Pharmacology

NEW ORLEANS – The efficacy and safety of Janus kinase (JAK) inhibitors for hair regrowth in adults with alopecia areata were reinforced by new results from clinical trials of two drugs presented at a late-breaker research session at the annual meeting of the American Academy of Dermatology.

Based on phase 3 studies that document robust hair growth in about one third of patients, deuruxolitinib (CTP-543), an inhibitor of the JAK1 and JAK2 enzymes, has the potential to become the second JAK inhibitor available for the treatment of alopecia areata. If approved, it will join baricitinib (Olumiant), which received U.S. approval almost 1 year ago.

In his talk on THRIVE-AA2, a phase 3 trial of the investigational medicine deuruxolitinib, the principal investigator, Brett A. King, MD, PhD, displayed several before-and-after photos and said, “The photos tell the whole story. This is why there is so much excitement about these drugs.”

THRIVE-AA2 was the second of two phase 3 studies of deuruxolitinib. King was a principal investigator for both pivotal trials, called THRIVE-AA1 and THRIVE AA-2. He characterized the results of the two THRIVE trials as “comparable.”

Dr. King also was a principal investigator for the trials with baricitinib, called BRAVE-AA1 and BRAVE AA-2, which were published last year in the New England Journal of Medicine. The trials for both drugs had similar designs and endpoints.
 

Deuruxolitinib and the THRIVE studies

In the THRIVE-AA2 trial, 517 adult patients were enrolled with moderate to severe alopecia areata, defined as a SALT (Severity of Alopecia Tool) score of ≥ 50%, which signifies a hair loss of at least 50%. Like THRIVE-AA1, patients participated at treatment centers in North America and Europe. About two-thirds were female. The mean age was 39 years. The majority of patients had complete or near complete hair loss at baseline.

“Many of these patients are the ones we have historically characterized as having alopecia totalis or universalis,” Dr. King said.

Participating patients were randomly assigned to 8 mg deuruxolitinib twice daily, 12 mg deuruxolitinib twice daily, or placebo. The primary endpoint was a SALT score of ≤ 20% at week 24.

At 24 weeks, almost no patients in the placebo group (1%) vs. 33% and 38% in the 8 mg and 12 mg twice-daily groups, respectively, met the primary endpoint. Each active treatment group was highly significant vs. placebo.

Of the responders, the majority achieved complete or near complete hair growth as defined by a SALT score of ≤ 10%, Dr. King reported.

Based on a graph that showed a relatively steep climb over the entire 24-week study period, deuruxolitinib “had a really fast onset of action,” Dr. King said. By week 8, which was the time of the first assessment, both doses of deuruxolitinib were superior to placebo.

The majority of patients had complete or significant loss of eyebrows and eye lashes at baseline, but more than two-thirds of these patients had regrowth by week 24, Dr. King said. Again, no significant regrowth was observed in the placebo arm.

On the Satisfaction of Hair Patient Reported Outcomes (SPRO), more than half of patients on both doses reported being satisfied or very satisfied with the improvement when evaluated at 24 weeks.

“The patient satisfaction overshot what one would expect by looking at the SALT scores, but a lot of subjects were at the precipice of the primary endpoint, sitting on SALT scores of 21, 25, or 30,” Dr. King said.
 

High participation in extension trial

More than 90% of the patients assigned to deuruxolitinib completed the trial and have entered an open-label extension (OLE). Dr. King credited the substantial rates of hair growth and the low rate of significant adverse events for the high rate of transition to OLE. Those who experienced the response were motivated to maintain it.  

“This is a devastating disease. Patients want to get better,” Dr. King said.

There were no serious treatment-emergent adverse events associated with deuruxolitinib, including no thromboembolic events or other off-target events that have been reported previously with other JAK inhibitors in other disease states, such as rheumatoid arthritis. Although some adverse events, such as nasopharyngitis, were observed more often in those taking deuruxolitinib than placebo, there were “very few” discontinuations because of an adverse event, he said.

The data of THRIVE-AA2 are wholly compatible with the previously reported 706-patient THRIVE-AA1, according to Dr. King. In THRIVE-AA1, the primary endpoint of SALT ≤ 20% was reached by 29.6%, 41.5%, and 0.8% of the 8 mg, 12 mg, and placebo groups, respectively. Patient satisfaction scores, safety, and tolerability were also similar, according to Dr. King.

The experience with deuruxolitinib in the THRIVE-AA phase 3 program is similar to the experience with baricitinib in the BRAVE-AA trials. Although they cannot be compared directly because of potential differences between study populations, the 4-mg dose of baricitinib also achieved SALT score ≤ 20 in about 35% of patients, he said. The proportion was lower in the 2-mg group but was also superior to the placebo group.

“JAK inhibitors are changing the paradigm of alopecia areata,” Dr. King said. Responding to a question about payers reluctant to reimburse therapies for a “cosmetic” condition, Dr. King added that the effective treatments are “changing the landscape of how we think about this disease.” Dr. King believes these kinds of data show that “we are literally transforming lives forever.”
 

Baricitinib and the BRAVE studies

When baricitinib received regulatory approval for alopecia areata last year, it was not just the first JAK inhibitor approved for this disease, but the first systemic therapy of any kind, according to Maryanne Senna, MD, an assistant professor of dermatology at Harvard Medical School, Boston, and the director of the Lahey Hair Loss Center of Excellence, Burlington, Mass. Dr. Senna was a clinical investigator of BRAVE-AA1, as well as of THRIVE-AA2.

Providing an update on the BRAVE-AA program, Dr. Senna reported 104-week data that appear to support the idea of a life-changing benefit from JAK inhibitor therapy. This is because the effects appear durable.

In the data she presented at the AAD, responders and mixed responders at 52 weeks were followed to 104 weeks. Mixed responders were defined as those without a SALT response of ≤ 20 at week 52 but who had achieved this degree of hair regrowth at some earlier point.

Of the responders, 90% maintained their response at 104 weeks. In addition, many of the mixed responders and patients with a partial response but who never achieved a SALT score ≤ 20% gained additional hair growth, including complete or near complete hair growth, when maintained on treatment over the 2 years of follow-up.

“The follow-up suggests that, if you keep patients on treatment, you can get many of them to a meaningful response,” she said.

Meanwhile, “there have been no new safety signals,” Dr. Senna said. She based this statement not only of the 104-week data but on follow-up of up to 3.6 years among patients who have remained on treatment after participating in previous studies.

According to Dr. Senna, the off-target events that have been reported previously in other diseases with other JAK inhibitors, such as major adverse cardiovascular events and thromboembolic events, have not so far been observed in the BRAVE-AA phase 3 program.

Baricitinib, much like all but one of the JAK inhibitors with dermatologic indications, carries a black box warning that lists multiple risks for drugs in this class, based on a rheumatoid arthritis study.

The Food and Drug Administration has granted deuruxolitinib Breakthrough Therapy designation for the treatment of adult patients with moderate to severe alopecia areata and Fast Track designation for the treatment of alopecia areata, according to its manufacturer Concert Pharmaceuticals.

Dr. King reports financial relationships with more than 15 pharmaceutical companies, including Concert Pharmaceuticals, which provided the funding for the THRIVE-AA trial program, and for Eli Lilly, which provided funding for the BRAVE-AA trial program. Dr. Senna reports financial relationships with Arena pharmaceuticals, Follica, and both Concert Pharmaceuticals and Eli Lilly.

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

NEW ORLEANS – The efficacy and safety of Janus kinase (JAK) inhibitors for hair regrowth in adults with alopecia areata were reinforced by new results from clinical trials of two drugs presented at a late-breaker research session at the annual meeting of the American Academy of Dermatology.

Based on phase 3 studies that document robust hair growth in about one third of patients, deuruxolitinib (CTP-543), an inhibitor of the JAK1 and JAK2 enzymes, has the potential to become the second JAK inhibitor available for the treatment of alopecia areata. If approved, it will join baricitinib (Olumiant), which received U.S. approval almost 1 year ago.

In his talk on THRIVE-AA2, a phase 3 trial of the investigational medicine deuruxolitinib, the principal investigator, Brett A. King, MD, PhD, displayed several before-and-after photos and said, “The photos tell the whole story. This is why there is so much excitement about these drugs.”

THRIVE-AA2 was the second of two phase 3 studies of deuruxolitinib. King was a principal investigator for both pivotal trials, called THRIVE-AA1 and THRIVE AA-2. He characterized the results of the two THRIVE trials as “comparable.”

Dr. King also was a principal investigator for the trials with baricitinib, called BRAVE-AA1 and BRAVE AA-2, which were published last year in the New England Journal of Medicine. The trials for both drugs had similar designs and endpoints.
 

Deuruxolitinib and the THRIVE studies

In the THRIVE-AA2 trial, 517 adult patients were enrolled with moderate to severe alopecia areata, defined as a SALT (Severity of Alopecia Tool) score of ≥ 50%, which signifies a hair loss of at least 50%. Like THRIVE-AA1, patients participated at treatment centers in North America and Europe. About two-thirds were female. The mean age was 39 years. The majority of patients had complete or near complete hair loss at baseline.

“Many of these patients are the ones we have historically characterized as having alopecia totalis or universalis,” Dr. King said.

Participating patients were randomly assigned to 8 mg deuruxolitinib twice daily, 12 mg deuruxolitinib twice daily, or placebo. The primary endpoint was a SALT score of ≤ 20% at week 24.

At 24 weeks, almost no patients in the placebo group (1%) vs. 33% and 38% in the 8 mg and 12 mg twice-daily groups, respectively, met the primary endpoint. Each active treatment group was highly significant vs. placebo.

Of the responders, the majority achieved complete or near complete hair growth as defined by a SALT score of ≤ 10%, Dr. King reported.

Based on a graph that showed a relatively steep climb over the entire 24-week study period, deuruxolitinib “had a really fast onset of action,” Dr. King said. By week 8, which was the time of the first assessment, both doses of deuruxolitinib were superior to placebo.

The majority of patients had complete or significant loss of eyebrows and eye lashes at baseline, but more than two-thirds of these patients had regrowth by week 24, Dr. King said. Again, no significant regrowth was observed in the placebo arm.

On the Satisfaction of Hair Patient Reported Outcomes (SPRO), more than half of patients on both doses reported being satisfied or very satisfied with the improvement when evaluated at 24 weeks.

“The patient satisfaction overshot what one would expect by looking at the SALT scores, but a lot of subjects were at the precipice of the primary endpoint, sitting on SALT scores of 21, 25, or 30,” Dr. King said.
 

High participation in extension trial

More than 90% of the patients assigned to deuruxolitinib completed the trial and have entered an open-label extension (OLE). Dr. King credited the substantial rates of hair growth and the low rate of significant adverse events for the high rate of transition to OLE. Those who experienced the response were motivated to maintain it.  

“This is a devastating disease. Patients want to get better,” Dr. King said.

There were no serious treatment-emergent adverse events associated with deuruxolitinib, including no thromboembolic events or other off-target events that have been reported previously with other JAK inhibitors in other disease states, such as rheumatoid arthritis. Although some adverse events, such as nasopharyngitis, were observed more often in those taking deuruxolitinib than placebo, there were “very few” discontinuations because of an adverse event, he said.

The data of THRIVE-AA2 are wholly compatible with the previously reported 706-patient THRIVE-AA1, according to Dr. King. In THRIVE-AA1, the primary endpoint of SALT ≤ 20% was reached by 29.6%, 41.5%, and 0.8% of the 8 mg, 12 mg, and placebo groups, respectively. Patient satisfaction scores, safety, and tolerability were also similar, according to Dr. King.

The experience with deuruxolitinib in the THRIVE-AA phase 3 program is similar to the experience with baricitinib in the BRAVE-AA trials. Although they cannot be compared directly because of potential differences between study populations, the 4-mg dose of baricitinib also achieved SALT score ≤ 20 in about 35% of patients, he said. The proportion was lower in the 2-mg group but was also superior to the placebo group.

“JAK inhibitors are changing the paradigm of alopecia areata,” Dr. King said. Responding to a question about payers reluctant to reimburse therapies for a “cosmetic” condition, Dr. King added that the effective treatments are “changing the landscape of how we think about this disease.” Dr. King believes these kinds of data show that “we are literally transforming lives forever.”
 

Baricitinib and the BRAVE studies

When baricitinib received regulatory approval for alopecia areata last year, it was not just the first JAK inhibitor approved for this disease, but the first systemic therapy of any kind, according to Maryanne Senna, MD, an assistant professor of dermatology at Harvard Medical School, Boston, and the director of the Lahey Hair Loss Center of Excellence, Burlington, Mass. Dr. Senna was a clinical investigator of BRAVE-AA1, as well as of THRIVE-AA2.

Providing an update on the BRAVE-AA program, Dr. Senna reported 104-week data that appear to support the idea of a life-changing benefit from JAK inhibitor therapy. This is because the effects appear durable.

In the data she presented at the AAD, responders and mixed responders at 52 weeks were followed to 104 weeks. Mixed responders were defined as those without a SALT response of ≤ 20 at week 52 but who had achieved this degree of hair regrowth at some earlier point.

Of the responders, 90% maintained their response at 104 weeks. In addition, many of the mixed responders and patients with a partial response but who never achieved a SALT score ≤ 20% gained additional hair growth, including complete or near complete hair growth, when maintained on treatment over the 2 years of follow-up.

“The follow-up suggests that, if you keep patients on treatment, you can get many of them to a meaningful response,” she said.

Meanwhile, “there have been no new safety signals,” Dr. Senna said. She based this statement not only of the 104-week data but on follow-up of up to 3.6 years among patients who have remained on treatment after participating in previous studies.

According to Dr. Senna, the off-target events that have been reported previously in other diseases with other JAK inhibitors, such as major adverse cardiovascular events and thromboembolic events, have not so far been observed in the BRAVE-AA phase 3 program.

Baricitinib, much like all but one of the JAK inhibitors with dermatologic indications, carries a black box warning that lists multiple risks for drugs in this class, based on a rheumatoid arthritis study.

The Food and Drug Administration has granted deuruxolitinib Breakthrough Therapy designation for the treatment of adult patients with moderate to severe alopecia areata and Fast Track designation for the treatment of alopecia areata, according to its manufacturer Concert Pharmaceuticals.

