Rheumatology News

The current trend of smaller medical practices consolidating into larger and larger ones has again called attention to the dicey issue of dismissing patients from a practice.

One might assume that, just as patients are free to accept or reject their doctors, physicians have an equal right to reject their patients; to a certain extent, that is true. There are no specific laws prohibiting a provider from terminating a patient relationship for any reason, other than a discriminatory one – race, nationality, religion, age, gender, sexual orientation, and so on. However, the evolution of ever-larger practice environments has raised new questions.

While verbal abuse, inappropriate treatment demands (particularly for controlled substances), refusal to adhere to mutually agreed treatment plans, and failure to keep appointments or pay bills remain the most common reasons for dismissal, evolving practice environments may require us to modify our responses.

What happens, for example, when a patient is banned from a large clinic that employs most of that community’s physicians, or is the only practice in town with the specialists required by that patient? The medical profession does have an obligation to not exclude such patients from care.

In a large cross-specialty system or consolidated specialist practice, firing a patient has a very different level of consequences than in a small office. There must be a balance between separating patients and doctors who don’t get along and seeing that the patient in question receives competent treatment. The physician, as the professional, has a higher standard to live up to with respect to handling this kind of situation.

If the problem is a personality conflict, the solution may be as simple as transferring the patient to another caregiver within the practice. While it does not make sense for a patient to continue seeing a doctor who does not want to see them, it also does not make sense to ban a patient from a large system where there could well be one or more other doctors who would be a good match. If a patient is unable to pay outstanding bills, a large clinic might prohibit them from making new appointments until they have worked out a payment plan rather than firing them outright.

If you are part of a large practice, take the time to research your group’s official policies for dealing with such situations. If there is no written policy, you might want to start that discussion with your colleagues.

The point is that in any practice, large or small, firing a patient should be a last resort. Try to make every effort to resolve the problem amicably. Communicate with the patient in question, explain your concerns, and discuss options for resolution. Take time to listen to the patient, as they may have an explanation (rational or not) for their objectionable behavior.

You can also send a letter, repeating your concerns and proposed solutions, as further documentation of your efforts to achieve an amicable resolution. All verbal and written warnings must, of course, be documented. If the patient has a managed care policy, we review the managed care contract, which sometimes includes specific requirements for dismissal of its patients.

When such efforts fail, we send the patient two letters – one certified with return receipt, the other by conventional first class, in case the patient refuses the certified copy – explaining the reason for dismissal, and that care will be discontinued in 30 days from the letter’s date. (Most attorneys and medical associations agree that 30 days is sufficient reasonable notice.) We offer to provide care during the interim period, include a list of names and contact information for potential alternate providers, and offer to transfer records after receiving written permission.

Following these precautions will usually protect you from charges of “patient abandonment,” which is generally defined as the unilateral severance by the physician of the physician-patient relationship without giving the patient sufficient advance notice to obtain the services of another practitioner, and at a time when the patient still requires medical attention.

Some states have their own unique definitions of patient abandonment. You should check with your state’s health department, and your attorney, for any unusual requirements in your state, because violating them could lead to intervention by your state licensing board. There is also the risk of civil litigation, which is typically not covered by malpractice policies, and may not be covered by your general liability policy either.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

The current trend of smaller medical practices consolidating into larger and larger ones has again called attention to the dicey issue of dismissing patients from a practice.

One might assume that, just as patients are free to accept or reject their doctors, physicians have an equal right to reject their patients; to a certain extent, that is true. There are no specific laws prohibiting a provider from terminating a patient relationship for any reason, other than a discriminatory one – race, nationality, religion, age, gender, sexual orientation, and so on. However, the evolution of ever-larger practice environments has raised new questions.

While verbal abuse, inappropriate treatment demands (particularly for controlled substances), refusal to adhere to mutually agreed treatment plans, and failure to keep appointments or pay bills remain the most common reasons for dismissal, evolving practice environments may require us to modify our responses.

What happens, for example, when a patient is banned from a large clinic that employs most of that community’s physicians, or is the only practice in town with the specialists required by that patient? The medical profession does have an obligation to not exclude such patients from care.

In a large cross-specialty system or consolidated specialist practice, firing a patient has a very different level of consequences than in a small office. There must be a balance between separating patients and doctors who don’t get along and seeing that the patient in question receives competent treatment. The physician, as the professional, has a higher standard to live up to with respect to handling this kind of situation.

If the problem is a personality conflict, the solution may be as simple as transferring the patient to another caregiver within the practice. While it does not make sense for a patient to continue seeing a doctor who does not want to see them, it also does not make sense to ban a patient from a large system where there could well be one or more other doctors who would be a good match. If a patient is unable to pay outstanding bills, a large clinic might prohibit them from making new appointments until they have worked out a payment plan rather than firing them outright.

If you are part of a large practice, take the time to research your group’s official policies for dealing with such situations. If there is no written policy, you might want to start that discussion with your colleagues.

The point is that in any practice, large or small, firing a patient should be a last resort. Try to make every effort to resolve the problem amicably. Communicate with the patient in question, explain your concerns, and discuss options for resolution. Take time to listen to the patient, as they may have an explanation (rational or not) for their objectionable behavior.

You can also send a letter, repeating your concerns and proposed solutions, as further documentation of your efforts to achieve an amicable resolution. All verbal and written warnings must, of course, be documented. If the patient has a managed care policy, we review the managed care contract, which sometimes includes specific requirements for dismissal of its patients.

When such efforts fail, we send the patient two letters – one certified with return receipt, the other by conventional first class, in case the patient refuses the certified copy – explaining the reason for dismissal, and that care will be discontinued in 30 days from the letter’s date. (Most attorneys and medical associations agree that 30 days is sufficient reasonable notice.) We offer to provide care during the interim period, include a list of names and contact information for potential alternate providers, and offer to transfer records after receiving written permission.

Following these precautions will usually protect you from charges of “patient abandonment,” which is generally defined as the unilateral severance by the physician of the physician-patient relationship without giving the patient sufficient advance notice to obtain the services of another practitioner, and at a time when the patient still requires medical attention.

Some states have their own unique definitions of patient abandonment. You should check with your state’s health department, and your attorney, for any unusual requirements in your state, because violating them could lead to intervention by your state licensing board. There is also the risk of civil litigation, which is typically not covered by malpractice policies, and may not be covered by your general liability policy either.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

The current trend of smaller medical practices consolidating into larger and larger ones has again called attention to the dicey issue of dismissing patients from a practice.

