 infection, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible.” There is also a possible compounding arrhythmic effect when hydroxychloroquine and azithromycin are used together, but that has not been studied.

There’s a known risk of torsade de pointes with chloroquine and a possible risk with the antiviral HIV combination drug lopinavir-ritonavir, two other candidates for COVID-19 treatment. Hydroxychloroquine and chloroquine, both antimalarials, might help prevent or treat infection by interfering with angiotensin-converting enzyme 2 receptors, which the COVID-19 virus uses for cell entry, the groups said.

“The urgency of COVID-19 must not diminish the scientific rigor with which we approach COVID-19 treatment. While these medications may work against COVID-19 individually or in combination, we recommend caution with these medications for patients with existing cardiovascular disease,” Robert A. Harrington, MD, AHA president and chair of the department of medicine at Stanford (Calif.) University, emphasized in a press release.

[email protected]

SOURCE: Roden DM et al. Circulation. 2020 Apr 8. doi:10.1161/CIRCULATIONAHA.120.047521.

The nation’s leading cardiology associations urged caution with hydroxychloroquine and azithromycin for COVID-19 in patients with cardiovascular disease.

Thinkstock

“Hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for COVID-19; both drugs are listed as definite causes of torsade de pointes” and increase in the risk of other arrhythmias and sudden death, the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society said in a joint statement April 8 in Circulation.

The statement came amid ongoing promotion by the Trump administration of hydroxychloroquine, in particular, for COVID-19 despite lack of strong data.

In addition to underlying cardiovascular disease, “seriously ill patients often have comorbidities that can increase risk of serious arrhythmias,” including hypokalemia, hypomagnesemia, fever, and systemic inflammation, the groups said.

They recommended withholding the drugs in patients with baseline QT prolongation (e.g., QTc of at least 500 msec) or with known congenital long QT syndrome; monitoring cardiac rhythm and QT interval and withdrawing hydroxychloroquine and azithromycin if QTc exceeds 500 msec; correcting hypokalemia to levels greater than 4 mEq/L and hypomagnesemia to more than 2 mg/dL; and avoiding other QTc-prolonging agents when possible.

The groups noted that, “in patients critically ill with COVID-19 infection, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible.” There is also a possible compounding arrhythmic effect when hydroxychloroquine and azithromycin are used together, but that has not been studied.

There’s a known risk of torsade de pointes with chloroquine and a possible risk with the antiviral HIV combination drug lopinavir-ritonavir, two other candidates for COVID-19 treatment. Hydroxychloroquine and chloroquine, both antimalarials, might help prevent or treat infection by interfering with angiotensin-converting enzyme 2 receptors, which the COVID-19 virus uses for cell entry, the groups said.

“The urgency of COVID-19 must not diminish the scientific rigor with which we approach COVID-19 treatment. While these medications may work against COVID-19 individually or in combination, we recommend caution with these medications for patients with existing cardiovascular disease,” Robert A. Harrington, MD, AHA president and chair of the department of medicine at Stanford (Calif.) University, emphasized in a press release.

[email protected]

SOURCE: Roden DM et al. Circulation. 2020 Apr 8. doi:10.1161/CIRCULATIONAHA.120.047521.

The nation’s leading cardiology associations urged caution with hydroxychloroquine and azithromycin for COVID-19 in patients with cardiovascular disease.

Thinkstock

“Hydroxychloroquine and azithromycin have been touted for potential prophylaxis or treatment for COVID-19; both drugs are listed as definite causes of torsade de pointes” and increase in the risk of other arrhythmias and sudden death, the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society said in a joint statement April 8 in Circulation.

The statement came amid ongoing promotion by the Trump administration of hydroxychloroquine, in particular, for COVID-19 despite lack of strong data.

In addition to underlying cardiovascular disease, “seriously ill patients often have comorbidities that can increase risk of serious arrhythmias,” including hypokalemia, hypomagnesemia, fever, and systemic inflammation, the groups said.