Dr. King reports financial relationships with more than 15 pharmaceutical companies, including Concert Pharmaceuticals, which provided the funding for the THRIVE-AA trial program, and for Eli Lilly, which provided funding for the BRAVE-AA trial program. Dr. Senna reports financial relationships with Arena pharmaceuticals, Follica, and both Concert Pharmaceuticals and Eli Lilly.

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

NEW ORLEANS – The efficacy and safety of Janus kinase (JAK) inhibitors for hair regrowth in adults with alopecia areata were reinforced by new results from clinical trials of two drugs presented at a late-breaker research session at the annual meeting of the American Academy of Dermatology.

Based on phase 3 studies that document robust hair growth in about one third of patients, deuruxolitinib (CTP-543), an inhibitor of the JAK1 and JAK2 enzymes, has the potential to become the second JAK inhibitor available for the treatment of alopecia areata. If approved, it will join baricitinib (Olumiant), which received U.S. approval almost 1 year ago.

In his talk on THRIVE-AA2, a phase 3 trial of the investigational medicine deuruxolitinib, the principal investigator, Brett A. King, MD, PhD, displayed several before-and-after photos and said, “The photos tell the whole story. This is why there is so much excitement about these drugs.”

THRIVE-AA2 was the second of two phase 3 studies of deuruxolitinib. King was a principal investigator for both pivotal trials, called THRIVE-AA1 and THRIVE AA-2. He characterized the results of the two THRIVE trials as “comparable.”

Dr. King also was a principal investigator for the trials with baricitinib, called BRAVE-AA1 and BRAVE AA-2, which were published last year in the New England Journal of Medicine. The trials for both drugs had similar designs and endpoints.
 

Deuruxolitinib and the THRIVE studies

In the THRIVE-AA2 trial, 517 adult patients were enrolled with moderate to severe alopecia areata, defined as a SALT (Severity of Alopecia Tool) score of ≥ 50%, which signifies a hair loss of at least 50%. Like THRIVE-AA1, patients participated at treatment centers in North America and Europe. About two-thirds were female. The mean age was 39 years. The majority of patients had complete or near complete hair loss at baseline.

“Many of these patients are the ones we have historically characterized as having alopecia totalis or universalis,” Dr. King said.

Participating patients were randomly assigned to 8 mg deuruxolitinib twice daily, 12 mg deuruxolitinib twice daily, or placebo. The primary endpoint was a SALT score of ≤ 20% at week 24.

At 24 weeks, almost no patients in the placebo group (1%) vs. 33% and 38% in the 8 mg and 12 mg twice-daily groups, respectively, met the primary endpoint. Each active treatment group was highly significant vs. placebo.

Of the responders, the majority achieved complete or near complete hair growth as defined by a SALT score of ≤ 10%, Dr. King reported.

Based on a graph that showed a relatively steep climb over the entire 24-week study period, deuruxolitinib “had a really fast onset of action,” Dr. King said. By week 8, which was the time of the first assessment, both doses of deuruxolitinib were superior to placebo.

The majority of patients had complete or significant loss of eyebrows and eye lashes at baseline, but more than two-thirds of these patients had regrowth by week 24, Dr. King said. Again, no significant regrowth was observed in the placebo arm.

On the Satisfaction of Hair Patient Reported Outcomes (SPRO), more than half of patients on both doses reported being satisfied or very satisfied with the improvement when evaluated at 24 weeks.

“The patient satisfaction overshot what one would expect by looking at the SALT scores, but a lot of subjects were at the precipice of the primary endpoint, sitting on SALT scores of 21, 25, or 30,” Dr. King said.
 

High participation in extension trial

More than 90% of the patients assigned to deuruxolitinib completed the trial and have entered an open-label extension (OLE). Dr. King credited the substantial rates of hair growth and the low rate of significant adverse events for the high rate of transition to OLE. Those who experienced the response were motivated to maintain it.  

“This is a devastating disease. Patients want to get better,” Dr. King said.

There were no serious treatment-emergent adverse events associated with deuruxolitinib, including no thromboembolic events or other off-target events that have been reported previously with other JAK inhibitors in other disease states, such as rheumatoid arthritis. Although some adverse events, such as nasopharyngitis, were observed more often in those taking deuruxolitinib than placebo, there were “very few” discontinuations because of an adverse event, he said.

The data of THRIVE-AA2 are wholly compatible with the previously reported 706-patient THRIVE-AA1, according to Dr. King. In THRIVE-AA1, the primary endpoint of SALT ≤ 20% was reached by 29.6%, 41.5%, and 0.8% of the 8 mg, 12 mg, and placebo groups, respectively. Patient satisfaction scores, safety, and tolerability were also similar, according to Dr. King.

The experience with deuruxolitinib in the THRIVE-AA phase 3 program is similar to the experience with baricitinib in the BRAVE-AA trials. Although they cannot be compared directly because of potential differences between study populations, the 4-mg dose of baricitinib also achieved SALT score ≤ 20 in about 35% of patients, he said. The proportion was lower in the 2-mg group but was also superior to the placebo group.

“JAK inhibitors are changing the paradigm of alopecia areata,” Dr. King said. Responding to a question about payers reluctant to reimburse therapies for a “cosmetic” condition, Dr. King added that the effective treatments are “changing the landscape of how we think about this disease.” Dr. King believes these kinds of data show that “we are literally transforming lives forever.”
 

Baricitinib and the BRAVE studies

When baricitinib received regulatory approval for alopecia areata last year, it was not just the first JAK inhibitor approved for this disease, but the first systemic therapy of any kind, according to Maryanne Senna, MD, an assistant professor of dermatology at Harvard Medical School, Boston, and the director of the Lahey Hair Loss Center of Excellence, Burlington, Mass. Dr. Senna was a clinical investigator of BRAVE-AA1, as well as of THRIVE-AA2.

Providing an update on the BRAVE-AA program, Dr. Senna reported 104-week data that appear to support the idea of a life-changing benefit from JAK inhibitor therapy. This is because the effects appear durable.

In the data she presented at the AAD, responders and mixed responders at 52 weeks were followed to 104 weeks. Mixed responders were defined as those without a SALT response of ≤ 20 at week 52 but who had achieved this degree of hair regrowth at some earlier point.

Of the responders, 90% maintained their response at 104 weeks. In addition, many of the mixed responders and patients with a partial response but who never achieved a SALT score ≤ 20% gained additional hair growth, including complete or near complete hair growth, when maintained on treatment over the 2 years of follow-up.

“The follow-up suggests that, if you keep patients on treatment, you can get many of them to a meaningful response,” she said.

Meanwhile, “there have been no new safety signals,” Dr. Senna said. She based this statement not only of the 104-week data but on follow-up of up to 3.6 years among patients who have remained on treatment after participating in previous studies.

According to Dr. Senna, the off-target events that have been reported previously in other diseases with other JAK inhibitors, such as major adverse cardiovascular events and thromboembolic events, have not so far been observed in the BRAVE-AA phase 3 program.

Baricitinib, much like all but one of the JAK inhibitors with dermatologic indications, carries a black box warning that lists multiple risks for drugs in this class, based on a rheumatoid arthritis study.

The Food and Drug Administration has granted deuruxolitinib Breakthrough Therapy designation for the treatment of adult patients with moderate to severe alopecia areata and Fast Track designation for the treatment of alopecia areata, according to its manufacturer Concert Pharmaceuticals.

Dr. King reports financial relationships with more than 15 pharmaceutical companies, including Concert Pharmaceuticals, which provided the funding for the THRIVE-AA trial program, and for Eli Lilly, which provided funding for the BRAVE-AA trial program. Dr. Senna reports financial relationships with Arena pharmaceuticals, Follica, and both Concert Pharmaceuticals and Eli Lilly.

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

Long-term osteoporosis medications are associated with a reduced mortality risk following a fracture, new data suggest.

The findings, from nearly 50,000 individuals in a nationwide Taiwanese database from 2009 until 2018, suggest that alendronate/risedronate, denosumab, and zoledronic acid all result in a significantly lower mortality risk post fracture of 17%-22%, compared with raloxifene and bazedoxifene.

“Treatment for osteoporosis has the potential to minimize mortality risk in people of all ages and sexes for any type of fracture. The longer-acting treatments could lower mortality risk,” wrote Chih-Hsing Wu, MD, of the Institute of Gerontology at National Cheng Kung University, Tainan, Taiwan, and colleagues.

The findings have been published online in the Journal of Clinical Endocrinology and Metabolism.

Robert A. Adler, MD, who is chief of endocrinology at the Central Virginia Veterans Affairs Health Care System, Richmond, told this news organization that he hopes these new findings from a “really good database ... may be helpful in talking to a patient about the pros and cons of taking these drugs.”

“Patients have been made very fearful of the unusual side effects, particularly of the antiresorptive drugs,” which he notes include the rare adverse effects of jaw necrosis and atypical femoral fracture, which occur in about 1 per 10,000 patient-years.

“And because of that we have a hard time convincing people to want to take the drug in the first place or to stay on the drug once they start,” said Dr. Adler, who stressed that his viewpoints are his own and not representative of the VA.

“These data should help reinforce the advice already given in professional guidelines that their benefit outweighs any risks,” he stresses.

Dr. Adler also pointed out that both bisphosphonates included in the study, alendronate and zoledronic acid, are now available as generics and therefore inexpensive, but the latter can be subject to facility fees depending on where the infusion is delivered.

He added that hip fracture, in particular, triples the overall 1-year mortality risk in women aged 75-84 years and quadruples the risk in men. The study’s findings suggest that bisphosphonates, in particular, have pleiotropic effects beyond the bone; however, the underlying mechanisms are hard to determine.

“We don’t know all the reasons why people die after a fracture. These are older people who often have multiple medical problems, so it’s hard to dissect that out,” he said.

But whatever the mechanism for the salutary effect of the drugs, Dr. Adler said: “This is one other factor that might change people’s minds. You’re less likely to die. Well, that’s pretty good.”
 

‘Denosumab is a more potent antiresorptive than bisphosphonates’

Dr. Wu and colleagues analyzed data for individuals from Taiwan’s National Health Insurance Research Database. Between 2009 and 2017, 219,461 individuals had been newly diagnosed with an osteoporotic fracture. Of those, 46,729 were aged 40 and older and had been prescribed at least one anti-osteoporosis medication.

Participants were a mean age of 74.5 years, were 80% women, and 32% died during a mean follow-up of 4.7 years. The most commonly used anti-osteoporosis medications were the bisphosphonates alendronate or risedronate, followed by denosumab and the selective estrogen-receptor modulators (SERMs) daily oral raloxifene or bazedoxifene.

Patients treated with SERMs were used as the reference group because those drugs have been shown to have a neutral effect on mortality.

After adjustments, all but one of the medications had significantly lower mortality risks during follow-up, compared with raloxifene and bazedoxifene.

Compared with SERMs, at all fracture sites, the hazard ratios for mortality were 0.83 for alendronate/risedronate, 0.86 for denosumab, and 0.78 for zoledronic acid. Only ibandronate did not show the same protective effect.

Similar results were found for hip and vertebral fractures analyzed individually.  

Women had a lower mortality risk than men.

Dr. Adler wrote an accompanying editorial for the article by Dr. Wu and colleagues.

Regarding the finding of benefit for denosumab, Dr. Adler notes: “I don’t know of another study that found denosumab leads to lower mortality. On the other hand, denosumab is a more potent antiresorptive than bisphosphonates.”

The study was funded by research grants from the Ministry of Science and Technology, Taiwan, partially supported by a research grant from the Taiwanese Osteoporosis Association and grants from National Cheng Kung University Hospital, Taiwan. Dr. Wu has reported receiving honoraria for lectures, attending meetings, and/or travel from Eli Lilly, Roche, Amgen, Merck, Servier, GE Lunar, Harvester, TCM Biotech, and Alvogen/Lotus. Dr. Adler has reported no relevant financial relationships.

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

Long-term osteoporosis medications are associated with a reduced mortality risk following a fracture, new data suggest.

The findings, from nearly 50,000 individuals in a nationwide Taiwanese database from 2009 until 2018, suggest that alendronate/risedronate, denosumab, and zoledronic acid all result in a significantly lower mortality risk post fracture of 17%-22%, compared with raloxifene and bazedoxifene.

“Treatment for osteoporosis has the potential to minimize mortality risk in people of all ages and sexes for any type of fracture. The longer-acting treatments could lower mortality risk,” wrote Chih-Hsing Wu, MD, of the Institute of Gerontology at National Cheng Kung University, Tainan, Taiwan, and colleagues.

The findings have been published online in the Journal of Clinical Endocrinology and Metabolism.

Robert A. Adler, MD, who is chief of endocrinology at the Central Virginia Veterans Affairs Health Care System, Richmond, told this news organization that he hopes these new findings from a “really good database ... may be helpful in talking to a patient about the pros and cons of taking these drugs.”

“Patients have been made very fearful of the unusual side effects, particularly of the antiresorptive drugs,” which he notes include the rare adverse effects of jaw necrosis and atypical femoral fracture, which occur in about 1 per 10,000 patient-years.

“And because of that we have a hard time convincing people to want to take the drug in the first place or to stay on the drug once they start,” said Dr. Adler, who stressed that his viewpoints are his own and not representative of the VA.

“These data should help reinforce the advice already given in professional guidelines that their benefit outweighs any risks,” he stresses.

Dr. Adler also pointed out that both bisphosphonates included in the study, alendronate and zoledronic acid, are now available as generics and therefore inexpensive, but the latter can be subject to facility fees depending on where the infusion is delivered.

He added that hip fracture, in particular, triples the overall 1-year mortality risk in women aged 75-84 years and quadruples the risk in men. The study’s findings suggest that bisphosphonates, in particular, have pleiotropic effects beyond the bone; however, the underlying mechanisms are hard to determine.

“We don’t know all the reasons why people die after a fracture. These are older people who often have multiple medical problems, so it’s hard to dissect that out,” he said.

But whatever the mechanism for the salutary effect of the drugs, Dr. Adler said: “This is one other factor that might change people’s minds. You’re less likely to die. Well, that’s pretty good.”
 