One might assume that, just as patients are free to accept or reject their doctors, physicians have an equal right to reject their patients; to a certain extent, that is true. There are no specific laws prohibiting a provider from terminating a patient relationship for any reason, other than a discriminatory one – race, nationality, religion, age, gender, sexual orientation, and so on. However, the evolution of ever-larger practice environments has raised new questions.

While verbal abuse, inappropriate treatment demands (particularly for controlled substances), refusal to adhere to mutually agreed treatment plans, and failure to keep appointments or pay bills remain the most common reasons for dismissal, evolving practice environments may require us to modify our responses.

What happens, for example, when a patient is banned from a large clinic that employs most of that community’s physicians, or is the only practice in town with the specialists required by that patient? The medical profession does have an obligation to not exclude such patients from care.

In a large cross-specialty system or consolidated specialist practice, firing a patient has a very different level of consequences than in a small office. There must be a balance between separating patients and doctors who don’t get along and seeing that the patient in question receives competent treatment. The physician, as the professional, has a higher standard to live up to with respect to handling this kind of situation.

If the problem is a personality conflict, the solution may be as simple as transferring the patient to another caregiver within the practice. While it does not make sense for a patient to continue seeing a doctor who does not want to see them, it also does not make sense to ban a patient from a large system where there could well be one or more other doctors who would be a good match. If a patient is unable to pay outstanding bills, a large clinic might prohibit them from making new appointments until they have worked out a payment plan rather than firing them outright.

If you are part of a large practice, take the time to research your group’s official policies for dealing with such situations. If there is no written policy, you might want to start that discussion with your colleagues.

The point is that in any practice, large or small, firing a patient should be a last resort. Try to make every effort to resolve the problem amicably. Communicate with the patient in question, explain your concerns, and discuss options for resolution. Take time to listen to the patient, as they may have an explanation (rational or not) for their objectionable behavior.

You can also send a letter, repeating your concerns and proposed solutions, as further documentation of your efforts to achieve an amicable resolution. All verbal and written warnings must, of course, be documented. If the patient has a managed care policy, we review the managed care contract, which sometimes includes specific requirements for dismissal of its patients.

When such efforts fail, we send the patient two letters – one certified with return receipt, the other by conventional first class, in case the patient refuses the certified copy – explaining the reason for dismissal, and that care will be discontinued in 30 days from the letter’s date. (Most attorneys and medical associations agree that 30 days is sufficient reasonable notice.) We offer to provide care during the interim period, include a list of names and contact information for potential alternate providers, and offer to transfer records after receiving written permission.

Following these precautions will usually protect you from charges of “patient abandonment,” which is generally defined as the unilateral severance by the physician of the physician-patient relationship without giving the patient sufficient advance notice to obtain the services of another practitioner, and at a time when the patient still requires medical attention.

Some states have their own unique definitions of patient abandonment. You should check with your state’s health department, and your attorney, for any unusual requirements in your state, because violating them could lead to intervention by your state licensing board. There is also the risk of civil litigation, which is typically not covered by malpractice policies, and may not be covered by your general liability policy either.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

A novel study provides strong evidence supporting the adoption of a healthy diet to protect the aging brain. In a cohort of deceased older adults, those who had adhered to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) and Mediterranean diets for nearly a decade before death had less global Alzheimer’s disease–related pathology, primarily less beta-amyloid, at autopsy.

Those who most closely followed these diets had almost 40% lower odds of having an Alzheimer’s disease diagnosis at death. The findings offer one mechanism by which healthy diets protect cognition.

“While our research doesn’t prove that a healthy diet resulted in fewer brain deposits of amyloid plaques ... we know there is a relationship, and following the MIND and Mediterranean diets may be one way that people can improve their brain health and protect cognition as they age,” study investigator Puja Agarwal, PhD, of RUSH University Medical Center in Chicago, said in a statement.

The study was published online in Neurology.
 

Green leafy veggies key

The MIND diet was pioneered by the late Martha Clare Morris, ScD, a Rush nutritional epidemiologist, who died of cancer in 2020 at age 64.

Although similar, the Mediterranean diet recommends vegetables, fruit, and three or more servings of fish per week, whereas the MIND diet prioritizes green leafy vegetables, such as spinach, kale, and collard greens, along with other vegetables. The MIND diet also prioritizes berries over other fruit and recommends one or more servings of fish per week. Both diets recommend small amounts of wine.

The current study focused on 581 older adults who died while participating in the Rush Memory and Aging Project (MAP). All participants agreed to undergo annual clinical evaluations and brain autopsy after death.

Participants completed annual food frequency questionnaires beginning at a mean age of 84. The mean age at death was 91. Mean follow-up was 6.8 years.

Around the time of death, 224 participants (39%) had a diagnosis of clinical dementia, and 383 participants (66%) had a pathologic Alzheimer’s disease diagnosis at time of death.

The researchers used a series of regression analyses to investigate the MIND and Mediterranean diets and dietary components associated with Alzheimer’s disease pathology. They controlled for age at death, sex, education, APO-epsilon 4 status, and total calories.

Overall, both diets were significantly associated with lower global Alzheimer’s disease pathology (MIND: beta = –0.022, P = .034; and Mediterranean: beta = –0.007, P = .039) – specifically, with less beta-amyloid (MIND: beta = –0.068, P = .050; and Mediterranean: beta = –0.040, P = .004).

The findings persisted when the analysis was further adjusted for physical activity, smoking, and vascular disease burden and when participants with mild cognitive impairment or dementia at the baseline dietary assessment were excluded.

Individuals who most closely followed the Mediterranean diet had average beta-amyloid load similar to being 18 years younger than peers with the lowest adherence. And those who most closely followed the MIND diet had average beta-amyloid amounts similar to being 12 years younger than those with the lowest adherence.

A MIND diet score 1 point higher corresponded to typical plaque deposition of participants who are 4.25 years younger in age.

Regarding individual dietary components, those who ate seven or more servings of green leafy vegetables weekly had less global Alzheimer’s disease pathology than peers who ate one or fewer (beta = –0.115, P = .0038). Those who ate seven or more servings per week had plaque amounts in their brains corresponding to being almost 19 years younger in comparison with those who ate the fewest servings per week.