They recommended withholding the drugs in patients with baseline QT prolongation (e.g., QTc of at least 500 msec) or with known congenital long QT syndrome; monitoring cardiac rhythm and QT interval and withdrawing hydroxychloroquine and azithromycin if QTc exceeds 500 msec; correcting hypokalemia to levels greater than 4 mEq/L and hypomagnesemia to more than 2 mg/dL; and avoiding other QTc-prolonging agents when possible.

The groups noted that, “in patients critically ill with COVID-19 infection, frequent caregiver contact may need to be minimized, so optimal electrocardiographic interval and rhythm monitoring may not be possible.” There is also a possible compounding arrhythmic effect when hydroxychloroquine and azithromycin are used together, but that has not been studied.

There’s a known risk of torsade de pointes with chloroquine and a possible risk with the antiviral HIV combination drug lopinavir-ritonavir, two other candidates for COVID-19 treatment. Hydroxychloroquine and chloroquine, both antimalarials, might help prevent or treat infection by interfering with angiotensin-converting enzyme 2 receptors, which the COVID-19 virus uses for cell entry, the groups said.

“The urgency of COVID-19 must not diminish the scientific rigor with which we approach COVID-19 treatment. While these medications may work against COVID-19 individually or in combination, we recommend caution with these medications for patients with existing cardiovascular disease,” Robert A. Harrington, MD, AHA president and chair of the department of medicine at Stanford (Calif.) University, emphasized in a press release.

[email protected]

SOURCE: Roden DM et al. Circulation. 2020 Apr 8. doi:10.1161/CIRCULATIONAHA.120.047521.

Beyond asthma and chronic obstructive pulmonary disease (COPD), inhalation therapy is a mainstay in the management of bronchiectasis, cystic fibrosis, and pulmonary artery hypertension. Several US Food and Drug Administration off-label indications for inhalational medications include hypoxia secondary to acute respiratory distress syndrome (ARDS) and intraoperative and postoperative pulmonary hypertension during and following cardiac surgery, respectively.^1-11 Therapeutic delivery of aerosols to the lung may be provided via nebulization, pressurized metered-dose inhalers (pMDI), and other devices (eg, dry powder inhalers, soft-mist inhalers, and smart inhalers).¹² The most common aerosolized medications given in the clinical setting are bronchodilators.¹²

Product selection is often guided by practice guidelines (Table 1), consideration of the formulation’s advantages and disadvantages (Table 2), and/or formulary considerations. For example, current guidelines for COPD state that there is no evidence for superiority of nebulized bronchodilator therapy over handheld devices in patients who can use them properly.² Due to equivalence, nebulized formulations are commonly used in hospitals, emergency departments (EDs) and ambulatory clinics based on the drug’s unit cost. In contrast, a pMDI is often more cost-effective for use in ambulatory patients who are administering multiple doses from the same canister.

The World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) recommend droplet and contact precautions for all patients suspected or diagnosed with novel coronavirus-19 (COVID-19).^13,14 Airborne precautions must be applied when performing aerosol-generating medical procedures (AGMPs), including but not limited to, open suctioning of the respiratory tract, intubation, bronchoscopy, and cardiopulmonary resuscitation (CPR). Data from the severe acute respiratory syndrome (SARS-CoV) epidemic suggest that nebulization of medication is also an AGMP.^15-17

Institutions must ensure that their health care workers (HCWs) are wearing appropriate personal protective equipment (PPE) including gloves, long-sleeved gowns, eye protection, and fit-tested particulate respirators (N95 mask) for airborne procedures and are carefully discarding PPE after use.^13,14 Due to severe shortages in available respirators in the US supply chain, the CDC has temporarily modified WHO recommendations. Face masks are now an acceptable alternative to protect HCWs from splashes and sprays from procedures not likely to generate aerosols and for cleaning of rooms, although there is no evidence to support this decision.