‘Denosumab is a more potent antiresorptive than bisphosphonates’

Dr. Wu and colleagues analyzed data for individuals from Taiwan’s National Health Insurance Research Database. Between 2009 and 2017, 219,461 individuals had been newly diagnosed with an osteoporotic fracture. Of those, 46,729 were aged 40 and older and had been prescribed at least one anti-osteoporosis medication.

Participants were a mean age of 74.5 years, were 80% women, and 32% died during a mean follow-up of 4.7 years. The most commonly used anti-osteoporosis medications were the bisphosphonates alendronate or risedronate, followed by denosumab and the selective estrogen-receptor modulators (SERMs) daily oral raloxifene or bazedoxifene.

Patients treated with SERMs were used as the reference group because those drugs have been shown to have a neutral effect on mortality.

After adjustments, all but one of the medications had significantly lower mortality risks during follow-up, compared with raloxifene and bazedoxifene.

Compared with SERMs, at all fracture sites, the hazard ratios for mortality were 0.83 for alendronate/risedronate, 0.86 for denosumab, and 0.78 for zoledronic acid. Only ibandronate did not show the same protective effect.

Similar results were found for hip and vertebral fractures analyzed individually.  

Women had a lower mortality risk than men.

Dr. Adler wrote an accompanying editorial for the article by Dr. Wu and colleagues.

Regarding the finding of benefit for denosumab, Dr. Adler notes: “I don’t know of another study that found denosumab leads to lower mortality. On the other hand, denosumab is a more potent antiresorptive than bisphosphonates.”

The study was funded by research grants from the Ministry of Science and Technology, Taiwan, partially supported by a research grant from the Taiwanese Osteoporosis Association and grants from National Cheng Kung University Hospital, Taiwan. Dr. Wu has reported receiving honoraria for lectures, attending meetings, and/or travel from Eli Lilly, Roche, Amgen, Merck, Servier, GE Lunar, Harvester, TCM Biotech, and Alvogen/Lotus. Dr. Adler has reported no relevant financial relationships.

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

Long-term osteoporosis medications are associated with a reduced mortality risk following a fracture, new data suggest.

The findings, from nearly 50,000 individuals in a nationwide Taiwanese database from 2009 until 2018, suggest that alendronate/risedronate, denosumab, and zoledronic acid all result in a significantly lower mortality risk post fracture of 17%-22%, compared with raloxifene and bazedoxifene.

“Treatment for osteoporosis has the potential to minimize mortality risk in people of all ages and sexes for any type of fracture. The longer-acting treatments could lower mortality risk,” wrote Chih-Hsing Wu, MD, of the Institute of Gerontology at National Cheng Kung University, Tainan, Taiwan, and colleagues.

The findings have been published online in the Journal of Clinical Endocrinology and Metabolism.

Robert A. Adler, MD, who is chief of endocrinology at the Central Virginia Veterans Affairs Health Care System, Richmond, told this news organization that he hopes these new findings from a “really good database ... may be helpful in talking to a patient about the pros and cons of taking these drugs.”

“Patients have been made very fearful of the unusual side effects, particularly of the antiresorptive drugs,” which he notes include the rare adverse effects of jaw necrosis and atypical femoral fracture, which occur in about 1 per 10,000 patient-years.

“And because of that we have a hard time convincing people to want to take the drug in the first place or to stay on the drug once they start,” said Dr. Adler, who stressed that his viewpoints are his own and not representative of the VA.

“These data should help reinforce the advice already given in professional guidelines that their benefit outweighs any risks,” he stresses.

Dr. Adler also pointed out that both bisphosphonates included in the study, alendronate and zoledronic acid, are now available as generics and therefore inexpensive, but the latter can be subject to facility fees depending on where the infusion is delivered.

He added that hip fracture, in particular, triples the overall 1-year mortality risk in women aged 75-84 years and quadruples the risk in men. The study’s findings suggest that bisphosphonates, in particular, have pleiotropic effects beyond the bone; however, the underlying mechanisms are hard to determine.

“We don’t know all the reasons why people die after a fracture. These are older people who often have multiple medical problems, so it’s hard to dissect that out,” he said.

But whatever the mechanism for the salutary effect of the drugs, Dr. Adler said: “This is one other factor that might change people’s minds. You’re less likely to die. Well, that’s pretty good.”
 

‘Denosumab is a more potent antiresorptive than bisphosphonates’

Dr. Wu and colleagues analyzed data for individuals from Taiwan’s National Health Insurance Research Database. Between 2009 and 2017, 219,461 individuals had been newly diagnosed with an osteoporotic fracture. Of those, 46,729 were aged 40 and older and had been prescribed at least one anti-osteoporosis medication.

Participants were a mean age of 74.5 years, were 80% women, and 32% died during a mean follow-up of 4.7 years. The most commonly used anti-osteoporosis medications were the bisphosphonates alendronate or risedronate, followed by denosumab and the selective estrogen-receptor modulators (SERMs) daily oral raloxifene or bazedoxifene.

Patients treated with SERMs were used as the reference group because those drugs have been shown to have a neutral effect on mortality.

After adjustments, all but one of the medications had significantly lower mortality risks during follow-up, compared with raloxifene and bazedoxifene.

Compared with SERMs, at all fracture sites, the hazard ratios for mortality were 0.83 for alendronate/risedronate, 0.86 for denosumab, and 0.78 for zoledronic acid. Only ibandronate did not show the same protective effect.

Similar results were found for hip and vertebral fractures analyzed individually.  

Women had a lower mortality risk than men.

Dr. Adler wrote an accompanying editorial for the article by Dr. Wu and colleagues.

Regarding the finding of benefit for denosumab, Dr. Adler notes: “I don’t know of another study that found denosumab leads to lower mortality. On the other hand, denosumab is a more potent antiresorptive than bisphosphonates.”

The study was funded by research grants from the Ministry of Science and Technology, Taiwan, partially supported by a research grant from the Taiwanese Osteoporosis Association and grants from National Cheng Kung University Hospital, Taiwan. Dr. Wu has reported receiving honoraria for lectures, attending meetings, and/or travel from Eli Lilly, Roche, Amgen, Merck, Servier, GE Lunar, Harvester, TCM Biotech, and Alvogen/Lotus. Dr. Adler has reported no relevant financial relationships.

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

Ascend Laboratories is recalling 10 lots of the oral anticoagulant dabigatran etexilate capsules (75 mg and 150 mg) because of unacceptable levels of a potential carcinogen.

The nationwide recall, to the consumer level, is because of the detection of the nitrosamine impurity, N-nitroso-dabigatran, which may increase the risk of cancer with prolonged exposure to levels higher than acceptable.

To date, Ascend Laboratories has not received any reports of adverse events related to this recall.

The recalled product was distributed nationwide to wholesalers, distributors, and retailers in the United States from June 2022 to October 2022.

Complete details of the recalled product, including national drug code, lot numbers, expiration dates, and configuration/counts, are provided in a company announcement that was posted on the Food and Drug Administration website.

The company is advising patients who have any dabigatran that has been recalled to continue taking their medication and to contact their physician for advice regarding an alternative treatment.

Wholesalers/distributors and pharmacies with an existing inventory of the affected lots should stop use and distribution and quarantine the product immediately. Wholesalers and distributors should also recall the distributed product.

Questions regarding this recall can call Ascend Laboratories at 877.272.7901 (24 hours, 7 days a week).

Problems with this product should be reported to the FDA through MedWatch, its adverse event reporting program.

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

Ascend Laboratories is recalling 10 lots of the oral anticoagulant dabigatran etexilate capsules (75 mg and 150 mg) because of unacceptable levels of a potential carcinogen.

The nationwide recall, to the consumer level, is because of the detection of the nitrosamine impurity, N-nitroso-dabigatran, which may increase the risk of cancer with prolonged exposure to levels higher than acceptable.

To date, Ascend Laboratories has not received any reports of adverse events related to this recall.

The recalled product was distributed nationwide to wholesalers, distributors, and retailers in the United States from June 2022 to October 2022.

Complete details of the recalled product, including national drug code, lot numbers, expiration dates, and configuration/counts, are provided in a company announcement that was posted on the Food and Drug Administration website.

The company is advising patients who have any dabigatran that has been recalled to continue taking their medication and to contact their physician for advice regarding an alternative treatment.

Wholesalers/distributors and pharmacies with an existing inventory of the affected lots should stop use and distribution and quarantine the product immediately. Wholesalers and distributors should also recall the distributed product.

Questions regarding this recall can call Ascend Laboratories at 877.272.7901 (24 hours, 7 days a week).

Problems with this product should be reported to the FDA through MedWatch, its adverse event reporting program.

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

Ascend Laboratories is recalling 10 lots of the oral anticoagulant dabigatran etexilate capsules (75 mg and 150 mg) because of unacceptable levels of a potential carcinogen.

The nationwide recall, to the consumer level, is because of the detection of the nitrosamine impurity, N-nitroso-dabigatran, which may increase the risk of cancer with prolonged exposure to levels higher than acceptable.

To date, Ascend Laboratories has not received any reports of adverse events related to this recall.

The recalled product was distributed nationwide to wholesalers, distributors, and retailers in the United States from June 2022 to October 2022.

Complete details of the recalled product, including national drug code, lot numbers, expiration dates, and configuration/counts, are provided in a company announcement that was posted on the Food and Drug Administration website.

The company is advising patients who have any dabigatran that has been recalled to continue taking their medication and to contact their physician for advice regarding an alternative treatment.

Wholesalers/distributors and pharmacies with an existing inventory of the affected lots should stop use and distribution and quarantine the product immediately. Wholesalers and distributors should also recall the distributed product.

Questions regarding this recall can call Ascend Laboratories at 877.272.7901 (24 hours, 7 days a week).

Problems with this product should be reported to the FDA through MedWatch, its adverse event reporting program.

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

Even after endorsement in updated guidelines, hydroxyurea is substantially underused in youth with sickle cell anemia (SCA), new research indicates.

SCA can lead to pain crises, stroke, and early death. Hydroxyurea, an oral disease-modifying medication, can reduce the complications.

In 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered as the primary therapy to all patients who were at least 9 months old and living with SCA, regardless of disease severity.
 

Low uptake even after guideline revision

Yet, a research team led by Sarah L. Reeves, PhD, MPH, with the Child Health Evaluation and Research Center at University of Michigan, Ann Arbor, found in their study of use in two sample states – Michigan and New York – that hydroxyurea use was low in children and adolescents enrolled in Medicaid and increased only slightly in Michigan and not at all in New York after the guideline revision.

After the guidelines were updated, the researchers observed that, on average, children and adolescents were getting the medication less than a third of the days in a year (32% maximum in the year with the highest uptake). The data were gathered from a study population that included 4,302 youths aged 1-17 years with SCA.

Findings were published online in JAMA Network Open.
 

‘A national issue’

Russell Ware, MD, PhD, chair of hematology translational research at Cincinnati Children’s Hospital, who was not part of the research, says that though data were gathered from Michigan and New York, “this is a national issue.”

Dr. Ware says the main problem is the way the health system describes the importance of hydroxyurea.

“There needs to be a realization that hydroxyurea is the standard of care for children with sickle cell anemia. It’s not just something they should take when they’re sick,” Dr. Ware said.

He added, “If you have diabetes, should you only take insulin if you’re really sick and hospitalized with a diabetic coma? Of course not.”

He said often providers aren’t giving a clear and consistent message to families.

“They’re not all sure they want to recommend it. They might offer it,” Dr. Ware said, which jeopardizes uptake. “Providers need to be more committed to it. They need to know how to dose it.”
 

Bad rap from past indications

Dr. Ware says hydroxyurea also gets a bad rap from use decades ago as a chemotherapeutic agent for cancer and then as an anti-HIV medication.

Now it’s used in a completely different way with SCA, but the fear of the association lingers.

“This label as a chemotherapeutic agent has really dogged hydroxyurea,” he said. “It’s a completely different mechanism. It’s a different dose. It’s a different purpose.”

The message to families should be more direct, he says: “Your child has sickle cell anemia and needs to be on disease-modifying therapy because this is a life-threatening disease.”

The underuse of this drug is particularly ironic, he says, as each capsule, taken daily, “costs about fifty cents.”
 

Medicaid support critical

Authors conclude that multifaceted interventions may be necessary to increase the number of filled prescriptions and use. They also point out that the interventions rely on states’ Medicaid support regarding hydroxyurea use. From 70% to 90% of young people with SCA are covered by Medicaid at some point, the researchers write.

“Variation may exist across states, as well as within states, in the coverage of hydroxyurea, outpatient visits, and associated lab monitoring,” they note.

The authors point to interventions in clinical trials that have had some success in hydroxyurea use.

Creary et al., for example, found that electronic directly observed therapy was associated with high adherence. That involved sending daily texts to patients to take hydroxyurea and patients recording and sending daily videos that show they took the medication.

The authors add that incorporating clinical pharmacists into the care team to provide education and support for families has been shown to be associated with successful outcomes for other chronic conditions – this approach may be particularly well suited to hydroxyurea given that this medication requires significant dosage monitoring.

Dr. Ware, however, says that solutions should focus on the health system more clearly communicating that hydroxyurea is the standard of care for all kids with SCA.

“We need to dispel these myths and these labels that are unfairly attributed to it. Then we’d probably do a lot better,” he said.

He added that children with SCA, “are a marginalized, neglected population of patients historically,” and addressing social determinants of health is also important in getting better uptake.

“Our pharmacy, for example, ships the drug to the families if they’re just getting a refill rather than making them drive all the way in,” Dr. Ware says.

Dr. Ware said given the interruption in doctor/patient relationships in the pandemic, the poor uptake of hydroxyurea could be even worse now.

The work was funded by the Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute. Coauthor Dr. Green was the principal investigator of an NIH-funded trial of hydroxyurea in Uganda with a study drug provided by Siklos. No other author disclosures were reported. In addition to receiving research funding from the National Institutes of Health, Dr. Ware receives research donations from Bristol Myers Squibb, Addmedica, and Hemex Health. He is a medical adviser for Nova Laboratories and Octapharma, and serves on Data Safety Monitoring Boards for Novartis and Editas.
 

Even after endorsement in updated guidelines, hydroxyurea is substantially underused in youth with sickle cell anemia (SCA), new research indicates.

SCA can lead to pain crises, stroke, and early death. Hydroxyurea, an oral disease-modifying medication, can reduce the complications.