“Our finding that eating more green leafy vegetables is in itself associated with fewer signs of Alzheimer’s disease in the brain is intriguing enough for people to consider adding more of these vegetables to their diet,” Dr. Agarwal said in the news release.

Previous data from the MAP cohort showed that adherence to the MIND diet can improve memory and thinking skills of older adults, even in the presence of Alzheimer’s disease pathology.
 

Novel study, intriguing results

Heather Snyder, PhD, vice president of medical and scientific relations with the Alzheimer’s Association, noted that a number of studies have linked overall nutrition – especially a balanced diet low in saturated fats and sugar and high in vegetables – with brain health, including cognition, as one ages.

This new study “takes what we know about the link between nutrition and risk for cognitive decline a step further by looking at the specific brain changes that occur in Alzheimer’s disease. The study found an association of certain nutrition behaviors with less of these Alzheimer’s brain changes,” said Dr. Snyder, who was not involved in the study.

“This is intriguing, and more research is needed to test via an intervention if healthy dietary behaviors can modify the presence of Alzheimer’s brain changes and reduce risk of cognitive decline.”

The Alzheimer’s Association is leading a 2-year clinical trial known as US POINTER to study how targeting known dementia risk factors in combination may reduce risk of cognitive decline in older adults. The MIND diet is being used in US POINTER.

“But while we work to find an exact ‘recipe’ for risk reduction, it’s important to eat a heart-healthy diet that incorporates nutrients that our bodies and brains need to be at their best,” Dr. Snyder said.

The study was funded by the National Institutes of Health. Dr. Agarwal and Dr. Snyder have disclosed no relevant financial relationships.

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

A novel study provides strong evidence supporting the adoption of a healthy diet to protect the aging brain. In a cohort of deceased older adults, those who had adhered to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) and Mediterranean diets for nearly a decade before death had less global Alzheimer’s disease–related pathology, primarily less beta-amyloid, at autopsy.

Those who most closely followed these diets had almost 40% lower odds of having an Alzheimer’s disease diagnosis at death. The findings offer one mechanism by which healthy diets protect cognition.

“While our research doesn’t prove that a healthy diet resulted in fewer brain deposits of amyloid plaques ... we know there is a relationship, and following the MIND and Mediterranean diets may be one way that people can improve their brain health and protect cognition as they age,” study investigator Puja Agarwal, PhD, of RUSH University Medical Center in Chicago, said in a statement.

The study was published online in Neurology.
 

Green leafy veggies key

The MIND diet was pioneered by the late Martha Clare Morris, ScD, a Rush nutritional epidemiologist, who died of cancer in 2020 at age 64.

Although similar, the Mediterranean diet recommends vegetables, fruit, and three or more servings of fish per week, whereas the MIND diet prioritizes green leafy vegetables, such as spinach, kale, and collard greens, along with other vegetables. The MIND diet also prioritizes berries over other fruit and recommends one or more servings of fish per week. Both diets recommend small amounts of wine.

The current study focused on 581 older adults who died while participating in the Rush Memory and Aging Project (MAP). All participants agreed to undergo annual clinical evaluations and brain autopsy after death.

Participants completed annual food frequency questionnaires beginning at a mean age of 84. The mean age at death was 91. Mean follow-up was 6.8 years.

Around the time of death, 224 participants (39%) had a diagnosis of clinical dementia, and 383 participants (66%) had a pathologic Alzheimer’s disease diagnosis at time of death.

The researchers used a series of regression analyses to investigate the MIND and Mediterranean diets and dietary components associated with Alzheimer’s disease pathology. They controlled for age at death, sex, education, APO-epsilon 4 status, and total calories.

Overall, both diets were significantly associated with lower global Alzheimer’s disease pathology (MIND: beta = –0.022, P = .034; and Mediterranean: beta = –0.007, P = .039) – specifically, with less beta-amyloid (MIND: beta = –0.068, P = .050; and Mediterranean: beta = –0.040, P = .004).

The findings persisted when the analysis was further adjusted for physical activity, smoking, and vascular disease burden and when participants with mild cognitive impairment or dementia at the baseline dietary assessment were excluded.

Individuals who most closely followed the Mediterranean diet had average beta-amyloid load similar to being 18 years younger than peers with the lowest adherence. And those who most closely followed the MIND diet had average beta-amyloid amounts similar to being 12 years younger than those with the lowest adherence.

A MIND diet score 1 point higher corresponded to typical plaque deposition of participants who are 4.25 years younger in age.

Regarding individual dietary components, those who ate seven or more servings of green leafy vegetables weekly had less global Alzheimer’s disease pathology than peers who ate one or fewer (beta = –0.115, P = .0038). Those who ate seven or more servings per week had plaque amounts in their brains corresponding to being almost 19 years younger in comparison with those who ate the fewest servings per week.

“Our finding that eating more green leafy vegetables is in itself associated with fewer signs of Alzheimer’s disease in the brain is intriguing enough for people to consider adding more of these vegetables to their diet,” Dr. Agarwal said in the news release.

Previous data from the MAP cohort showed that adherence to the MIND diet can improve memory and thinking skills of older adults, even in the presence of Alzheimer’s disease pathology.
 

Novel study, intriguing results

Heather Snyder, PhD, vice president of medical and scientific relations with the Alzheimer’s Association, noted that a number of studies have linked overall nutrition – especially a balanced diet low in saturated fats and sugar and high in vegetables – with brain health, including cognition, as one ages.

This new study “takes what we know about the link between nutrition and risk for cognitive decline a step further by looking at the specific brain changes that occur in Alzheimer’s disease. The study found an association of certain nutrition behaviors with less of these Alzheimer’s brain changes,” said Dr. Snyder, who was not involved in the study.

“This is intriguing, and more research is needed to test via an intervention if healthy dietary behaviors can modify the presence of Alzheimer’s brain changes and reduce risk of cognitive decline.”

The Alzheimer’s Association is leading a 2-year clinical trial known as US POINTER to study how targeting known dementia risk factors in combination may reduce risk of cognitive decline in older adults. The MIND diet is being used in US POINTER.