Internationally, HCWs are falling ill with COVID-19. Data from Italy and Spain show that about 9% to 13% of these countries’ cases are HCWs.^18,19 Within the US, the Ohio health department reports approximately 16% of cases are HCWs.²⁰ It is possible that 20% of frontline HCWs will become infected.²¹ Evolving laboratory research shows that COVID-19 remains viable in aerosols for up to 3 hours postaerosolization, thus making aerosol transmission plausible.²² Nebulizers convert liquids into aerosols and during dispersal may potentially cause secondary inhalation of fugitive emissions.²³ Since interim CDC infection control guidance is to allow only essential personnel to enter the room of patients with COVID-19, many facilities will rely on their frontline nursing staff to clean and disinfect high-touch surfaces following routine care activities.²⁴

Achieving adequate fomite disinfection following viral aerosolization may pose a significant problem for any patient receiving scheduled doses of nebulized medications. Additionally, for personnel who clean rooms following intermittent drug nebulization while wearing PPE that includes a face mask, protection from aerosolized virus may be inadequate. Subsequently, fugitive emissions from nebulized medications may potentially contribute to both nosocomial COVID-19 transmission and viral infections in the medical staff until proven otherwise by studies conducted outside of the laboratory. Prevention of infection in the medical staff is imperative since federal health care systems cannot sustain a significant loss of its workforce.

Recommendations

We recommend that health care systems stop business as usual and adopt public health recommendations issued by Canadian and Hong Kong health care authorities for the management of suspected or confirmed COVID-19 disease.^25-28 We have further clarified and expanded on these interventions. During viral pandemics, prescribers and health care systems should:

1. Deprescribe nebulized therapies on medical wards and intensive care units as an infection control measure. Also avoid use in any outpatient health care setting (eg, community-based clinics, EDs, triage).
2. Avoid initiation of nebulized unproven therapies (eg, n-acetylcysteine, hypertonic saline).¹
3. Use alternative bronchodilator formulations as appropriate (eg, oral β-2 agonist, recognizing its slower onset) before prescribing nebulized agents to patients who are uncooperative or unable to follow directions needed to use a pMDI with a spacer or have experienced a prior poor response to a pMDI with spacer (eg, OptiChamber Diamond, Philips).^25,27
4.  Limit nebulized drug utilization (eg, bronchodilators, epoprostenol) to patients who are on mechanical ventilation and will receive nebulized therapies via a closed system or to patients housed in negative pressure hospital rooms.²² Use a viral filter (eg, Salter Labs system) to decrease the spread of infection for those receiving epoprostenol via face mask.²⁵
5. Adjust procurement practices (eg, pharmacy, logistics) to address the transition from nebulized drugs to alternatives.
6. Add a safety net to the drug-ordering process by restricting new orders for nebulized therapies to the prior authorization process.²⁷ Apply the exclusion criterion of suspected or definite COVID-19.
7. Add a safety net to environmental service practices. Nursing staff should track patients who received ≥ 1 nebulizations via open (before diagnosis) or closed systems so that staff wear suitable PPE to include a N-95 mask while cleaning the room.

Conclusions

To implement the aggressive infection control guidance promulgated here, we recommend collaboration with infection control, pharmacy service (eg, prior authorization team, clinical pharmacy team, and procurement team), respiratory therapy, pulmonary and other critical care physicians, EDs, CPR committee, and other stakeholders. When making significant transitions in clinical care during a viral pandemic, guidelines must be timely, use imperative wording, and consist of easily identifiable education and/or instructions for the affected frontline staff in order to change attitudes.²⁹ Additionally, when transitioning from nebulized bronchodilators to pMDI, educational in-services should be provided to frontline staff to avoid misconceptions regarding pMDI treatment efficacy and patients’ ability to use their pMDI with spacer.³⁰

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville.