In 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered as the primary therapy to all patients who were at least 9 months old and living with SCA, regardless of disease severity.
 

Low uptake even after guideline revision

Yet, a research team led by Sarah L. Reeves, PhD, MPH, with the Child Health Evaluation and Research Center at University of Michigan, Ann Arbor, found in their study of use in two sample states – Michigan and New York – that hydroxyurea use was low in children and adolescents enrolled in Medicaid and increased only slightly in Michigan and not at all in New York after the guideline revision.

After the guidelines were updated, the researchers observed that, on average, children and adolescents were getting the medication less than a third of the days in a year (32% maximum in the year with the highest uptake). The data were gathered from a study population that included 4,302 youths aged 1-17 years with SCA.

Findings were published online in JAMA Network Open.
 

‘A national issue’

Russell Ware, MD, PhD, chair of hematology translational research at Cincinnati Children’s Hospital, who was not part of the research, says that though data were gathered from Michigan and New York, “this is a national issue.”

Dr. Ware says the main problem is the way the health system describes the importance of hydroxyurea.

“There needs to be a realization that hydroxyurea is the standard of care for children with sickle cell anemia. It’s not just something they should take when they’re sick,” Dr. Ware said.

He added, “If you have diabetes, should you only take insulin if you’re really sick and hospitalized with a diabetic coma? Of course not.”

He said often providers aren’t giving a clear and consistent message to families.

“They’re not all sure they want to recommend it. They might offer it,” Dr. Ware said, which jeopardizes uptake. “Providers need to be more committed to it. They need to know how to dose it.”
 

Bad rap from past indications

Dr. Ware says hydroxyurea also gets a bad rap from use decades ago as a chemotherapeutic agent for cancer and then as an anti-HIV medication.

Now it’s used in a completely different way with SCA, but the fear of the association lingers.

“This label as a chemotherapeutic agent has really dogged hydroxyurea,” he said. “It’s a completely different mechanism. It’s a different dose. It’s a different purpose.”

The message to families should be more direct, he says: “Your child has sickle cell anemia and needs to be on disease-modifying therapy because this is a life-threatening disease.”

The underuse of this drug is particularly ironic, he says, as each capsule, taken daily, “costs about fifty cents.”
 

Medicaid support critical

Authors conclude that multifaceted interventions may be necessary to increase the number of filled prescriptions and use. They also point out that the interventions rely on states’ Medicaid support regarding hydroxyurea use. From 70% to 90% of young people with SCA are covered by Medicaid at some point, the researchers write.

“Variation may exist across states, as well as within states, in the coverage of hydroxyurea, outpatient visits, and associated lab monitoring,” they note.

The authors point to interventions in clinical trials that have had some success in hydroxyurea use.

Creary et al., for example, found that electronic directly observed therapy was associated with high adherence. That involved sending daily texts to patients to take hydroxyurea and patients recording and sending daily videos that show they took the medication.

The authors add that incorporating clinical pharmacists into the care team to provide education and support for families has been shown to be associated with successful outcomes for other chronic conditions – this approach may be particularly well suited to hydroxyurea given that this medication requires significant dosage monitoring.

Dr. Ware, however, says that solutions should focus on the health system more clearly communicating that hydroxyurea is the standard of care for all kids with SCA.

“We need to dispel these myths and these labels that are unfairly attributed to it. Then we’d probably do a lot better,” he said.

He added that children with SCA, “are a marginalized, neglected population of patients historically,” and addressing social determinants of health is also important in getting better uptake.

“Our pharmacy, for example, ships the drug to the families if they’re just getting a refill rather than making them drive all the way in,” Dr. Ware says.

Dr. Ware said given the interruption in doctor/patient relationships in the pandemic, the poor uptake of hydroxyurea could be even worse now.

The work was funded by the Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute. Coauthor Dr. Green was the principal investigator of an NIH-funded trial of hydroxyurea in Uganda with a study drug provided by Siklos. No other author disclosures were reported. In addition to receiving research funding from the National Institutes of Health, Dr. Ware receives research donations from Bristol Myers Squibb, Addmedica, and Hemex Health. He is a medical adviser for Nova Laboratories and Octapharma, and serves on Data Safety Monitoring Boards for Novartis and Editas.
 

Even after endorsement in updated guidelines, hydroxyurea is substantially underused in youth with sickle cell anemia (SCA), new research indicates.

SCA can lead to pain crises, stroke, and early death. Hydroxyurea, an oral disease-modifying medication, can reduce the complications.

In 2014, the National Heart, Lung, and Blood Institute published revised guidelines that hydroxyurea should be offered as the primary therapy to all patients who were at least 9 months old and living with SCA, regardless of disease severity.
 

Low uptake even after guideline revision

Yet, a research team led by Sarah L. Reeves, PhD, MPH, with the Child Health Evaluation and Research Center at University of Michigan, Ann Arbor, found in their study of use in two sample states – Michigan and New York – that hydroxyurea use was low in children and adolescents enrolled in Medicaid and increased only slightly in Michigan and not at all in New York after the guideline revision.

After the guidelines were updated, the researchers observed that, on average, children and adolescents were getting the medication less than a third of the days in a year (32% maximum in the year with the highest uptake). The data were gathered from a study population that included 4,302 youths aged 1-17 years with SCA.

Findings were published online in JAMA Network Open.
 

‘A national issue’

Russell Ware, MD, PhD, chair of hematology translational research at Cincinnati Children’s Hospital, who was not part of the research, says that though data were gathered from Michigan and New York, “this is a national issue.”

Dr. Ware says the main problem is the way the health system describes the importance of hydroxyurea.

“There needs to be a realization that hydroxyurea is the standard of care for children with sickle cell anemia. It’s not just something they should take when they’re sick,” Dr. Ware said.

He added, “If you have diabetes, should you only take insulin if you’re really sick and hospitalized with a diabetic coma? Of course not.”

He said often providers aren’t giving a clear and consistent message to families.

“They’re not all sure they want to recommend it. They might offer it,” Dr. Ware said, which jeopardizes uptake. “Providers need to be more committed to it. They need to know how to dose it.”
 

Bad rap from past indications

Dr. Ware says hydroxyurea also gets a bad rap from use decades ago as a chemotherapeutic agent for cancer and then as an anti-HIV medication.

Now it’s used in a completely different way with SCA, but the fear of the association lingers.

“This label as a chemotherapeutic agent has really dogged hydroxyurea,” he said. “It’s a completely different mechanism. It’s a different dose. It’s a different purpose.”

The message to families should be more direct, he says: “Your child has sickle cell anemia and needs to be on disease-modifying therapy because this is a life-threatening disease.”

The underuse of this drug is particularly ironic, he says, as each capsule, taken daily, “costs about fifty cents.”
 

Medicaid support critical

Authors conclude that multifaceted interventions may be necessary to increase the number of filled prescriptions and use. They also point out that the interventions rely on states’ Medicaid support regarding hydroxyurea use. From 70% to 90% of young people with SCA are covered by Medicaid at some point, the researchers write.

“Variation may exist across states, as well as within states, in the coverage of hydroxyurea, outpatient visits, and associated lab monitoring,” they note.

The authors point to interventions in clinical trials that have had some success in hydroxyurea use.

Creary et al., for example, found that electronic directly observed therapy was associated with high adherence. That involved sending daily texts to patients to take hydroxyurea and patients recording and sending daily videos that show they took the medication.

The authors add that incorporating clinical pharmacists into the care team to provide education and support for families has been shown to be associated with successful outcomes for other chronic conditions – this approach may be particularly well suited to hydroxyurea given that this medication requires significant dosage monitoring.

Dr. Ware, however, says that solutions should focus on the health system more clearly communicating that hydroxyurea is the standard of care for all kids with SCA.

“We need to dispel these myths and these labels that are unfairly attributed to it. Then we’d probably do a lot better,” he said.

He added that children with SCA, “are a marginalized, neglected population of patients historically,” and addressing social determinants of health is also important in getting better uptake.

“Our pharmacy, for example, ships the drug to the families if they’re just getting a refill rather than making them drive all the way in,” Dr. Ware says.

Dr. Ware said given the interruption in doctor/patient relationships in the pandemic, the poor uptake of hydroxyurea could be even worse now.

The work was funded by the Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute. Coauthor Dr. Green was the principal investigator of an NIH-funded trial of hydroxyurea in Uganda with a study drug provided by Siklos. No other author disclosures were reported. In addition to receiving research funding from the National Institutes of Health, Dr. Ware receives research donations from Bristol Myers Squibb, Addmedica, and Hemex Health. He is a medical adviser for Nova Laboratories and Octapharma, and serves on Data Safety Monitoring Boards for Novartis and Editas.
 

NEW ORLEANS – Treatment of patients with heart failure with preserved ejection fraction (HFpEF) with the SGLT2 inhibitor dapagliflozin (Farxiga) for 24 weeks produced significant and beneficial reductions in left-heart filling pressures in a mechanistic, randomized clinical study.

The findings “provide new insight into the mechanisms underlying the favorable clinical effects of dapagliflozin in patients with HFpEF,” Barry A. Borlaug, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. “Elevations in left heart filling pressures at rest and during exercise are fundamental pathophysiologic features of HFpEF,” he noted.

Results from prior studies documented the benefit of dapagliflozin for improving clinical outcomes in patients with HFpEF in the DELIVER trial, and for the related sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) in the EMPEROR-Preserved trial. The new findings presented by Dr. Borlaug provide evidence from a placebo-controlled, prospective study for one way by which these SGLT2 inhibitors exert this benefit in patients with HFpEF.

The results of his single-center study showed that, in patients with HFpEF who also exhibited “severe” elevations in pulmonary capillary wedge pressure (PCWP) during exercise, 24 weeks of treatment with dapagliflozin led to a significant reduction in PCWP during exercise. The treatment produced an average 6.1–mm Hg drop from baseline compared with control patients who received placebo. A similar pattern occurred when these patients were at rest, when dapagliflozin treatment linked with a significant average reduction in PCWP from baseline of 3.5 mm Hg compared with controls.
 

Improving a ‘specific and fundamental’ feature of HFpEF

“This fantastic study looked at one of the fundamental aspects of HFpEF,” said John R. Teerlink, MD, designated discussant for the study. “You’ve shown that dapagliflozin targets a specific and fundamental” manifestation of HFpEF by lowering PCWP, said Dr. Teerlink, director of Heart Failure at the San Francisco Veterans Affairs Medical Center.

However, Dr. Teerlink added, the study did not directly address the related question of what physiologic action of dapagliflozin produces this notable drop in PCWP.

“We’re just starting to look at that,” replied Dr. Borlaug, a cardiologist and professor at the Mayo Clinic in Rochester, Minn.

He reported finding an intriguing correlate in the current study linked to the cut in PCWP with dapagliflozin treatment. The SGLT2 inhibitor at a standard daily 10-mg dose produced an average 3.5-kg drop in body weight in the dapagliflozin-treated patients that significantly linked with the changes in PCWP both at rest and during exercise. Dapagliflozin-treated patients also showed a significant reduction from their baseline plasma volume compared with placebo-treated patients, but this “poorly correlated” with the dapagliflozin-linked cuts in PCWP, Dr. Borlaug said.

“I don’t think this means weight loss is the cause of the hemodynamic benefit, but maybe it’s an indicator. When patients [with HFpEF] lose weight, they are in a metabolic state that leads to good changes in hemodynamics,” he suggested. “My guess is that there is probably a combination of many different little things [caused by dapagliflozin treatment of patients with HFpEF] that together result in the 20%-25% relative improvement we see in filling pressure.”
 

An ‘obese, cardiometabolic’ HFpEF phenotype

The study enrolled patients with HFpEF and a left ventricular ejection fraction of at least 50%, a New York Heart Association functional class of 2 or 3, and a PCWP during exercise of at least 25 mm Hg. Of the 37 evaluable patients, about two-thirds of the patients were women, more than two-thirds were in functional class 3, about 70% were obese, and their average ejection fraction was about 62%. The study excluded patients with HFpEF who also had type 1 diabetes, cardiomyopathy, pericardial disease, or other causes of dyspnea or heart failure.

Dr. Teerlink asked about the generalizability of the findings, as the study cohort seemed to differ in certain respects from the patients enrolled in the DELIVER trial, and because of the many apparently distinct patient phenotypes that exist within the scope of HFpEF.

An “obese, cardiometabolic phenotype” predominated the study cohort, Dr. Borlaug said. “The patients we enrolled look like the HFpEF patients seen in U.S. clinics.” However, he added that “in reality, many [HFpEF phenotypes] coexist in one patient. It’s not that simple,” that every patient with HFpEF can be categorized into a single HFpEF phenotype.

The researchers monitored PCWP invasively with high-fidelity micromanometer catheters.

The study was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Borlaug has received research funding from AstraZeneca, as well as from Corvia, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax. Dr. Teerlink has had financial relationships with AstraZeneca, as well as with Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics.

NEW ORLEANS – Treatment of patients with heart failure with preserved ejection fraction (HFpEF) with the SGLT2 inhibitor dapagliflozin (Farxiga) for 24 weeks produced significant and beneficial reductions in left-heart filling pressures in a mechanistic, randomized clinical study.

The findings “provide new insight into the mechanisms underlying the favorable clinical effects of dapagliflozin in patients with HFpEF,” Barry A. Borlaug, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. “Elevations in left heart filling pressures at rest and during exercise are fundamental pathophysiologic features of HFpEF,” he noted.

Results from prior studies documented the benefit of dapagliflozin for improving clinical outcomes in patients with HFpEF in the DELIVER trial, and for the related sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) in the EMPEROR-Preserved trial. The new findings presented by Dr. Borlaug provide evidence from a placebo-controlled, prospective study for one way by which these SGLT2 inhibitors exert this benefit in patients with HFpEF.

The results of his single-center study showed that, in patients with HFpEF who also exhibited “severe” elevations in pulmonary capillary wedge pressure (PCWP) during exercise, 24 weeks of treatment with dapagliflozin led to a significant reduction in PCWP during exercise. The treatment produced an average 6.1–mm Hg drop from baseline compared with control patients who received placebo. A similar pattern occurred when these patients were at rest, when dapagliflozin treatment linked with a significant average reduction in PCWP from baseline of 3.5 mm Hg compared with controls.
 