“But while we work to find an exact ‘recipe’ for risk reduction, it’s important to eat a heart-healthy diet that incorporates nutrients that our bodies and brains need to be at their best,” Dr. Snyder said.

The study was funded by the National Institutes of Health. Dr. Agarwal and Dr. Snyder have disclosed no relevant financial relationships.

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

A novel study provides strong evidence supporting the adoption of a healthy diet to protect the aging brain. In a cohort of deceased older adults, those who had adhered to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) and Mediterranean diets for nearly a decade before death had less global Alzheimer’s disease–related pathology, primarily less beta-amyloid, at autopsy.

Those who most closely followed these diets had almost 40% lower odds of having an Alzheimer’s disease diagnosis at death. The findings offer one mechanism by which healthy diets protect cognition.

“While our research doesn’t prove that a healthy diet resulted in fewer brain deposits of amyloid plaques ... we know there is a relationship, and following the MIND and Mediterranean diets may be one way that people can improve their brain health and protect cognition as they age,” study investigator Puja Agarwal, PhD, of RUSH University Medical Center in Chicago, said in a statement.

The study was published online in Neurology.
 

Green leafy veggies key

The MIND diet was pioneered by the late Martha Clare Morris, ScD, a Rush nutritional epidemiologist, who died of cancer in 2020 at age 64.

Although similar, the Mediterranean diet recommends vegetables, fruit, and three or more servings of fish per week, whereas the MIND diet prioritizes green leafy vegetables, such as spinach, kale, and collard greens, along with other vegetables. The MIND diet also prioritizes berries over other fruit and recommends one or more servings of fish per week. Both diets recommend small amounts of wine.

The current study focused on 581 older adults who died while participating in the Rush Memory and Aging Project (MAP). All participants agreed to undergo annual clinical evaluations and brain autopsy after death.

Participants completed annual food frequency questionnaires beginning at a mean age of 84. The mean age at death was 91. Mean follow-up was 6.8 years.

Around the time of death, 224 participants (39%) had a diagnosis of clinical dementia, and 383 participants (66%) had a pathologic Alzheimer’s disease diagnosis at time of death.

The researchers used a series of regression analyses to investigate the MIND and Mediterranean diets and dietary components associated with Alzheimer’s disease pathology. They controlled for age at death, sex, education, APO-epsilon 4 status, and total calories.

Overall, both diets were significantly associated with lower global Alzheimer’s disease pathology (MIND: beta = –0.022, P = .034; and Mediterranean: beta = –0.007, P = .039) – specifically, with less beta-amyloid (MIND: beta = –0.068, P = .050; and Mediterranean: beta = –0.040, P = .004).

The findings persisted when the analysis was further adjusted for physical activity, smoking, and vascular disease burden and when participants with mild cognitive impairment or dementia at the baseline dietary assessment were excluded.

Individuals who most closely followed the Mediterranean diet had average beta-amyloid load similar to being 18 years younger than peers with the lowest adherence. And those who most closely followed the MIND diet had average beta-amyloid amounts similar to being 12 years younger than those with the lowest adherence.

A MIND diet score 1 point higher corresponded to typical plaque deposition of participants who are 4.25 years younger in age.

Regarding individual dietary components, those who ate seven or more servings of green leafy vegetables weekly had less global Alzheimer’s disease pathology than peers who ate one or fewer (beta = –0.115, P = .0038). Those who ate seven or more servings per week had plaque amounts in their brains corresponding to being almost 19 years younger in comparison with those who ate the fewest servings per week.

“Our finding that eating more green leafy vegetables is in itself associated with fewer signs of Alzheimer’s disease in the brain is intriguing enough for people to consider adding more of these vegetables to their diet,” Dr. Agarwal said in the news release.

Previous data from the MAP cohort showed that adherence to the MIND diet can improve memory and thinking skills of older adults, even in the presence of Alzheimer’s disease pathology.
 

Novel study, intriguing results

Heather Snyder, PhD, vice president of medical and scientific relations with the Alzheimer’s Association, noted that a number of studies have linked overall nutrition – especially a balanced diet low in saturated fats and sugar and high in vegetables – with brain health, including cognition, as one ages.

This new study “takes what we know about the link between nutrition and risk for cognitive decline a step further by looking at the specific brain changes that occur in Alzheimer’s disease. The study found an association of certain nutrition behaviors with less of these Alzheimer’s brain changes,” said Dr. Snyder, who was not involved in the study.

“This is intriguing, and more research is needed to test via an intervention if healthy dietary behaviors can modify the presence of Alzheimer’s brain changes and reduce risk of cognitive decline.”

The Alzheimer’s Association is leading a 2-year clinical trial known as US POINTER to study how targeting known dementia risk factors in combination may reduce risk of cognitive decline in older adults. The MIND diet is being used in US POINTER.

“But while we work to find an exact ‘recipe’ for risk reduction, it’s important to eat a heart-healthy diet that incorporates nutrients that our bodies and brains need to be at their best,” Dr. Snyder said.

The study was funded by the National Institutes of Health. Dr. Agarwal and Dr. Snyder have disclosed no relevant financial relationships.

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

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

When the Food and Drug Administration approved avacopan (Tavneos) as an adjunctive treatment for severe, active antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) in October 2021, the oral complement C5a receptor inhibitor was hailed by its developer, ChemoCentryx, as a “new hope” for patients with the disease.

But avacopan’s novelty as a new drug for the rare diseases granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), coupled with its approval as an adjunctive to standard therapy, including glucocorticoids, rather than strictly as a glucocorticoid-sparing agent as it was tested, has so far led to little reported real-world experience with the drug.

M. Alexander Otto

In the phase 3 ADVOCATE trial, the pivotal trial that served as the basis for avacopan’s approval, 331 patients with active newly diagnosed or relapsing GPA or MPA received either avacopan or an oral prednisone taper over 20 weeks on a background of cyclophosphamide followed by azathioprine or rituximab. The results of the trial showed avacopan was noninferior to the group that received prednisone taper for remission at 26 weeks and superior to prednisone taper for sustained remission at 52 weeks, but the FDA was concerned that its complex design made it difficult to define the clinically meaningful benefit of avacopan and its role in the management of AAV.

The FDA noted that, in the avacopan arm of the trial, 86% of patients received glucocorticoids outside of the study protocol. Despite this, avacopan reduced the cumulative glucocorticoid dose over the trial’s 52 weeks by nearly two-thirds, compared with the prednisone group (1,349 mg vs. 3,655 mg).