Beyond asthma and chronic obstructive pulmonary disease (COPD), inhalation therapy is a mainstay in the management of bronchiectasis, cystic fibrosis, and pulmonary artery hypertension. Several US Food and Drug Administration off-label indications for inhalational medications include hypoxia secondary to acute respiratory distress syndrome (ARDS) and intraoperative and postoperative pulmonary hypertension during and following cardiac surgery, respectively.^1-11 Therapeutic delivery of aerosols to the lung may be provided via nebulization, pressurized metered-dose inhalers (pMDI), and other devices (eg, dry powder inhalers, soft-mist inhalers, and smart inhalers).¹² The most common aerosolized medications given in the clinical setting are bronchodilators.¹²

Product selection is often guided by practice guidelines (Table 1), consideration of the formulation’s advantages and disadvantages (Table 2), and/or formulary considerations. For example, current guidelines for COPD state that there is no evidence for superiority of nebulized bronchodilator therapy over handheld devices in patients who can use them properly.² Due to equivalence, nebulized formulations are commonly used in hospitals, emergency departments (EDs) and ambulatory clinics based on the drug’s unit cost. In contrast, a pMDI is often more cost-effective for use in ambulatory patients who are administering multiple doses from the same canister.

The World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) recommend droplet and contact precautions for all patients suspected or diagnosed with novel coronavirus-19 (COVID-19).^13,14 Airborne precautions must be applied when performing aerosol-generating medical procedures (AGMPs), including but not limited to, open suctioning of the respiratory tract, intubation, bronchoscopy, and cardiopulmonary resuscitation (CPR). Data from the severe acute respiratory syndrome (SARS-CoV) epidemic suggest that nebulization of medication is also an AGMP.^15-17

Institutions must ensure that their health care workers (HCWs) are wearing appropriate personal protective equipment (PPE) including gloves, long-sleeved gowns, eye protection, and fit-tested particulate respirators (N95 mask) for airborne procedures and are carefully discarding PPE after use.^13,14 Due to severe shortages in available respirators in the US supply chain, the CDC has temporarily modified WHO recommendations. Face masks are now an acceptable alternative to protect HCWs from splashes and sprays from procedures not likely to generate aerosols and for cleaning of rooms, although there is no evidence to support this decision.

Internationally, HCWs are falling ill with COVID-19. Data from Italy and Spain show that about 9% to 13% of these countries’ cases are HCWs.^18,19 Within the US, the Ohio health department reports approximately 16% of cases are HCWs.²⁰ It is possible that 20% of frontline HCWs will become infected.²¹ Evolving laboratory research shows that COVID-19 remains viable in aerosols for up to 3 hours postaerosolization, thus making aerosol transmission plausible.²² Nebulizers convert liquids into aerosols and during dispersal may potentially cause secondary inhalation of fugitive emissions.²³ Since interim CDC infection control guidance is to allow only essential personnel to enter the room of patients with COVID-19, many facilities will rely on their frontline nursing staff to clean and disinfect high-touch surfaces following routine care activities.²⁴

Achieving adequate fomite disinfection following viral aerosolization may pose a significant problem for any patient receiving scheduled doses of nebulized medications. Additionally, for personnel who clean rooms following intermittent drug nebulization while wearing PPE that includes a face mask, protection from aerosolized virus may be inadequate. Subsequently, fugitive emissions from nebulized medications may potentially contribute to both nosocomial COVID-19 transmission and viral infections in the medical staff until proven otherwise by studies conducted outside of the laboratory. Prevention of infection in the medical staff is imperative since federal health care systems cannot sustain a significant loss of its workforce.

Recommendations

We recommend that health care systems stop business as usual and adopt public health recommendations issued by Canadian and Hong Kong health care authorities for the management of suspected or confirmed COVID-19 disease.^25-28 We have further clarified and expanded on these interventions. During viral pandemics, prescribers and health care systems should:

1. Deprescribe nebulized therapies on medical wards and intensive care units as an infection control measure. Also avoid use in any outpatient health care setting (eg, community-based clinics, EDs, triage).
2. Avoid initiation of nebulized unproven therapies (eg, n-acetylcysteine, hypertonic saline).¹
3. Use alternative bronchodilator formulations as appropriate (eg, oral β-2 agonist, recognizing its slower onset) before prescribing nebulized agents to patients who are uncooperative or unable to follow directions needed to use a pMDI with a spacer or have experienced a prior poor response to a pMDI with spacer (eg, OptiChamber Diamond, Philips).^25,27
4.  Limit nebulized drug utilization (eg, bronchodilators, epoprostenol) to patients who are on mechanical ventilation and will receive nebulized therapies via a closed system or to patients housed in negative pressure hospital rooms.²² Use a viral filter (eg, Salter Labs system) to decrease the spread of infection for those receiving epoprostenol via face mask.²⁵
5. Adjust procurement practices (eg, pharmacy, logistics) to address the transition from nebulized drugs to alternatives.
6. Add a safety net to the drug-ordering process by restricting new orders for nebulized therapies to the prior authorization process.²⁷ Apply the exclusion criterion of suspected or definite COVID-19.
7. Add a safety net to environmental service practices. Nursing staff should track patients who received ≥ 1 nebulizations via open (before diagnosis) or closed systems so that staff wear suitable PPE to include a N-95 mask while cleaning the room.

Conclusions

To implement the aggressive infection control guidance promulgated here, we recommend collaboration with infection control, pharmacy service (eg, prior authorization team, clinical pharmacy team, and procurement team), respiratory therapy, pulmonary and other critical care physicians, EDs, CPR committee, and other stakeholders. When making significant transitions in clinical care during a viral pandemic, guidelines must be timely, use imperative wording, and consist of easily identifiable education and/or instructions for the affected frontline staff in order to change attitudes.²⁹ Additionally, when transitioning from nebulized bronchodilators to pMDI, educational in-services should be provided to frontline staff to avoid misconceptions regarding pMDI treatment efficacy and patients’ ability to use their pMDI with spacer.³⁰

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville.

Beyond asthma and chronic obstructive pulmonary disease (COPD), inhalation therapy is a mainstay in the management of bronchiectasis, cystic fibrosis, and pulmonary artery hypertension. Several US Food and Drug Administration off-label indications for inhalational medications include hypoxia secondary to acute respiratory distress syndrome (ARDS) and intraoperative and postoperative pulmonary hypertension during and following cardiac surgery, respectively.^1-11 Therapeutic delivery of aerosols to the lung may be provided via nebulization, pressurized metered-dose inhalers (pMDI), and other devices (eg, dry powder inhalers, soft-mist inhalers, and smart inhalers).¹² The most common aerosolized medications given in the clinical setting are bronchodilators.¹²

Product selection is often guided by practice guidelines (Table 1), consideration of the formulation’s advantages and disadvantages (Table 2), and/or formulary considerations. For example, current guidelines for COPD state that there is no evidence for superiority of nebulized bronchodilator therapy over handheld devices in patients who can use them properly.² Due to equivalence, nebulized formulations are commonly used in hospitals, emergency departments (EDs) and ambulatory clinics based on the drug’s unit cost. In contrast, a pMDI is often more cost-effective for use in ambulatory patients who are administering multiple doses from the same canister.

The World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) recommend droplet and contact precautions for all patients suspected or diagnosed with novel coronavirus-19 (COVID-19).^13,14 Airborne precautions must be applied when performing aerosol-generating medical procedures (AGMPs), including but not limited to, open suctioning of the respiratory tract, intubation, bronchoscopy, and cardiopulmonary resuscitation (CPR). Data from the severe acute respiratory syndrome (SARS-CoV) epidemic suggest that nebulization of medication is also an AGMP.^15-17

Institutions must ensure that their health care workers (HCWs) are wearing appropriate personal protective equipment (PPE) including gloves, long-sleeved gowns, eye protection, and fit-tested particulate respirators (N95 mask) for airborne procedures and are carefully discarding PPE after use.^13,14 Due to severe shortages in available respirators in the US supply chain, the CDC has temporarily modified WHO recommendations. Face masks are now an acceptable alternative to protect HCWs from splashes and sprays from procedures not likely to generate aerosols and for cleaning of rooms, although there is no evidence to support this decision.