Improving a ‘specific and fundamental’ feature of HFpEF

“This fantastic study looked at one of the fundamental aspects of HFpEF,” said John R. Teerlink, MD, designated discussant for the study. “You’ve shown that dapagliflozin targets a specific and fundamental” manifestation of HFpEF by lowering PCWP, said Dr. Teerlink, director of Heart Failure at the San Francisco Veterans Affairs Medical Center.

However, Dr. Teerlink added, the study did not directly address the related question of what physiologic action of dapagliflozin produces this notable drop in PCWP.

“We’re just starting to look at that,” replied Dr. Borlaug, a cardiologist and professor at the Mayo Clinic in Rochester, Minn.

He reported finding an intriguing correlate in the current study linked to the cut in PCWP with dapagliflozin treatment. The SGLT2 inhibitor at a standard daily 10-mg dose produced an average 3.5-kg drop in body weight in the dapagliflozin-treated patients that significantly linked with the changes in PCWP both at rest and during exercise. Dapagliflozin-treated patients also showed a significant reduction from their baseline plasma volume compared with placebo-treated patients, but this “poorly correlated” with the dapagliflozin-linked cuts in PCWP, Dr. Borlaug said.

“I don’t think this means weight loss is the cause of the hemodynamic benefit, but maybe it’s an indicator. When patients [with HFpEF] lose weight, they are in a metabolic state that leads to good changes in hemodynamics,” he suggested. “My guess is that there is probably a combination of many different little things [caused by dapagliflozin treatment of patients with HFpEF] that together result in the 20%-25% relative improvement we see in filling pressure.”
 

An ‘obese, cardiometabolic’ HFpEF phenotype

The study enrolled patients with HFpEF and a left ventricular ejection fraction of at least 50%, a New York Heart Association functional class of 2 or 3, and a PCWP during exercise of at least 25 mm Hg. Of the 37 evaluable patients, about two-thirds of the patients were women, more than two-thirds were in functional class 3, about 70% were obese, and their average ejection fraction was about 62%. The study excluded patients with HFpEF who also had type 1 diabetes, cardiomyopathy, pericardial disease, or other causes of dyspnea or heart failure.

Dr. Teerlink asked about the generalizability of the findings, as the study cohort seemed to differ in certain respects from the patients enrolled in the DELIVER trial, and because of the many apparently distinct patient phenotypes that exist within the scope of HFpEF.

An “obese, cardiometabolic phenotype” predominated the study cohort, Dr. Borlaug said. “The patients we enrolled look like the HFpEF patients seen in U.S. clinics.” However, he added that “in reality, many [HFpEF phenotypes] coexist in one patient. It’s not that simple,” that every patient with HFpEF can be categorized into a single HFpEF phenotype.

The researchers monitored PCWP invasively with high-fidelity micromanometer catheters.

The study was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Borlaug has received research funding from AstraZeneca, as well as from Corvia, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax. Dr. Teerlink has had financial relationships with AstraZeneca, as well as with Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics.

NEW ORLEANS – Treatment of patients with heart failure with preserved ejection fraction (HFpEF) with the SGLT2 inhibitor dapagliflozin (Farxiga) for 24 weeks produced significant and beneficial reductions in left-heart filling pressures in a mechanistic, randomized clinical study.

The findings “provide new insight into the mechanisms underlying the favorable clinical effects of dapagliflozin in patients with HFpEF,” Barry A. Borlaug, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. “Elevations in left heart filling pressures at rest and during exercise are fundamental pathophysiologic features of HFpEF,” he noted.

Results from prior studies documented the benefit of dapagliflozin for improving clinical outcomes in patients with HFpEF in the DELIVER trial, and for the related sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) in the EMPEROR-Preserved trial. The new findings presented by Dr. Borlaug provide evidence from a placebo-controlled, prospective study for one way by which these SGLT2 inhibitors exert this benefit in patients with HFpEF.

The results of his single-center study showed that, in patients with HFpEF who also exhibited “severe” elevations in pulmonary capillary wedge pressure (PCWP) during exercise, 24 weeks of treatment with dapagliflozin led to a significant reduction in PCWP during exercise. The treatment produced an average 6.1–mm Hg drop from baseline compared with control patients who received placebo. A similar pattern occurred when these patients were at rest, when dapagliflozin treatment linked with a significant average reduction in PCWP from baseline of 3.5 mm Hg compared with controls.
 

Improving a ‘specific and fundamental’ feature of HFpEF

“This fantastic study looked at one of the fundamental aspects of HFpEF,” said John R. Teerlink, MD, designated discussant for the study. “You’ve shown that dapagliflozin targets a specific and fundamental” manifestation of HFpEF by lowering PCWP, said Dr. Teerlink, director of Heart Failure at the San Francisco Veterans Affairs Medical Center.

However, Dr. Teerlink added, the study did not directly address the related question of what physiologic action of dapagliflozin produces this notable drop in PCWP.

“We’re just starting to look at that,” replied Dr. Borlaug, a cardiologist and professor at the Mayo Clinic in Rochester, Minn.

He reported finding an intriguing correlate in the current study linked to the cut in PCWP with dapagliflozin treatment. The SGLT2 inhibitor at a standard daily 10-mg dose produced an average 3.5-kg drop in body weight in the dapagliflozin-treated patients that significantly linked with the changes in PCWP both at rest and during exercise. Dapagliflozin-treated patients also showed a significant reduction from their baseline plasma volume compared with placebo-treated patients, but this “poorly correlated” with the dapagliflozin-linked cuts in PCWP, Dr. Borlaug said.

“I don’t think this means weight loss is the cause of the hemodynamic benefit, but maybe it’s an indicator. When patients [with HFpEF] lose weight, they are in a metabolic state that leads to good changes in hemodynamics,” he suggested. “My guess is that there is probably a combination of many different little things [caused by dapagliflozin treatment of patients with HFpEF] that together result in the 20%-25% relative improvement we see in filling pressure.”
 

An ‘obese, cardiometabolic’ HFpEF phenotype

The study enrolled patients with HFpEF and a left ventricular ejection fraction of at least 50%, a New York Heart Association functional class of 2 or 3, and a PCWP during exercise of at least 25 mm Hg. Of the 37 evaluable patients, about two-thirds of the patients were women, more than two-thirds were in functional class 3, about 70% were obese, and their average ejection fraction was about 62%. The study excluded patients with HFpEF who also had type 1 diabetes, cardiomyopathy, pericardial disease, or other causes of dyspnea or heart failure.

Dr. Teerlink asked about the generalizability of the findings, as the study cohort seemed to differ in certain respects from the patients enrolled in the DELIVER trial, and because of the many apparently distinct patient phenotypes that exist within the scope of HFpEF.

An “obese, cardiometabolic phenotype” predominated the study cohort, Dr. Borlaug said. “The patients we enrolled look like the HFpEF patients seen in U.S. clinics.” However, he added that “in reality, many [HFpEF phenotypes] coexist in one patient. It’s not that simple,” that every patient with HFpEF can be categorized into a single HFpEF phenotype.

The researchers monitored PCWP invasively with high-fidelity micromanometer catheters.

The study was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Borlaug has received research funding from AstraZeneca, as well as from Corvia, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, and Tenax. Dr. Teerlink has had financial relationships with AstraZeneca, as well as with Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics.

The Food and Drug Administration has approved retifanlimab-dlwr (Zynyz), an intravenous programmed death–1 (PD-1) inhibitor, for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC), the agency announced.

This marks the first regulatory approval for the PD-1 inhibitor. The FDA granted accelerated approval for the drug on the basis of tumor response rate and duration of response from the POD1UM-201 trial. Drugmaker Incyte said that “continued approval of Zynyz for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”

MCC is a rare and aggressive skin cancer with a high rate of metastatic disease and an estimated 5-year overall survival of just 14% among those who present with metastatic disease. Incidence is rapidly increasing in the United States, particularly among adults older than 65 years, Incyte noted.

“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” principal author Shailender Bhatia, MD, of the University of Washington and Fred Hutchinson Cancer Center, both in Seattle, said in a news release. “The approval of Zynyz offers health care providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease.”

POD1UM-201 was an open-label, single-arm, phase 2 study that evaluated the agent in 65 systemic treatment–naive adults with metastatic or recurrent locally advanced MCC.

Overall, 52% of patients had an objective response rate. A complete response was observed in 12 patients (18%), and a partial response was observed in 22 patients (34%).

Duration of response ranged from 1.1 to 24.9 months; 76% of responders experienced responses of 6 months or longer, and 62% experienced responses of 12 months or longer.

Study participants received a 500-mg dose of retifanlimab every 4 weeks for up to 24 weeks or until disease progression or unacceptable toxicity. Serious adverse events occurred in 22% of patients and most often included fatigue, arrhythmia, and pneumonitis; 11% of patients discontinued treatment because of serious adverse events.

Retifanlimab may cause a severe or life-threatening immune response during treatment or after discontinuation. Patients should be advised to immediately report any new or worsening signs or symptoms to their health care provider. Side effects can also be reported to the FDA.

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

The Food and Drug Administration has approved retifanlimab-dlwr (Zynyz), an intravenous programmed death–1 (PD-1) inhibitor, for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC), the agency announced.

This marks the first regulatory approval for the PD-1 inhibitor. The FDA granted accelerated approval for the drug on the basis of tumor response rate and duration of response from the POD1UM-201 trial. Drugmaker Incyte said that “continued approval of Zynyz for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”

MCC is a rare and aggressive skin cancer with a high rate of metastatic disease and an estimated 5-year overall survival of just 14% among those who present with metastatic disease. Incidence is rapidly increasing in the United States, particularly among adults older than 65 years, Incyte noted.

“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” principal author Shailender Bhatia, MD, of the University of Washington and Fred Hutchinson Cancer Center, both in Seattle, said in a news release. “The approval of Zynyz offers health care providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease.”

POD1UM-201 was an open-label, single-arm, phase 2 study that evaluated the agent in 65 systemic treatment–naive adults with metastatic or recurrent locally advanced MCC.

Overall, 52% of patients had an objective response rate. A complete response was observed in 12 patients (18%), and a partial response was observed in 22 patients (34%).

Duration of response ranged from 1.1 to 24.9 months; 76% of responders experienced responses of 6 months or longer, and 62% experienced responses of 12 months or longer.

Study participants received a 500-mg dose of retifanlimab every 4 weeks for up to 24 weeks or until disease progression or unacceptable toxicity. Serious adverse events occurred in 22% of patients and most often included fatigue, arrhythmia, and pneumonitis; 11% of patients discontinued treatment because of serious adverse events.

Retifanlimab may cause a severe or life-threatening immune response during treatment or after discontinuation. Patients should be advised to immediately report any new or worsening signs or symptoms to their health care provider. Side effects can also be reported to the FDA.

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

The Food and Drug Administration has approved retifanlimab-dlwr (Zynyz), an intravenous programmed death–1 (PD-1) inhibitor, for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC), the agency announced.

This marks the first regulatory approval for the PD-1 inhibitor. The FDA granted accelerated approval for the drug on the basis of tumor response rate and duration of response from the POD1UM-201 trial. Drugmaker Incyte said that “continued approval of Zynyz for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.”

MCC is a rare and aggressive skin cancer with a high rate of metastatic disease and an estimated 5-year overall survival of just 14% among those who present with metastatic disease. Incidence is rapidly increasing in the United States, particularly among adults older than 65 years, Incyte noted.

“More than a third of patients with MCC present with regional or distant metastases, which are associated with high rates of mortality,” principal author Shailender Bhatia, MD, of the University of Washington and Fred Hutchinson Cancer Center, both in Seattle, said in a news release. “The approval of Zynyz offers health care providers another first-line treatment option against MCC that can result in durable responses in patients with metastatic disease.”

POD1UM-201 was an open-label, single-arm, phase 2 study that evaluated the agent in 65 systemic treatment–naive adults with metastatic or recurrent locally advanced MCC.

Overall, 52% of patients had an objective response rate. A complete response was observed in 12 patients (18%), and a partial response was observed in 22 patients (34%).

Duration of response ranged from 1.1 to 24.9 months; 76% of responders experienced responses of 6 months or longer, and 62% experienced responses of 12 months or longer.

Study participants received a 500-mg dose of retifanlimab every 4 weeks for up to 24 weeks or until disease progression or unacceptable toxicity. Serious adverse events occurred in 22% of patients and most often included fatigue, arrhythmia, and pneumonitis; 11% of patients discontinued treatment because of serious adverse events.

Retifanlimab may cause a severe or life-threatening immune response during treatment or after discontinuation. Patients should be advised to immediately report any new or worsening signs or symptoms to their health care provider. Side effects can also be reported to the FDA.

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

Five different nonreceptor tyrosine kinase inhibitors were effective against viral replication of pandemic viruses and seasonal influenza viruses in an ex vivo lung model.

Influenza viruses remain a high cause of morbidity and mortality worldwide as viral mutations outwit vaccine efficacy, Robert Meineke, PhD, of the University of Veterinary Medicine in Hannover, Germany, and colleagues wrote.

“As with previous influenza pandemics and the current SARS-CoV-2 pandemic, effective vaccines are not readily available at early stages of a pandemic,” they noted. To help manage the limitations of timing and effectiveness of current vaccines, the researchers proposed repurposing nonreceptor tyrosine kinase inhibitors (NRTKIs) to block seasonal flu and COVID-19 viral replication.

In a study published in iScience, the researchers identified six NRTKIs currently approved by the U.S. Food and Drug Administration that showed in vitro inhibition of both pandemic viruses (H1N1) and seasonal influenza viruses (H3N2). These included defactinib, acalabrutinib, saracatinib, and bosutinib, all of which reduced hPCLS infectivity by approximately 50%. In addition, ibrutinib and bosutinib had the largest impact on viral titers. The antiviral effects of NRTKIs appeared to be independent of multiplicity of infection.

The researchers then tested the NRIKIs on an ex vivo model of human precision-cut lung slices to validate the effects of NRTKIs as antivirals against influenza A viruses (IAVs).

In this model, the highest peak titers were achieved at 48 hpi following infection with virus strains NL09 and NL11. The hPCLS models also showed consistent tolerability to 1x concentrations. “Our cytotoxicity cut-off was 20% of the positive control treatment; none of the NRTKIs surpassed this cutoff at [1x] max,” the researchers wrote.