The data also indicate a higher sustained remission rate at 52 weeks in patients who received induction with rituximab, compared with cyclophosphamide. But trial did not include a maintenance therapy dose of rituximab and is thereby not a good comparison against the standard of care, the FDA said. (ADVOCATE began enrolling patients prior to the FDA's 2018 approval of an expanded indication for patients with GPA or MPA who have achieved disease control after induction treatment.)

At the FDA’s Arthritis Advisory Committee meeting in May 2021, committee members were split on whether to recommend avacopan for approval. The committee voted 9-9 on whether the ADVOCATE trial showed efficacy supporting approval of avacopan, 10-8 in favor of whether the drug’s safety profile supported approval, and 10-8 in favor of the overall benefit-risk profile of avacopan for approval. But rather than give an indication to avacopan to reduce the use of glucocorticoids in adults with GPA or MPA, the agency approved avacopan as an adjunctive treatment for severe, active disease, noting in particular that avacopan “does not eliminate glucocorticoid use.”

The European Union’s marketing authorization for avacopan states its indication for use in combination with a rituximab or cyclophosphamide regimen for the treatment of adult patients with severe, active GPA or MPA and does not mention a role for reducing glucocorticoids. Avacopan will appear in forthcoming guidelines on management of AAV released by the European Alliance of Associations for Rheumatology.

In North America, the Canadian Vasculitis Research Network recently released an addendum to their guidelines on AAV specifically for avacopan, which includes recommendations to consider adding oral avacopan (30 mg twice daily) for induction of remission in patients with new or relapsing GPA or MPA who are also receiving cyclophosphamide or rituximab. The guidelines also recommend clinicians consider a glucocorticoid tapering schedule that aims for discontinuation at 4 weeks, and continuing avacopan for at least 1 year after induction therapy. The American College of Rheumatology guideline for AAV management, updated in 2021, acknowledges avacopan but did not consider its inclusion prior to FDA approval.

There have been few real-world studies of how patients with AAV are responding to avacopan, but recent studies from researchers in the Netherlands and in France have evaluated prednisone tapering and clinical outcomes.

Anisha B. Dua, MD, an associate professor of rheumatology at Northwestern University, Chicago, said those real-world studies “seemed to re-enforce the findings from the ADVOCATE study demonstrating the efficacy of avacopan in severe disease with steroid-sparing effects.”

However, Carol Langford, MD, MHS, director of the Center for Vasculitis Care and Research at the Cleveland Clinic, emphasized caution is needed when drawing conclusions about avacopan use outside formal studies.

“We are all interested in what other settings this might be used. I think those are things that really require formal investigation to really try and understand better as far as through a study process,” she said.
 

Prescribing experience with avacopan

A spokesperson from Amgen, which recently acquired ChemoCentryx, said in an interview that over 800 physicians in the United States have prescribed avacopan to patients with new or relapsing ANCA-associated vasculitis as induction or maintenance treatment, and physicians have reported outcomes consistent with the ADVOCATE trial.

Many rheumatologists are likely familiar with avacopan but are not used to prescribing it, said Lindsay S. Lally, MD, a rheumatologist with Hospital for Special Surgery in New York.

“Rituximab was approved for GPA and MPA a decade ago at this point. It was a drug that we as rheumatologists were used to using. We used it for other indications. Avacopan is a totally new drug, a new mechanism of action, so there’s not a lot of extractable data that we have in terms of comfort with the drug, and so I think that’s one of the biggest hurdles,” she said.

Mehrnaz Hojjati, MD, a rheumatologist with Loma Linda (Calif.) University Health, said that, when the FDA approved avacopan, it was an “exciting time” in her practice. “I have used avacopan now in a handful of my patients with severe ANCA-associated vasculitis, and the results are similar to what [was] reported in the ADVOCATE trial.”

Amgen offers help for clinicians in obtaining avacopan for patients, financial assistance for patients, and support in navigating insurance, which several rheumatologists noted was important for patients. Dr. Langford said the process of working with the manufacturer to get avacopan while insurance information is being processed has been “fairly smooth.”

“Certainly, the ability to get a very rapid 30-day supply with the goal of trying to initiate this as early as possible in the disease process has been helpful,” she said.

In Dr. Dua’s experience, while there were “some glitches or difficulty for providers early on” in how to access and prescribe avacopan, since then “it has been much easier to obtain the medication with the first month being provided to patients free while the authorization process is managed.”

Prescribing avacopan from inpatient pharmacies has been more challenging, she said. “The inpatient side is trickier because each hospital system has their own pharmacy system and regulations that have to be navigated. For outpatients, all the provider needs to do is fill out the start form available on their website, have the patients sign it, and then have it sent in.”
 

Concerns about affordability, insurance approval

Another consideration is cost, with avacopan having an estimated price of $150,000-$200,000 per patient per year.

Dr. Hojjati noted that, while it is easy to prescribe, avacopan is hard to get approved through insurance. “We face the same challenge every time a new medication comes to the market on how to convince the payers to pay for it given higher prices,” she said.

Rheumatologist Michael Putman, MD, MSCI, assistant professor of medicine at the Medical College of Wisconsin, Milwaukee, also acknowledged some difficulties in prescribing the medication. “The insurance companies have no interest in spending $150,000 on a drug that they know nothing about, and patients are a little hesitant to take it because it’s just so new,” he said.

While Dr. Lally said avacopan has not been difficult to get for patients with commercial insurance, reimbursement through Medicare has been problematic. “In many of the Medicare patients it has not really been a feasible option for them to be on the drug for the year of therapy.”
 

Patient response

Dr. Dua said almost all her patients with new or relapsing AAV who require induction are being prescribed avacopan, and that the medication is well tolerated. “The remission and ability to wean prednisone has really paralleled the findings from the clinical trial.”

In her practice, Dr. Hojjati starts patients on avacopan immediately after discharge from the hospital after a major vasculitis flare requiring high-dose glucocorticoids. “Avacopan does not eliminate/replace GC [glucocorticoid] use but has a notable GC-sparing effect and assists in rapid tapering of the GC while treating our severe ANCA-associated vasculitis patients,” she said.