Internationally, HCWs are falling ill with COVID-19. Data from Italy and Spain show that about 9% to 13% of these countries’ cases are HCWs.^18,19 Within the US, the Ohio health department reports approximately 16% of cases are HCWs.²⁰ It is possible that 20% of frontline HCWs will become infected.²¹ Evolving laboratory research shows that COVID-19 remains viable in aerosols for up to 3 hours postaerosolization, thus making aerosol transmission plausible.²² Nebulizers convert liquids into aerosols and during dispersal may potentially cause secondary inhalation of fugitive emissions.²³ Since interim CDC infection control guidance is to allow only essential personnel to enter the room of patients with COVID-19, many facilities will rely on their frontline nursing staff to clean and disinfect high-touch surfaces following routine care activities.²⁴

Achieving adequate fomite disinfection following viral aerosolization may pose a significant problem for any patient receiving scheduled doses of nebulized medications. Additionally, for personnel who clean rooms following intermittent drug nebulization while wearing PPE that includes a face mask, protection from aerosolized virus may be inadequate. Subsequently, fugitive emissions from nebulized medications may potentially contribute to both nosocomial COVID-19 transmission and viral infections in the medical staff until proven otherwise by studies conducted outside of the laboratory. Prevention of infection in the medical staff is imperative since federal health care systems cannot sustain a significant loss of its workforce.

Recommendations

We recommend that health care systems stop business as usual and adopt public health recommendations issued by Canadian and Hong Kong health care authorities for the management of suspected or confirmed COVID-19 disease.^25-28 We have further clarified and expanded on these interventions. During viral pandemics, prescribers and health care systems should:

1. Deprescribe nebulized therapies on medical wards and intensive care units as an infection control measure. Also avoid use in any outpatient health care setting (eg, community-based clinics, EDs, triage).
2. Avoid initiation of nebulized unproven therapies (eg, n-acetylcysteine, hypertonic saline).¹
3. Use alternative bronchodilator formulations as appropriate (eg, oral β-2 agonist, recognizing its slower onset) before prescribing nebulized agents to patients who are uncooperative or unable to follow directions needed to use a pMDI with a spacer or have experienced a prior poor response to a pMDI with spacer (eg, OptiChamber Diamond, Philips).^25,27
4.  Limit nebulized drug utilization (eg, bronchodilators, epoprostenol) to patients who are on mechanical ventilation and will receive nebulized therapies via a closed system or to patients housed in negative pressure hospital rooms.²² Use a viral filter (eg, Salter Labs system) to decrease the spread of infection for those receiving epoprostenol via face mask.²⁵
5. Adjust procurement practices (eg, pharmacy, logistics) to address the transition from nebulized drugs to alternatives.
6. Add a safety net to the drug-ordering process by restricting new orders for nebulized therapies to the prior authorization process.²⁷ Apply the exclusion criterion of suspected or definite COVID-19.
7. Add a safety net to environmental service practices. Nursing staff should track patients who received ≥ 1 nebulizations via open (before diagnosis) or closed systems so that staff wear suitable PPE to include a N-95 mask while cleaning the room.

Conclusions

To implement the aggressive infection control guidance promulgated here, we recommend collaboration with infection control, pharmacy service (eg, prior authorization team, clinical pharmacy team, and procurement team), respiratory therapy, pulmonary and other critical care physicians, EDs, CPR committee, and other stakeholders. When making significant transitions in clinical care during a viral pandemic, guidelines must be timely, use imperative wording, and consist of easily identifiable education and/or instructions for the affected frontline staff in order to change attitudes.²⁹ Additionally, when transitioning from nebulized bronchodilators to pMDI, educational in-services should be provided to frontline staff to avoid misconceptions regarding pMDI treatment efficacy and patients’ ability to use their pMDI with spacer.³⁰

Acknowledgments

This material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System in Nashville.

The US Food and Drug Administration has approved the immunotherapy durvalumab (Imfinzi, AstraZeneca) in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).

Durvalumab plus chemotherapy “can be considered a new standard in ES-SCLC,” said Myung-Ju Ahn, MD, Sungkyunkwan University, Seoul, South Korea, last year at the European Society of Medical Oncology (ESMO) annual meeting, where he discussed results from the phase 3 trial known as CASPIAN.