Five of the six identified NRTKIs were validated in the ex vivo setting. All five reduced viral titers by at least 10-fold to more than 1,000-fold. Of these, ibrutinib, bosutinib, and bosutinib showed a significant effect at all concentrations, while treatments with acalabrutinib and defactinib were significant at 24 hpi and 48 hpi. The NRTKs also showed a high genetic barrier against emerging resistant virus mutations.

The study demonstrates the ability of NRTKIs to target kinases required for replication of IAV, the researchers wrote, and that NRTKIs “represent promising drugs for the development of the next generation of antivirals.”

More research is needed to determine the therapeutic window given that NRTKIs are targeting host factors versus virus-targeted antivirals, but the advantages of NRTKIs include localized delivery that can limit possible cytotoxic effects, and their safety and bioavailability are well established, they said.

The findings were limited by several factors including the use of lung tissue mainly from older donors with lung cancer, the researchers noted. However, this population could be considered at increased risk for IAVs and therefore the data are more clinically applicable.

In addition, “because many viruses utilize the same (or related) host kinases to facilitate replication and transmission, our studies have broader implications for the potential use of these SMKIs to treat infections by other viruses,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Five different nonreceptor tyrosine kinase inhibitors were effective against viral replication of pandemic viruses and seasonal influenza viruses in an ex vivo lung model.

Influenza viruses remain a high cause of morbidity and mortality worldwide as viral mutations outwit vaccine efficacy, Robert Meineke, PhD, of the University of Veterinary Medicine in Hannover, Germany, and colleagues wrote.

“As with previous influenza pandemics and the current SARS-CoV-2 pandemic, effective vaccines are not readily available at early stages of a pandemic,” they noted. To help manage the limitations of timing and effectiveness of current vaccines, the researchers proposed repurposing nonreceptor tyrosine kinase inhibitors (NRTKIs) to block seasonal flu and COVID-19 viral replication.

In a study published in iScience, the researchers identified six NRTKIs currently approved by the U.S. Food and Drug Administration that showed in vitro inhibition of both pandemic viruses (H1N1) and seasonal influenza viruses (H3N2). These included defactinib, acalabrutinib, saracatinib, and bosutinib, all of which reduced hPCLS infectivity by approximately 50%. In addition, ibrutinib and bosutinib had the largest impact on viral titers. The antiviral effects of NRTKIs appeared to be independent of multiplicity of infection.

The researchers then tested the NRIKIs on an ex vivo model of human precision-cut lung slices to validate the effects of NRTKIs as antivirals against influenza A viruses (IAVs).

In this model, the highest peak titers were achieved at 48 hpi following infection with virus strains NL09 and NL11. The hPCLS models also showed consistent tolerability to 1x concentrations. “Our cytotoxicity cut-off was 20% of the positive control treatment; none of the NRTKIs surpassed this cutoff at [1x] max,” the researchers wrote.

Five of the six identified NRTKIs were validated in the ex vivo setting. All five reduced viral titers by at least 10-fold to more than 1,000-fold. Of these, ibrutinib, bosutinib, and bosutinib showed a significant effect at all concentrations, while treatments with acalabrutinib and defactinib were significant at 24 hpi and 48 hpi. The NRTKs also showed a high genetic barrier against emerging resistant virus mutations.

The study demonstrates the ability of NRTKIs to target kinases required for replication of IAV, the researchers wrote, and that NRTKIs “represent promising drugs for the development of the next generation of antivirals.”

More research is needed to determine the therapeutic window given that NRTKIs are targeting host factors versus virus-targeted antivirals, but the advantages of NRTKIs include localized delivery that can limit possible cytotoxic effects, and their safety and bioavailability are well established, they said.

The findings were limited by several factors including the use of lung tissue mainly from older donors with lung cancer, the researchers noted. However, this population could be considered at increased risk for IAVs and therefore the data are more clinically applicable.

In addition, “because many viruses utilize the same (or related) host kinases to facilitate replication and transmission, our studies have broader implications for the potential use of these SMKIs to treat infections by other viruses,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Five different nonreceptor tyrosine kinase inhibitors were effective against viral replication of pandemic viruses and seasonal influenza viruses in an ex vivo lung model.

Influenza viruses remain a high cause of morbidity and mortality worldwide as viral mutations outwit vaccine efficacy, Robert Meineke, PhD, of the University of Veterinary Medicine in Hannover, Germany, and colleagues wrote.

“As with previous influenza pandemics and the current SARS-CoV-2 pandemic, effective vaccines are not readily available at early stages of a pandemic,” they noted. To help manage the limitations of timing and effectiveness of current vaccines, the researchers proposed repurposing nonreceptor tyrosine kinase inhibitors (NRTKIs) to block seasonal flu and COVID-19 viral replication.

In a study published in iScience, the researchers identified six NRTKIs currently approved by the U.S. Food and Drug Administration that showed in vitro inhibition of both pandemic viruses (H1N1) and seasonal influenza viruses (H3N2). These included defactinib, acalabrutinib, saracatinib, and bosutinib, all of which reduced hPCLS infectivity by approximately 50%. In addition, ibrutinib and bosutinib had the largest impact on viral titers. The antiviral effects of NRTKIs appeared to be independent of multiplicity of infection.

The researchers then tested the NRIKIs on an ex vivo model of human precision-cut lung slices to validate the effects of NRTKIs as antivirals against influenza A viruses (IAVs).

In this model, the highest peak titers were achieved at 48 hpi following infection with virus strains NL09 and NL11. The hPCLS models also showed consistent tolerability to 1x concentrations. “Our cytotoxicity cut-off was 20% of the positive control treatment; none of the NRTKIs surpassed this cutoff at [1x] max,” the researchers wrote.

Five of the six identified NRTKIs were validated in the ex vivo setting. All five reduced viral titers by at least 10-fold to more than 1,000-fold. Of these, ibrutinib, bosutinib, and bosutinib showed a significant effect at all concentrations, while treatments with acalabrutinib and defactinib were significant at 24 hpi and 48 hpi. The NRTKs also showed a high genetic barrier against emerging resistant virus mutations.

The study demonstrates the ability of NRTKIs to target kinases required for replication of IAV, the researchers wrote, and that NRTKIs “represent promising drugs for the development of the next generation of antivirals.”

More research is needed to determine the therapeutic window given that NRTKIs are targeting host factors versus virus-targeted antivirals, but the advantages of NRTKIs include localized delivery that can limit possible cytotoxic effects, and their safety and bioavailability are well established, they said.

The findings were limited by several factors including the use of lung tissue mainly from older donors with lung cancer, the researchers noted. However, this population could be considered at increased risk for IAVs and therefore the data are more clinically applicable.

In addition, “because many viruses utilize the same (or related) host kinases to facilitate replication and transmission, our studies have broader implications for the potential use of these SMKIs to treat infections by other viruses,” they concluded.

The study received no outside funding. The researchers had no financial conflicts to disclose.

The U.S. Food and Drug Administration has expanded the indicated age range for evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals), which was approved 2 years ago as an adjunct to other lipid-lowering therapies for homozygous familial hypercholesterolemia (HoFH) in patients aged 12 and older.

Olivier Le Moal/Getty Images

The antibody-based agent’s indication now also covers patients aged 5-11 years with the rare genetic disorder, Regeneron announced. It blocks angiopoietin-like 3 (ANGPTL3), inhibiting lipoprotein lipase and endothelial lipase, thereby cutting LDL-cholesterol levels by mechanisms not directly involving the LDL receptor.

The expanded indication is based on a study that saw a 48% drop in LDL-cholesterol levels over 24 weeks, the primary endpoint, across 20 HoFH patients aged 5-11 years who received evinacumab-dgnb on top of maximally tolerated standard lipid-modifying therapy, the company reports.

Levels of apolipoprotein B, non-HDL cholesterol, and total cholesterol also fell significantly in the trial, which was completed in January.

The drug’s efficacy and safety resembled those of a previously reported larger study of patients with HoFH aged 12 years and older (mean age about 40 years) that led to its initial approval.

“The safety and effectiveness of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia,” the company states. Nor is it known whether the drug affects clinical outcomes.

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

The U.S. Food and Drug Administration has expanded the indicated age range for evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals), which was approved 2 years ago as an adjunct to other lipid-lowering therapies for homozygous familial hypercholesterolemia (HoFH) in patients aged 12 and older.

Olivier Le Moal/Getty Images

The antibody-based agent’s indication now also covers patients aged 5-11 years with the rare genetic disorder, Regeneron announced. It blocks angiopoietin-like 3 (ANGPTL3), inhibiting lipoprotein lipase and endothelial lipase, thereby cutting LDL-cholesterol levels by mechanisms not directly involving the LDL receptor.

The expanded indication is based on a study that saw a 48% drop in LDL-cholesterol levels over 24 weeks, the primary endpoint, across 20 HoFH patients aged 5-11 years who received evinacumab-dgnb on top of maximally tolerated standard lipid-modifying therapy, the company reports.

Levels of apolipoprotein B, non-HDL cholesterol, and total cholesterol also fell significantly in the trial, which was completed in January.

The drug’s efficacy and safety resembled those of a previously reported larger study of patients with HoFH aged 12 years and older (mean age about 40 years) that led to its initial approval.

“The safety and effectiveness of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia,” the company states. Nor is it known whether the drug affects clinical outcomes.

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

The U.S. Food and Drug Administration has expanded the indicated age range for evinacumab-dgnb (Evkeeza, Regeneron Pharmaceuticals), which was approved 2 years ago as an adjunct to other lipid-lowering therapies for homozygous familial hypercholesterolemia (HoFH) in patients aged 12 and older.

Olivier Le Moal/Getty Images

The antibody-based agent’s indication now also covers patients aged 5-11 years with the rare genetic disorder, Regeneron announced. It blocks angiopoietin-like 3 (ANGPTL3), inhibiting lipoprotein lipase and endothelial lipase, thereby cutting LDL-cholesterol levels by mechanisms not directly involving the LDL receptor.

The expanded indication is based on a study that saw a 48% drop in LDL-cholesterol levels over 24 weeks, the primary endpoint, across 20 HoFH patients aged 5-11 years who received evinacumab-dgnb on top of maximally tolerated standard lipid-modifying therapy, the company reports.

Levels of apolipoprotein B, non-HDL cholesterol, and total cholesterol also fell significantly in the trial, which was completed in January.

The drug’s efficacy and safety resembled those of a previously reported larger study of patients with HoFH aged 12 years and older (mean age about 40 years) that led to its initial approval.

“The safety and effectiveness of Evkeeza have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous familial hypercholesterolemia,” the company states. Nor is it known whether the drug affects clinical outcomes.

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

WASHINGTON – Left atrial appendage closure can be performed safely and effectively in older patients, those with end-stage renal disease, and likely others not included in the pivotal clinical trials, according to a series of new studies, including a late-breaker, presented on the both older and newer Watchman devices at the Cardiovascular Research Technologies conference.

In the case of the late-breaking clinical trial report, which included more than 60,000 patients, the goal was to look at the safety of the Watchman FLX, which is the newest of the devices in real-world practice, according to Samir R. Kapadia, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic.

Ted Bosworth/MDedge News

In the SURPASS registry, the number of patients discharged on the Watchman FLX climbed from zero in August 2020, when data accrual began, to 66,894 by March 2022. For the current analysis, 45-day follow-up was available for 61,963 patients and 1-year follow-up was available for 18,233.

Based on this number of patients treated by more than 2,300 clinicians at more than 740 sites, the SURPASS registry establishes that Watchman FLX “can be accomplished safely with clinical outcomes similar to pivotal trials at 45 days and 1 year,” Dr. Kapadia reported.
 

No surprises found in real-world outcome

At 7 days or hospital discharge (whichever came last), the rate of all-cause death was 0.18%, the rate of ischemic stroke was 0.13%, and there were no systemic emboli. By 45 days, the rate of all-cause death (0.84%) and stroke of any kind (0.32%) remained less than 1% and there were still no systemic emboli. Major bleeding events, of which about one-third occurred during hospitalization, had reached 3.34% by day 45.

By 1 year, all-cause mortality had risen to 8.3%, the stroke rate was 1.6%, and major bleeding reached 6.7%. The rate of systemic emboli remained very low (0.1%). The rates of death and stroke rose at a slow but steady rate throughout the 1-year follow-up. In contrast, major bleeding events rose steeply in the first 90 days and were followed by a much slower accrual subsequently.

At 1 year, 84.4% of patients had a complete seal. Leaks ≤ 3 mm were observed in 12.1%. The remaining leaks were larger, but just 0.7% had a leak > 5 mm.

Relative to the first-generation Watchman, the Watchman FLX has numerous design changes, including a shorter profile, more struts, and a reduced metal exposure. Most of these changes were performed to make the device easier to deploy.

When the SURPASS data are compared to the pivotal trials with Watchman FLX or to the Ewolution and National Cardiovascular Data (NCD) registries, which were created to monitor efficacy and safety with the earlier generation Watchman, the outcomes are similar or, in many cases, numerically favorable for such outcomes as bleeding and rates of stroke.

In addition to providing reassurance for the real-world safety of Watchman FLX, Dr. Kapadia said that these data establish reasonable benchmarks for centers tracking in-hospital and 1-year outcomes.

Dr. Kapadia also reported that outcomes overall in SURPASS were similar in women and men with the exception of major bleeding, a finding common to other interventional studies.

The late-breaker panelists generally agreed that SURPASS provides a robust set of data by which to be reassured, but David J. Cohen, MD, director of Clinical and Outcomes Research at the Cardiovascular Research Foundation in New York, said that he thinks the rate of bleeding is unnecessarily high.

“You really need to figure out a way to get the rate of bleeding at 45 days down,” Dr. Cohen said. He called for studies of anticoagulation in the post-procedural period that offer a better benefit-to-risk ratio.
 

Elderly patients benefit equally from Watchman

Yet, Watchman devices are generally regarded as a success story, and this has led investigators to evaluate safety in patients not well represented or explicitly excluded from clinical trials, such as the elderly and those with end-stage renal disease (ESRD). New data derived from experience in both of these groups were presented at the conference, which was sponsored by MedStar Heart & Vascular Institute.