Dr. Lally said her patients are tolerating avacopan well and hasn’t seen any of the safety signals seen in the trial, including liver function abnormalities. She has treated about 20-25 patients with avacopan.

Dr. Putman noted that he has treated about five patients with avacopan but hasn’t seen dramatic efficacy or side effects in his practice, compared with standard therapy.

Unanswered questions about avacopan

A key unanswered question with avacopan is the timeline for tapering glucocorticoids once patients start treatment. “I would like to see much more data on how prednisone is being tapered in clinical practice as well as outcomes in patients who are treated with the standard of care second dose of rituximab at 6 months,” Dr. Dua said.

Dr. Lally noted she has tried to expedite the steroid taper in her patients. “That’s really where I feel this drug is going to have most relevance, is getting it started early in active disease and getting patients off of the reliance on high doses of oral steroids. I have been able to see that in practice, and I do think ultimately that’s going to lead to better outcomes and quality of life for these patients.”

Of the rheumatologists Dr. Lally has spoken to about avacopan, there is “some confusion about what type of patients are appropriate, [and] how sick or not sick the patient needs to be.”

Dr. Putman noted he is unsure which of his patients should be receiving avacopan. “I don’t totally have a sense for where avacopan stands and how often we should be using it” outside of patients with severe disease. He added that the drug is still trying to find a niche because most patients with AAV who take rituximab and steroids get better without additional treatments.

“I think we do a pretty good job treating these diseases even in the preavacopan era. But it’s really a matter of how to really optimize these outcomes, reduce damage, reduce steroid-related and treatment-related toxicity for our patients,” Dr. Lally said.

Dr. Dua reported being a consultant and serving on advisory boards for ChemoCentryx; she was also a site principal investigator for the ADVOCATE trial. Dr. Hojjati reported being on the speaker’s bureau for Amgen. Dr. Langford reported being an investigator in the ADVOCATE trial, and her institution received funding to conduct the trial. Dr. Lally reported being a consultant for Amgen on avacopan. Dr. Putman reported no relevant financial disclosures.

*This story was updated 3/15/2023.

Practicing yoga was associated with improvements in several frailty markers in previously inactive older adults, a multistudy review finds.

“Up to 50% of adults aged 80 years or older are estimated to be frail, and the global prevalence is expected to rise given the aging of our population,” therefore more interventions are needed to help with frailty, corresponding author Julia Loewenthal, MD, said in an interview.

Yoga integrates across multiple body systems including the musculoskeletal system, nervous system, and others, said Dr. Loewenthal of Brigham and Women’s Hospital, Boston. Previous research has shown that yoga has a positive effect on cardiovascular risk factors, mood, and quality of life, but the effects of yoga on frailty have not been well studied.

“We wanted to evaluate whether [yoga] might help with frailty, since it touches on so many systems, as frailty does,” she noted.

In a systematic review published in Annals of Internal Medicine, the researchers identified 33 randomized, controlled trials of yoga-based interventions including 2,384 adults aged 65 years and older. The studies mainly involved Iyengar or chair-based yoga methods. The study population included community-dwelling seniors, nursing home residents, and individuals with chronic diseases.

The studies assessed the effect of a range of yoga practices on frailty markers including gait speed, handgrip strength, balance, lower extremity strength and endurance, and multicomponent measures of physical performance.

Overall, individuals who were randomized to engage in a yoga practice showed improved gait speed and lower extremity strength, compared with controls who were inactive or received an education intervention, with moderate-certainty evidence. The researchers also found low-certainty evidence in favor of yoga for improved balance and for a composite measure of physical function, and low-certainty evidence in favor of yoga for improved handgrip strength.

The findings were limited by several factors, mainly the heterogenous study designs, populations, and yoga styles, the researchers noted. Other limitations included the small sample sizes, variation in descriptions of the studies’ randomizations, and a lack of data on race and ethnicity of the participants.
 

Yoga’s role in healthy aging

“Overall, we were not surprised by the results since we have seen similar findings from other mind-body practices such as tai chi,” Dr. Loewenthal said in an interview. “We were surprised by the degree of improvement many of the participants had with gait speed.

“Yoga practices usually include a mix of poses in the standing, seated, and lying-down positions,” Dr. Loewenthal said. Some of the studies in the review also involved chair-based methods with few standing poses, and some involved gentle or slow-paced practices. “We know that many of the practices helped with leg strength, and perhaps they are also helping with coordination between the brain and body for walking.”

The findings suggest that clinicians can view yoga practice in general as part of a strategy to support healthy aging, Dr. Loewenthal said. “While our work looked at frailty markers and not overall frailty, I think it would be reasonable to offer yoga as a strategy along with already-established interventions such as resistance training and the Mediterranean diet, and if older adults are already practicing yoga, this could help them understand how the practice is impacting the aging process.”

There are many styles of yoga that overlap and are related to one another, so it is hard to make recommendations about a single type, said Dr. Loewenthal. Many of the studies in the review involved Iyengar yoga, named for yoga master B.K.S. Iyengar, which focuses on precise alignment and breath and seems to be conducive for older populations. Iyengar yoga also involves use of props such as blocks, bolsters, straps, and chairs, which makes it well suited for older individuals who may have a chronic condition or other limitations.

“Some styles of yoga are very physical and may reach energy expenditure and cardiovascular effects similar to aerobic exercise, but this is generally not the case for most styles of yoga,” she added.

As for additional research, “I think it is important that trials use a validated definition of frailty as an outcome; all of the trials in our study used markers of frailty but did not look at overall frailty,” said Dr. Loewenthal. In addition, it is important to understand how yoga affects people who have different levels of frailty, since previous research shows that those who are the most frail benefit most from physical activity interventions.
 

Yoga as an entry point for physical activity

With the increasing population of older adults in the United States and around the world, frailty is a major health concern because its association with significant declines in health and potential loss of independence, Amanda Paluch, PhD, said in an interview.

“Therefore, it is important to identify programs that can prevent frailty to support longevity and living independently for older adults. Yoga can be a feasible solution to promote movement and prevent frailty,” said Dr. Paluch, of the University of Massachusetts, Amherst, an assistant professor in the department of kinesiology and Institute for Applied Life Sciences.