The new approval is based on efficacy and safety data from that trial, conducted in patients with previously untreated ES-SCLC. In the experimental group (n = 268), durvalumab plus etoposide and a platinum agent (EP) was followed by maintenance durvalumab, and in the control group (n = 269) patients received the EP regimen alone.

Median overall survival (OS) was 13 months in the durvalumab plus chemotherapy group compared with 10.3 months in the chemotherapy alone group (hazard ratio 0.73; 95% confidence interval, 0.59-0.91; P = .0047).

Reporting these results, trial investigator Luis Paz-Ares, MD, Hospital Universitario 12 de Octubre, Madrid, put the new survival benefit in the context of standard treatments at the ESMO meeting last year.

“Initial response rates to etoposide plus a platinum are high, but responses are not durable and patients treated with EP typically relapse within 6 months of starting treatment with a median OS of approximately 10 months,” he said.

In addition to the primary endpoint of OS, additional efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR).

Median PFS was not statistically significant with immunotherapy; it was 5.1 months (95% CI, 4.7-6.2) in the durvalumab plus chemotherapy group and 5.4 months (95% CI, 4.8-6.2) in the chemotherapy alone group (HR, 0.78; 95% CI, 0.65-0.94).

The investigator-assessed ORR was 68% in the durvalumab plus chemotherapy group and 58% in the chemotherapy alone group.

The most common adverse reactions (≥ 20%) in patients with ES-SCLC were nausea, fatigue/asthenia, and alopecia, according to the FDA.

At ESMO, Paz-Ares reported that rates of serious adverse events (AEs) were comparable at 30.9% and 36.1% for the durvalumab plus EP group vs. EP alone, respectively; rates of AEs leading to discontinuation were identical in both groups at 9.4%. Unsurprisingly, immune-mediated AEs were higher at 19.6% in the durvalumab combination group vs. 2.6% in the EP alone group.

In this setting, durvalumab is administered prior to chemotherapy on the same day. The recommended durvalumab dose (when administered with etoposide and carboplatin or cisplatin) is 1,500 mg every 3 weeks prior to chemotherapy and then every 4 weeks as a single-agent maintenance therapy.

Durvalumab is already approved for metastatic non–small cell lung cancer in patients whose tumors have only spread in the chest, and is also approved for use in urothelial cancer.

This article first appeared on Medscape.com.

The US Food and Drug Administration has approved the immunotherapy durvalumab (Imfinzi, AstraZeneca) in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).

Durvalumab plus chemotherapy “can be considered a new standard in ES-SCLC,” said Myung-Ju Ahn, MD, Sungkyunkwan University, Seoul, South Korea, last year at the European Society of Medical Oncology (ESMO) annual meeting, where he discussed results from the phase 3 trial known as CASPIAN.

The new approval is based on efficacy and safety data from that trial, conducted in patients with previously untreated ES-SCLC. In the experimental group (n = 268), durvalumab plus etoposide and a platinum agent (EP) was followed by maintenance durvalumab, and in the control group (n = 269) patients received the EP regimen alone.

Median overall survival (OS) was 13 months in the durvalumab plus chemotherapy group compared with 10.3 months in the chemotherapy alone group (hazard ratio 0.73; 95% confidence interval, 0.59-0.91; P = .0047).

Reporting these results, trial investigator Luis Paz-Ares, MD, Hospital Universitario 12 de Octubre, Madrid, put the new survival benefit in the context of standard treatments at the ESMO meeting last year.

“Initial response rates to etoposide plus a platinum are high, but responses are not durable and patients treated with EP typically relapse within 6 months of starting treatment with a median OS of approximately 10 months,” he said.

In addition to the primary endpoint of OS, additional efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR).

Median PFS was not statistically significant with immunotherapy; it was 5.1 months (95% CI, 4.7-6.2) in the durvalumab plus chemotherapy group and 5.4 months (95% CI, 4.8-6.2) in the chemotherapy alone group (HR, 0.78; 95% CI, 0.65-0.94).