To tease out the relative safety of Watchman in octogenarians, Samian Sulaiman, MD, a cardiology fellow at West Virginia University Heart and Vascular Institute, Morgantown, performed a competing risk analysis to study the relative benefit of Watchman devices after controlling for the greater overall risk of complications in the elderly.

In raw data comparisons of those 80 years of age or older to those younger in published trials, the not-surprising result is that overall rates of death and ischemic events are far higher in the elderly, according to Dr. Sulaiman, but it’s an “unfair comparison,” he said.

“It is easy to mistakenly conclude that left atrial appendage closure is associated with worse outcomes, but older patients have far higher rates of these events independent of other factors,” Dr. Sulaiman noted.

In fact, in his comparison of 472 older patients to 1,404 younger patients, the seal rates at 45 days, 6 months, and 12 months are almost identical. Moreover, after the extensive adjustments performed for competing risk analysis, the rates of death, stroke, and bleeding were also almost identical for those 80 years or older whether or not they received a Watchman.

Although he acknowledged the risk for residual confounding, Dr. Sulaiman concluded that elderly patients derive about the same benefits as younger patients from the Watchman. He concluded age alone should not be a factor in selecting candidates for this device.
 

ESRD is not Watchman contraindication

A similar point was made about ESRD based on analysis of 237 patients who received either an earlier generation Watchman or the Watchman FLX. Initiated in Spain, the study was amended to collect data from centers elsewhere in Europe, the United States, and Australia.

Successful implantation was achieved in 99.2% of the patients, reported Armando Perez de Prado, MD, PhD, head of interventional cardiology at the University of Leon, Spain.

Ted Bosworth/MDedge News

WASHINGTON – Left atrial appendage closure can be performed safely and effectively in older patients, those with end-stage renal disease, and likely others not included in the pivotal clinical trials, according to a series of new studies, including a late-breaker, presented on the both older and newer Watchman devices at the Cardiovascular Research Technologies conference.

In the case of the late-breaking clinical trial report, which included more than 60,000 patients, the goal was to look at the safety of the Watchman FLX, which is the newest of the devices in real-world practice, according to Samir R. Kapadia, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic.

Ted Bosworth/MDedge News

In the SURPASS registry, the number of patients discharged on the Watchman FLX climbed from zero in August 2020, when data accrual began, to 66,894 by March 2022. For the current analysis, 45-day follow-up was available for 61,963 patients and 1-year follow-up was available for 18,233.

Based on this number of patients treated by more than 2,300 clinicians at more than 740 sites, the SURPASS registry establishes that Watchman FLX “can be accomplished safely with clinical outcomes similar to pivotal trials at 45 days and 1 year,” Dr. Kapadia reported.
 

No surprises found in real-world outcome

At 7 days or hospital discharge (whichever came last), the rate of all-cause death was 0.18%, the rate of ischemic stroke was 0.13%, and there were no systemic emboli. By 45 days, the rate of all-cause death (0.84%) and stroke of any kind (0.32%) remained less than 1% and there were still no systemic emboli. Major bleeding events, of which about one-third occurred during hospitalization, had reached 3.34% by day 45.

By 1 year, all-cause mortality had risen to 8.3%, the stroke rate was 1.6%, and major bleeding reached 6.7%. The rate of systemic emboli remained very low (0.1%). The rates of death and stroke rose at a slow but steady rate throughout the 1-year follow-up. In contrast, major bleeding events rose steeply in the first 90 days and were followed by a much slower accrual subsequently.

At 1 year, 84.4% of patients had a complete seal. Leaks ≤ 3 mm were observed in 12.1%. The remaining leaks were larger, but just 0.7% had a leak > 5 mm.

Relative to the first-generation Watchman, the Watchman FLX has numerous design changes, including a shorter profile, more struts, and a reduced metal exposure. Most of these changes were performed to make the device easier to deploy.

When the SURPASS data are compared to the pivotal trials with Watchman FLX or to the Ewolution and National Cardiovascular Data (NCD) registries, which were created to monitor efficacy and safety with the earlier generation Watchman, the outcomes are similar or, in many cases, numerically favorable for such outcomes as bleeding and rates of stroke.

In addition to providing reassurance for the real-world safety of Watchman FLX, Dr. Kapadia said that these data establish reasonable benchmarks for centers tracking in-hospital and 1-year outcomes.

Dr. Kapadia also reported that outcomes overall in SURPASS were similar in women and men with the exception of major bleeding, a finding common to other interventional studies.

The late-breaker panelists generally agreed that SURPASS provides a robust set of data by which to be reassured, but David J. Cohen, MD, director of Clinical and Outcomes Research at the Cardiovascular Research Foundation in New York, said that he thinks the rate of bleeding is unnecessarily high.

“You really need to figure out a way to get the rate of bleeding at 45 days down,” Dr. Cohen said. He called for studies of anticoagulation in the post-procedural period that offer a better benefit-to-risk ratio.
 

Elderly patients benefit equally from Watchman

Yet, Watchman devices are generally regarded as a success story, and this has led investigators to evaluate safety in patients not well represented or explicitly excluded from clinical trials, such as the elderly and those with end-stage renal disease (ESRD). New data derived from experience in both of these groups were presented at the conference, which was sponsored by MedStar Heart & Vascular Institute.

To tease out the relative safety of Watchman in octogenarians, Samian Sulaiman, MD, a cardiology fellow at West Virginia University Heart and Vascular Institute, Morgantown, performed a competing risk analysis to study the relative benefit of Watchman devices after controlling for the greater overall risk of complications in the elderly.

In raw data comparisons of those 80 years of age or older to those younger in published trials, the not-surprising result is that overall rates of death and ischemic events are far higher in the elderly, according to Dr. Sulaiman, but it’s an “unfair comparison,” he said.

“It is easy to mistakenly conclude that left atrial appendage closure is associated with worse outcomes, but older patients have far higher rates of these events independent of other factors,” Dr. Sulaiman noted.

In fact, in his comparison of 472 older patients to 1,404 younger patients, the seal rates at 45 days, 6 months, and 12 months are almost identical. Moreover, after the extensive adjustments performed for competing risk analysis, the rates of death, stroke, and bleeding were also almost identical for those 80 years or older whether or not they received a Watchman.

Although he acknowledged the risk for residual confounding, Dr. Sulaiman concluded that elderly patients derive about the same benefits as younger patients from the Watchman. He concluded age alone should not be a factor in selecting candidates for this device.
 

ESRD is not Watchman contraindication

A similar point was made about ESRD based on analysis of 237 patients who received either an earlier generation Watchman or the Watchman FLX. Initiated in Spain, the study was amended to collect data from centers elsewhere in Europe, the United States, and Australia.

Successful implantation was achieved in 99.2% of the patients, reported Armando Perez de Prado, MD, PhD, head of interventional cardiology at the University of Leon, Spain.

Ted Bosworth/MDedge News

WASHINGTON – Left atrial appendage closure can be performed safely and effectively in older patients, those with end-stage renal disease, and likely others not included in the pivotal clinical trials, according to a series of new studies, including a late-breaker, presented on the both older and newer Watchman devices at the Cardiovascular Research Technologies conference.

In the case of the late-breaking clinical trial report, which included more than 60,000 patients, the goal was to look at the safety of the Watchman FLX, which is the newest of the devices in real-world practice, according to Samir R. Kapadia, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic.

Ted Bosworth/MDedge News

In the SURPASS registry, the number of patients discharged on the Watchman FLX climbed from zero in August 2020, when data accrual began, to 66,894 by March 2022. For the current analysis, 45-day follow-up was available for 61,963 patients and 1-year follow-up was available for 18,233.

Based on this number of patients treated by more than 2,300 clinicians at more than 740 sites, the SURPASS registry establishes that Watchman FLX “can be accomplished safely with clinical outcomes similar to pivotal trials at 45 days and 1 year,” Dr. Kapadia reported.
 

No surprises found in real-world outcome

At 7 days or hospital discharge (whichever came last), the rate of all-cause death was 0.18%, the rate of ischemic stroke was 0.13%, and there were no systemic emboli. By 45 days, the rate of all-cause death (0.84%) and stroke of any kind (0.32%) remained less than 1% and there were still no systemic emboli. Major bleeding events, of which about one-third occurred during hospitalization, had reached 3.34% by day 45.

By 1 year, all-cause mortality had risen to 8.3%, the stroke rate was 1.6%, and major bleeding reached 6.7%. The rate of systemic emboli remained very low (0.1%). The rates of death and stroke rose at a slow but steady rate throughout the 1-year follow-up. In contrast, major bleeding events rose steeply in the first 90 days and were followed by a much slower accrual subsequently.

At 1 year, 84.4% of patients had a complete seal. Leaks ≤ 3 mm were observed in 12.1%. The remaining leaks were larger, but just 0.7% had a leak > 5 mm.

Relative to the first-generation Watchman, the Watchman FLX has numerous design changes, including a shorter profile, more struts, and a reduced metal exposure. Most of these changes were performed to make the device easier to deploy.

When the SURPASS data are compared to the pivotal trials with Watchman FLX or to the Ewolution and National Cardiovascular Data (NCD) registries, which were created to monitor efficacy and safety with the earlier generation Watchman, the outcomes are similar or, in many cases, numerically favorable for such outcomes as bleeding and rates of stroke.

In addition to providing reassurance for the real-world safety of Watchman FLX, Dr. Kapadia said that these data establish reasonable benchmarks for centers tracking in-hospital and 1-year outcomes.

Dr. Kapadia also reported that outcomes overall in SURPASS were similar in women and men with the exception of major bleeding, a finding common to other interventional studies.

The late-breaker panelists generally agreed that SURPASS provides a robust set of data by which to be reassured, but David J. Cohen, MD, director of Clinical and Outcomes Research at the Cardiovascular Research Foundation in New York, said that he thinks the rate of bleeding is unnecessarily high.

“You really need to figure out a way to get the rate of bleeding at 45 days down,” Dr. Cohen said. He called for studies of anticoagulation in the post-procedural period that offer a better benefit-to-risk ratio.
 

Elderly patients benefit equally from Watchman

Yet, Watchman devices are generally regarded as a success story, and this has led investigators to evaluate safety in patients not well represented or explicitly excluded from clinical trials, such as the elderly and those with end-stage renal disease (ESRD). New data derived from experience in both of these groups were presented at the conference, which was sponsored by MedStar Heart & Vascular Institute.

To tease out the relative safety of Watchman in octogenarians, Samian Sulaiman, MD, a cardiology fellow at West Virginia University Heart and Vascular Institute, Morgantown, performed a competing risk analysis to study the relative benefit of Watchman devices after controlling for the greater overall risk of complications in the elderly.

In raw data comparisons of those 80 years of age or older to those younger in published trials, the not-surprising result is that overall rates of death and ischemic events are far higher in the elderly, according to Dr. Sulaiman, but it’s an “unfair comparison,” he said.

“It is easy to mistakenly conclude that left atrial appendage closure is associated with worse outcomes, but older patients have far higher rates of these events independent of other factors,” Dr. Sulaiman noted.

In fact, in his comparison of 472 older patients to 1,404 younger patients, the seal rates at 45 days, 6 months, and 12 months are almost identical. Moreover, after the extensive adjustments performed for competing risk analysis, the rates of death, stroke, and bleeding were also almost identical for those 80 years or older whether or not they received a Watchman.

Although he acknowledged the risk for residual confounding, Dr. Sulaiman concluded that elderly patients derive about the same benefits as younger patients from the Watchman. He concluded age alone should not be a factor in selecting candidates for this device.
 

ESRD is not Watchman contraindication

A similar point was made about ESRD based on analysis of 237 patients who received either an earlier generation Watchman or the Watchman FLX. Initiated in Spain, the study was amended to collect data from centers elsewhere in Europe, the United States, and Australia.

Successful implantation was achieved in 99.2% of the patients, reported Armando Perez de Prado, MD, PhD, head of interventional cardiology at the University of Leon, Spain.

Ted Bosworth/MDedge News

A nationwide shortage of liquid albuterol is having minimal impact on patient care, as treatment alternatives are available, and supply appears to be recovering fast, suggest accounts from experts at health care centers around the country.

The shortage of 0.5% albuterol sulfate inhalation solution, first reported by the FDA last October, gained increasing attention earlier this month when Akorn Pharmaceuticals – one of just two companies making the product – shut down after years of financial and regulatory troubles.

The other manufacturer, Nephron Pharmaceuticals, is producing 0.5% albuterol “as fast as possible” to overcome the shortage, CEO Lou Kennedy said in a written comment.

Meanwhile, the more commonly used version of liquid albuterol, with a concentration of 0.083%, remains in “good supply from several manufacturers,” according to an FDA spokesperson.

Even infants and toddlers can use inhalers

Although Dr. Stukus noted that certain patients do require nebulizers, such as those with conditions that physically limit their breathing, like muscular dystrophy, most patients can use inhalers just fine. He said it’s a “pretty common misconception, even among medical professionals,” that infants and toddlers need nebulizers instead.

“In our institution, for example, we rarely ever start babies on a nebulizer when we diagnose them with asthma,” Dr. Stukus said. “We often just start right away with an inhaler with a spacer and a face mask.”

The shortage of liquid albuterol may therefore have a silver lining, he suggested, as it prompts clinicians to reconsider their routine practice.

“When situations like this arise, it’s a great opportunity for all of us to just take a step back and reevaluate the way we do things,” Dr. Stukus said. “Sometimes we just get caught up with inertia and we continue to do things the same way even though new options are available, or evidence has changed to the contrary.”

National Jewish Health

Nathan Rabinovitch, MD, professor of pediatrics in the division of pediatric allergy and clinical immunology at National Jewish Health, Denver, said that his center had trouble obtaining liquid albuterol about 2 weeks ago, so they pivoted to the more expensive levalbuterol for about a week and a half, until their albuterol supply was restored.

While Dr. Rabinovitch agreed that most children don’t need a nebulizer, he said about 5%-10% of kids with severe asthma should have one on hand in case their inhaler fails to control an exacerbation.

Personal preferences may also considered, he added.

“If [a parent] says, ‘I like to use the nebulizer. The kid likes it,’ I’m fine if they just use a nebulizer.”

Michican Medicine

One possible downside of relying on a nebulizer, however, is portability, according to Kelly O’Shea, MD, assistant professor in the division of allergy and clinical immunology at the University of Michigan, Ann Arbor.