“Other studies have demonstrated that light-intensity movement, as in yoga, may be particularly beneficial for older adults,” Dr. Paluch said. “Additionally, research has demonstrated that balance training activities are important to maintain physical function, prevent falls, and maintain their independence for older adults, so it makes sense that yoga was associated with lower likelihood of frailty.”

Although there may be additional benefits with higher intensity activity, “yoga could be a great place to start for older adults who are starting at low activity levels,” she said.

The takeaway for clinicians is to consider encouraging more physical activity for their patients to support healthy aging, including reducing the risk factors for frailty, said Dr. Paluch. “Particularly for older adults, physical activity may not need to be of high intensity for benefits. Activities such as yoga that focus on flexibility, balance, and movement at lower intensities can support healthy aging, and yoga may be a particularly good option for older adults who are least active.”

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

Practicing yoga was associated with improvements in several frailty markers in previously inactive older adults, a multistudy review finds.

“Up to 50% of adults aged 80 years or older are estimated to be frail, and the global prevalence is expected to rise given the aging of our population,” therefore more interventions are needed to help with frailty, corresponding author Julia Loewenthal, MD, said in an interview.

Yoga integrates across multiple body systems including the musculoskeletal system, nervous system, and others, said Dr. Loewenthal of Brigham and Women’s Hospital, Boston. Previous research has shown that yoga has a positive effect on cardiovascular risk factors, mood, and quality of life, but the effects of yoga on frailty have not been well studied.

“We wanted to evaluate whether [yoga] might help with frailty, since it touches on so many systems, as frailty does,” she noted.

In a systematic review published in Annals of Internal Medicine, the researchers identified 33 randomized, controlled trials of yoga-based interventions including 2,384 adults aged 65 years and older. The studies mainly involved Iyengar or chair-based yoga methods. The study population included community-dwelling seniors, nursing home residents, and individuals with chronic diseases.

The studies assessed the effect of a range of yoga practices on frailty markers including gait speed, handgrip strength, balance, lower extremity strength and endurance, and multicomponent measures of physical performance.

Overall, individuals who were randomized to engage in a yoga practice showed improved gait speed and lower extremity strength, compared with controls who were inactive or received an education intervention, with moderate-certainty evidence. The researchers also found low-certainty evidence in favor of yoga for improved balance and for a composite measure of physical function, and low-certainty evidence in favor of yoga for improved handgrip strength.

The findings were limited by several factors, mainly the heterogenous study designs, populations, and yoga styles, the researchers noted. Other limitations included the small sample sizes, variation in descriptions of the studies’ randomizations, and a lack of data on race and ethnicity of the participants.
 

Yoga’s role in healthy aging

“Overall, we were not surprised by the results since we have seen similar findings from other mind-body practices such as tai chi,” Dr. Loewenthal said in an interview. “We were surprised by the degree of improvement many of the participants had with gait speed.

“Yoga practices usually include a mix of poses in the standing, seated, and lying-down positions,” Dr. Loewenthal said. Some of the studies in the review also involved chair-based methods with few standing poses, and some involved gentle or slow-paced practices. “We know that many of the practices helped with leg strength, and perhaps they are also helping with coordination between the brain and body for walking.”

The findings suggest that clinicians can view yoga practice in general as part of a strategy to support healthy aging, Dr. Loewenthal said. “While our work looked at frailty markers and not overall frailty, I think it would be reasonable to offer yoga as a strategy along with already-established interventions such as resistance training and the Mediterranean diet, and if older adults are already practicing yoga, this could help them understand how the practice is impacting the aging process.”

There are many styles of yoga that overlap and are related to one another, so it is hard to make recommendations about a single type, said Dr. Loewenthal. Many of the studies in the review involved Iyengar yoga, named for yoga master B.K.S. Iyengar, which focuses on precise alignment and breath and seems to be conducive for older populations. Iyengar yoga also involves use of props such as blocks, bolsters, straps, and chairs, which makes it well suited for older individuals who may have a chronic condition or other limitations.

“Some styles of yoga are very physical and may reach energy expenditure and cardiovascular effects similar to aerobic exercise, but this is generally not the case for most styles of yoga,” she added.

As for additional research, “I think it is important that trials use a validated definition of frailty as an outcome; all of the trials in our study used markers of frailty but did not look at overall frailty,” said Dr. Loewenthal. In addition, it is important to understand how yoga affects people who have different levels of frailty, since previous research shows that those who are the most frail benefit most from physical activity interventions.
 

Yoga as an entry point for physical activity

With the increasing population of older adults in the United States and around the world, frailty is a major health concern because its association with significant declines in health and potential loss of independence, Amanda Paluch, PhD, said in an interview.

“Therefore, it is important to identify programs that can prevent frailty to support longevity and living independently for older adults. Yoga can be a feasible solution to promote movement and prevent frailty,” said Dr. Paluch, of the University of Massachusetts, Amherst, an assistant professor in the department of kinesiology and Institute for Applied Life Sciences.

“Other studies have demonstrated that light-intensity movement, as in yoga, may be particularly beneficial for older adults,” Dr. Paluch said. “Additionally, research has demonstrated that balance training activities are important to maintain physical function, prevent falls, and maintain their independence for older adults, so it makes sense that yoga was associated with lower likelihood of frailty.”

Although there may be additional benefits with higher intensity activity, “yoga could be a great place to start for older adults who are starting at low activity levels,” she said.

The takeaway for clinicians is to consider encouraging more physical activity for their patients to support healthy aging, including reducing the risk factors for frailty, said Dr. Paluch. “Particularly for older adults, physical activity may not need to be of high intensity for benefits. Activities such as yoga that focus on flexibility, balance, and movement at lower intensities can support healthy aging, and yoga may be a particularly good option for older adults who are least active.”

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

Practicing yoga was associated with improvements in several frailty markers in previously inactive older adults, a multistudy review finds.

“Up to 50% of adults aged 80 years or older are estimated to be frail, and the global prevalence is expected to rise given the aging of our population,” therefore more interventions are needed to help with frailty, corresponding author Julia Loewenthal, MD, said in an interview.

Yoga integrates across multiple body systems including the musculoskeletal system, nervous system, and others, said Dr. Loewenthal of Brigham and Women’s Hospital, Boston. Previous research has shown that yoga has a positive effect on cardiovascular risk factors, mood, and quality of life, but the effects of yoga on frailty have not been well studied.