The investigator-assessed ORR was 68% in the durvalumab plus chemotherapy group and 58% in the chemotherapy alone group.

The most common adverse reactions (≥ 20%) in patients with ES-SCLC were nausea, fatigue/asthenia, and alopecia, according to the FDA.

At ESMO, Paz-Ares reported that rates of serious adverse events (AEs) were comparable at 30.9% and 36.1% for the durvalumab plus EP group vs. EP alone, respectively; rates of AEs leading to discontinuation were identical in both groups at 9.4%. Unsurprisingly, immune-mediated AEs were higher at 19.6% in the durvalumab combination group vs. 2.6% in the EP alone group.

In this setting, durvalumab is administered prior to chemotherapy on the same day. The recommended durvalumab dose (when administered with etoposide and carboplatin or cisplatin) is 1,500 mg every 3 weeks prior to chemotherapy and then every 4 weeks as a single-agent maintenance therapy.

Durvalumab is already approved for metastatic non–small cell lung cancer in patients whose tumors have only spread in the chest, and is also approved for use in urothelial cancer.

This article first appeared on Medscape.com.

The US Food and Drug Administration has approved the immunotherapy durvalumab (Imfinzi, AstraZeneca) in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).

Durvalumab plus chemotherapy “can be considered a new standard in ES-SCLC,” said Myung-Ju Ahn, MD, Sungkyunkwan University, Seoul, South Korea, last year at the European Society of Medical Oncology (ESMO) annual meeting, where he discussed results from the phase 3 trial known as CASPIAN.

The new approval is based on efficacy and safety data from that trial, conducted in patients with previously untreated ES-SCLC. In the experimental group (n = 268), durvalumab plus etoposide and a platinum agent (EP) was followed by maintenance durvalumab, and in the control group (n = 269) patients received the EP regimen alone.

Median overall survival (OS) was 13 months in the durvalumab plus chemotherapy group compared with 10.3 months in the chemotherapy alone group (hazard ratio 0.73; 95% confidence interval, 0.59-0.91; P = .0047).

Reporting these results, trial investigator Luis Paz-Ares, MD, Hospital Universitario 12 de Octubre, Madrid, put the new survival benefit in the context of standard treatments at the ESMO meeting last year.

“Initial response rates to etoposide plus a platinum are high, but responses are not durable and patients treated with EP typically relapse within 6 months of starting treatment with a median OS of approximately 10 months,” he said.

In addition to the primary endpoint of OS, additional efficacy outcome measures were investigator-assessed progression-free survival (PFS) and objective response rate (ORR).

Median PFS was not statistically significant with immunotherapy; it was 5.1 months (95% CI, 4.7-6.2) in the durvalumab plus chemotherapy group and 5.4 months (95% CI, 4.8-6.2) in the chemotherapy alone group (HR, 0.78; 95% CI, 0.65-0.94).

The investigator-assessed ORR was 68% in the durvalumab plus chemotherapy group and 58% in the chemotherapy alone group.

The most common adverse reactions (≥ 20%) in patients with ES-SCLC were nausea, fatigue/asthenia, and alopecia, according to the FDA.

At ESMO, Paz-Ares reported that rates of serious adverse events (AEs) were comparable at 30.9% and 36.1% for the durvalumab plus EP group vs. EP alone, respectively; rates of AEs leading to discontinuation were identical in both groups at 9.4%. Unsurprisingly, immune-mediated AEs were higher at 19.6% in the durvalumab combination group vs. 2.6% in the EP alone group.

In this setting, durvalumab is administered prior to chemotherapy on the same day. The recommended durvalumab dose (when administered with etoposide and carboplatin or cisplatin) is 1,500 mg every 3 weeks prior to chemotherapy and then every 4 weeks as a single-agent maintenance therapy.

Durvalumab is already approved for metastatic non–small cell lung cancer in patients whose tumors have only spread in the chest, and is also approved for use in urothelial cancer.

This article first appeared on Medscape.com.