“If you’re out at the park or out at a soccer game with your kids, and they are having trouble breathing ... and they need their albuterol, you don’t have that ability if you are tied to a nebulizer,” Dr. O’Shea said in an interview. “As long as a parent feels comfortable – they feel like [their child] can get deep breaths in, I agree that you can use [an inhaler] in the infant and toddler population.”

She also agreed that a nebulizer may serve as a kind of second step if an inhaler isn’t controlling an exacerbation; however, she emphasized that a nebulizer should not be considered a replacement for professional care, and should not give a false sense of security.

“I caution parents to make sure that when they need it, they also take the next step and head over to the emergency room,” Dr. O’Shea said.
 

Generic drug shortages becoming more common

While the present scarcity of liquid albuterol appears relatively mild in terms of clinical impact, it brings up broader concerns about generic drug supply, and why shortages like this are becoming more common, according to Katie J. Suda, PharmD, MS, professor of medicine and pharmacy, and associate director, center for pharmaceutical policy and prescribing at the University of Pittsburgh.

University of Pittsburgh School of Medicine

“Drug shortages continue to increase in frequency, and the duration and severity of the shortages are also getting worse,” Dr. Suda said in an interview.

The reasons for these shortages can be elusive, according to 2022 report by the American Society of Health-System Pharmacists, which found that more than half of shortages came with no explanation from manufacturers.

The same report showed that only 5% of shortages were due to a “business decision,” but this factor is likely more central than publicly stated.

A recent FDA analysis on drug shortages, for instance, lists “lack of incentives to produce less profitable drugs,” as the first “root cause,” and Dr. Suda agrees.

“It’s important that we have generic medicines to decrease costs to our health systems, as well as for our patients,” Dr. Suda said. “But frequently, with those generic products, the price is driven so low that it increases the risk of a shortage.”

The drive to maintain profit margins may motivate companies to cut corners in production, Dr. Suda explained. She emphasized that this connection is speculative, because motivations are effectively unknowable, but the rationale is supported by past and present shortages.

Akorn Pharmaceuticals, for example, received a warning letter from the FDA in 2019 because of a variety of manufacturing issues, including defective bottles, questionable data, and metal shavings on aseptic filling equipment.

When a manufacturer like Akorn fails, the effects can be far-reaching, Dr. Suda said, noting their broad catalog of agents. Beyond liquid albuterol, Akorn was producing cardiac drugs, antibiotics, vitamins, local anesthetics, eye products, and others.

Drug shortages cause “a significant strain on our health care system,” Dr. Suda said, and substituting other medications increases risk of medical errors.

Fortunately, the increasing number of drug shortages is not going unnoticed, according to Dr. Suda. The FDA and multiple other organizations, including the ASHP, American Medical Association, and National Academies of Sciences, Engineering, and Medicine, are all taking steps to ensure that essential medicines are in steady supply, including moves to gather more data from manufacturers.

“I hope that a lot of the efforts that are moving forward ... will help us decrease the impact of shortages on our patients,” Dr. Suda said.

Lou Kennedy is the CEO of Nephron Pharmaceuticals, which commercially produces liquid albuterol. The other interviewees disclosed no relevant conflicts of interest.

A nationwide shortage of liquid albuterol is having minimal impact on patient care, as treatment alternatives are available, and supply appears to be recovering fast, suggest accounts from experts at health care centers around the country.

The shortage of 0.5% albuterol sulfate inhalation solution, first reported by the FDA last October, gained increasing attention earlier this month when Akorn Pharmaceuticals – one of just two companies making the product – shut down after years of financial and regulatory troubles.

The other manufacturer, Nephron Pharmaceuticals, is producing 0.5% albuterol “as fast as possible” to overcome the shortage, CEO Lou Kennedy said in a written comment.

Meanwhile, the more commonly used version of liquid albuterol, with a concentration of 0.083%, remains in “good supply from several manufacturers,” according to an FDA spokesperson.

Even infants and toddlers can use inhalers

Although Dr. Stukus noted that certain patients do require nebulizers, such as those with conditions that physically limit their breathing, like muscular dystrophy, most patients can use inhalers just fine. He said it’s a “pretty common misconception, even among medical professionals,” that infants and toddlers need nebulizers instead.

“In our institution, for example, we rarely ever start babies on a nebulizer when we diagnose them with asthma,” Dr. Stukus said. “We often just start right away with an inhaler with a spacer and a face mask.”

The shortage of liquid albuterol may therefore have a silver lining, he suggested, as it prompts clinicians to reconsider their routine practice.

“When situations like this arise, it’s a great opportunity for all of us to just take a step back and reevaluate the way we do things,” Dr. Stukus said. “Sometimes we just get caught up with inertia and we continue to do things the same way even though new options are available, or evidence has changed to the contrary.”

National Jewish Health

Nathan Rabinovitch, MD, professor of pediatrics in the division of pediatric allergy and clinical immunology at National Jewish Health, Denver, said that his center had trouble obtaining liquid albuterol about 2 weeks ago, so they pivoted to the more expensive levalbuterol for about a week and a half, until their albuterol supply was restored.

While Dr. Rabinovitch agreed that most children don’t need a nebulizer, he said about 5%-10% of kids with severe asthma should have one on hand in case their inhaler fails to control an exacerbation.

Personal preferences may also considered, he added.

“If [a parent] says, ‘I like to use the nebulizer. The kid likes it,’ I’m fine if they just use a nebulizer.”

Michican Medicine

One possible downside of relying on a nebulizer, however, is portability, according to Kelly O’Shea, MD, assistant professor in the division of allergy and clinical immunology at the University of Michigan, Ann Arbor.

“If you’re out at the park or out at a soccer game with your kids, and they are having trouble breathing ... and they need their albuterol, you don’t have that ability if you are tied to a nebulizer,” Dr. O’Shea said in an interview. “As long as a parent feels comfortable – they feel like [their child] can get deep breaths in, I agree that you can use [an inhaler] in the infant and toddler population.”

She also agreed that a nebulizer may serve as a kind of second step if an inhaler isn’t controlling an exacerbation; however, she emphasized that a nebulizer should not be considered a replacement for professional care, and should not give a false sense of security.

“I caution parents to make sure that when they need it, they also take the next step and head over to the emergency room,” Dr. O’Shea said.
 

Generic drug shortages becoming more common

While the present scarcity of liquid albuterol appears relatively mild in terms of clinical impact, it brings up broader concerns about generic drug supply, and why shortages like this are becoming more common, according to Katie J. Suda, PharmD, MS, professor of medicine and pharmacy, and associate director, center for pharmaceutical policy and prescribing at the University of Pittsburgh.

University of Pittsburgh School of Medicine

“Drug shortages continue to increase in frequency, and the duration and severity of the shortages are also getting worse,” Dr. Suda said in an interview.

The reasons for these shortages can be elusive, according to 2022 report by the American Society of Health-System Pharmacists, which found that more than half of shortages came with no explanation from manufacturers.

The same report showed that only 5% of shortages were due to a “business decision,” but this factor is likely more central than publicly stated.

A recent FDA analysis on drug shortages, for instance, lists “lack of incentives to produce less profitable drugs,” as the first “root cause,” and Dr. Suda agrees.

“It’s important that we have generic medicines to decrease costs to our health systems, as well as for our patients,” Dr. Suda said. “But frequently, with those generic products, the price is driven so low that it increases the risk of a shortage.”

The drive to maintain profit margins may motivate companies to cut corners in production, Dr. Suda explained. She emphasized that this connection is speculative, because motivations are effectively unknowable, but the rationale is supported by past and present shortages.

Akorn Pharmaceuticals, for example, received a warning letter from the FDA in 2019 because of a variety of manufacturing issues, including defective bottles, questionable data, and metal shavings on aseptic filling equipment.

When a manufacturer like Akorn fails, the effects can be far-reaching, Dr. Suda said, noting their broad catalog of agents. Beyond liquid albuterol, Akorn was producing cardiac drugs, antibiotics, vitamins, local anesthetics, eye products, and others.

Drug shortages cause “a significant strain on our health care system,” Dr. Suda said, and substituting other medications increases risk of medical errors.

Fortunately, the increasing number of drug shortages is not going unnoticed, according to Dr. Suda. The FDA and multiple other organizations, including the ASHP, American Medical Association, and National Academies of Sciences, Engineering, and Medicine, are all taking steps to ensure that essential medicines are in steady supply, including moves to gather more data from manufacturers.

“I hope that a lot of the efforts that are moving forward ... will help us decrease the impact of shortages on our patients,” Dr. Suda said.

Lou Kennedy is the CEO of Nephron Pharmaceuticals, which commercially produces liquid albuterol. The other interviewees disclosed no relevant conflicts of interest.

A nationwide shortage of liquid albuterol is having minimal impact on patient care, as treatment alternatives are available, and supply appears to be recovering fast, suggest accounts from experts at health care centers around the country.

The shortage of 0.5% albuterol sulfate inhalation solution, first reported by the FDA last October, gained increasing attention earlier this month when Akorn Pharmaceuticals – one of just two companies making the product – shut down after years of financial and regulatory troubles.

The other manufacturer, Nephron Pharmaceuticals, is producing 0.5% albuterol “as fast as possible” to overcome the shortage, CEO Lou Kennedy said in a written comment.

Meanwhile, the more commonly used version of liquid albuterol, with a concentration of 0.083%, remains in “good supply from several manufacturers,” according to an FDA spokesperson.

Even infants and toddlers can use inhalers

Although Dr. Stukus noted that certain patients do require nebulizers, such as those with conditions that physically limit their breathing, like muscular dystrophy, most patients can use inhalers just fine. He said it’s a “pretty common misconception, even among medical professionals,” that infants and toddlers need nebulizers instead.

“In our institution, for example, we rarely ever start babies on a nebulizer when we diagnose them with asthma,” Dr. Stukus said. “We often just start right away with an inhaler with a spacer and a face mask.”

The shortage of liquid albuterol may therefore have a silver lining, he suggested, as it prompts clinicians to reconsider their routine practice.

“When situations like this arise, it’s a great opportunity for all of us to just take a step back and reevaluate the way we do things,” Dr. Stukus said. “Sometimes we just get caught up with inertia and we continue to do things the same way even though new options are available, or evidence has changed to the contrary.”

National Jewish Health

Nathan Rabinovitch, MD, professor of pediatrics in the division of pediatric allergy and clinical immunology at National Jewish Health, Denver, said that his center had trouble obtaining liquid albuterol about 2 weeks ago, so they pivoted to the more expensive levalbuterol for about a week and a half, until their albuterol supply was restored.

While Dr. Rabinovitch agreed that most children don’t need a nebulizer, he said about 5%-10% of kids with severe asthma should have one on hand in case their inhaler fails to control an exacerbation.

Personal preferences may also considered, he added.

“If [a parent] says, ‘I like to use the nebulizer. The kid likes it,’ I’m fine if they just use a nebulizer.”

Michican Medicine

One possible downside of relying on a nebulizer, however, is portability, according to Kelly O’Shea, MD, assistant professor in the division of allergy and clinical immunology at the University of Michigan, Ann Arbor.

“If you’re out at the park or out at a soccer game with your kids, and they are having trouble breathing ... and they need their albuterol, you don’t have that ability if you are tied to a nebulizer,” Dr. O’Shea said in an interview. “As long as a parent feels comfortable – they feel like [their child] can get deep breaths in, I agree that you can use [an inhaler] in the infant and toddler population.”

She also agreed that a nebulizer may serve as a kind of second step if an inhaler isn’t controlling an exacerbation; however, she emphasized that a nebulizer should not be considered a replacement for professional care, and should not give a false sense of security.

“I caution parents to make sure that when they need it, they also take the next step and head over to the emergency room,” Dr. O’Shea said.
 

Generic drug shortages becoming more common

While the present scarcity of liquid albuterol appears relatively mild in terms of clinical impact, it brings up broader concerns about generic drug supply, and why shortages like this are becoming more common, according to Katie J. Suda, PharmD, MS, professor of medicine and pharmacy, and associate director, center for pharmaceutical policy and prescribing at the University of Pittsburgh.

University of Pittsburgh School of Medicine

“Drug shortages continue to increase in frequency, and the duration and severity of the shortages are also getting worse,” Dr. Suda said in an interview.

The reasons for these shortages can be elusive, according to 2022 report by the American Society of Health-System Pharmacists, which found that more than half of shortages came with no explanation from manufacturers.

The same report showed that only 5% of shortages were due to a “business decision,” but this factor is likely more central than publicly stated.

A recent FDA analysis on drug shortages, for instance, lists “lack of incentives to produce less profitable drugs,” as the first “root cause,” and Dr. Suda agrees.

“It’s important that we have generic medicines to decrease costs to our health systems, as well as for our patients,” Dr. Suda said. “But frequently, with those generic products, the price is driven so low that it increases the risk of a shortage.”

The drive to maintain profit margins may motivate companies to cut corners in production, Dr. Suda explained. She emphasized that this connection is speculative, because motivations are effectively unknowable, but the rationale is supported by past and present shortages.

Akorn Pharmaceuticals, for example, received a warning letter from the FDA in 2019 because of a variety of manufacturing issues, including defective bottles, questionable data, and metal shavings on aseptic filling equipment.

When a manufacturer like Akorn fails, the effects can be far-reaching, Dr. Suda said, noting their broad catalog of agents. Beyond liquid albuterol, Akorn was producing cardiac drugs, antibiotics, vitamins, local anesthetics, eye products, and others.

Drug shortages cause “a significant strain on our health care system,” Dr. Suda said, and substituting other medications increases risk of medical errors.

Fortunately, the increasing number of drug shortages is not going unnoticed, according to Dr. Suda. The FDA and multiple other organizations, including the ASHP, American Medical Association, and National Academies of Sciences, Engineering, and Medicine, are all taking steps to ensure that essential medicines are in steady supply, including moves to gather more data from manufacturers.

“I hope that a lot of the efforts that are moving forward ... will help us decrease the impact of shortages on our patients,” Dr. Suda said.

Lou Kennedy is the CEO of Nephron Pharmaceuticals, which commercially produces liquid albuterol. The other interviewees disclosed no relevant conflicts of interest.