“We wanted to evaluate whether [yoga] might help with frailty, since it touches on so many systems, as frailty does,” she noted.

In a systematic review published in Annals of Internal Medicine, the researchers identified 33 randomized, controlled trials of yoga-based interventions including 2,384 adults aged 65 years and older. The studies mainly involved Iyengar or chair-based yoga methods. The study population included community-dwelling seniors, nursing home residents, and individuals with chronic diseases.

The studies assessed the effect of a range of yoga practices on frailty markers including gait speed, handgrip strength, balance, lower extremity strength and endurance, and multicomponent measures of physical performance.

Overall, individuals who were randomized to engage in a yoga practice showed improved gait speed and lower extremity strength, compared with controls who were inactive or received an education intervention, with moderate-certainty evidence. The researchers also found low-certainty evidence in favor of yoga for improved balance and for a composite measure of physical function, and low-certainty evidence in favor of yoga for improved handgrip strength.

The findings were limited by several factors, mainly the heterogenous study designs, populations, and yoga styles, the researchers noted. Other limitations included the small sample sizes, variation in descriptions of the studies’ randomizations, and a lack of data on race and ethnicity of the participants.
 

Yoga’s role in healthy aging

“Overall, we were not surprised by the results since we have seen similar findings from other mind-body practices such as tai chi,” Dr. Loewenthal said in an interview. “We were surprised by the degree of improvement many of the participants had with gait speed.

“Yoga practices usually include a mix of poses in the standing, seated, and lying-down positions,” Dr. Loewenthal said. Some of the studies in the review also involved chair-based methods with few standing poses, and some involved gentle or slow-paced practices. “We know that many of the practices helped with leg strength, and perhaps they are also helping with coordination between the brain and body for walking.”

The findings suggest that clinicians can view yoga practice in general as part of a strategy to support healthy aging, Dr. Loewenthal said. “While our work looked at frailty markers and not overall frailty, I think it would be reasonable to offer yoga as a strategy along with already-established interventions such as resistance training and the Mediterranean diet, and if older adults are already practicing yoga, this could help them understand how the practice is impacting the aging process.”

There are many styles of yoga that overlap and are related to one another, so it is hard to make recommendations about a single type, said Dr. Loewenthal. Many of the studies in the review involved Iyengar yoga, named for yoga master B.K.S. Iyengar, which focuses on precise alignment and breath and seems to be conducive for older populations. Iyengar yoga also involves use of props such as blocks, bolsters, straps, and chairs, which makes it well suited for older individuals who may have a chronic condition or other limitations.

“Some styles of yoga are very physical and may reach energy expenditure and cardiovascular effects similar to aerobic exercise, but this is generally not the case for most styles of yoga,” she added.

As for additional research, “I think it is important that trials use a validated definition of frailty as an outcome; all of the trials in our study used markers of frailty but did not look at overall frailty,” said Dr. Loewenthal. In addition, it is important to understand how yoga affects people who have different levels of frailty, since previous research shows that those who are the most frail benefit most from physical activity interventions.
 

Yoga as an entry point for physical activity

With the increasing population of older adults in the United States and around the world, frailty is a major health concern because its association with significant declines in health and potential loss of independence, Amanda Paluch, PhD, said in an interview.

“Therefore, it is important to identify programs that can prevent frailty to support longevity and living independently for older adults. Yoga can be a feasible solution to promote movement and prevent frailty,” said Dr. Paluch, of the University of Massachusetts, Amherst, an assistant professor in the department of kinesiology and Institute for Applied Life Sciences.

“Other studies have demonstrated that light-intensity movement, as in yoga, may be particularly beneficial for older adults,” Dr. Paluch said. “Additionally, research has demonstrated that balance training activities are important to maintain physical function, prevent falls, and maintain their independence for older adults, so it makes sense that yoga was associated with lower likelihood of frailty.”

Although there may be additional benefits with higher intensity activity, “yoga could be a great place to start for older adults who are starting at low activity levels,” she said.

The takeaway for clinicians is to consider encouraging more physical activity for their patients to support healthy aging, including reducing the risk factors for frailty, said Dr. Paluch. “Particularly for older adults, physical activity may not need to be of high intensity for benefits. Activities such as yoga that focus on flexibility, balance, and movement at lower intensities can support healthy aging, and yoga may be a particularly good option for older adults who are least active.”

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

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

NEW ORLEANS – An investigational, first-in class agent that delivers a completely new type of intervention to patients with pulmonary arterial hypertension (PAH) scored a clear win in the STELLAR trial, the first to complete among three phase 3 trials that are testing this agent.

Sotatercept, administered subcutaneously every 3 weeks for 24 weeks, improved from baseline average 6-minute walk distance (6MWD) by a significant and clinically meaningful 40.8 meters, compared with placebo, for the trial’s primary efficacy endpoint (P < .001). The treatment also “delivered broad clinical benefit across multiple domains including hemodynamics, World Health Organization functional class, disease biomarkers, risk scores and patient-reported outcomes,” Marius M. Hoeper, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Mitchel L. Zoler/MDedge News

“These results establish the clinical utility of sotatercept, administered in combination with approved PAH therapies, as a new treatment for PAH,” added Dr. Hoeper, professor and deputy director of the department of respiratory medicine at Hannover (Germany) Medical School,

“The most important aspect was the hemodynamic improvement,” with sotatercept treatment, which led to an average 235 dyn/sec per cm⁻⁵ reduction in pulmonary vascular resistance from baseline and an average cut in pulmonary artery pressure of 13.9 mm Hg from baseline, compared with placebo, a result that’s “unheard of,” Dr. Hoeper said in a press conference during the meeting.

“With other tested agents we usually see very little improvement in pulmonary artery pressure. This is a signal that we achieved some reversing of the pathological changes in the pulmonary vessels that lead to” PAH, he added.

Simultaneously with his report the findings also appeared online in the New England Journal of Medicine.
 

‘A new hope’ for patients with PAH

Based on the reported findings, sotatercept is a “very exciting boutique molecule” that will “offer patients with PAH a very exciting new treatment,” commented Rhonda Cooper-DeHoff, PharmD, a designated discussant and a researcher at the University of Florida, Gainesville.

Mitchel L. Zoler/MDedge News

“This study is a new hope for patients with PAH. Until now, they’ve had really bad outcomes, but [in this study] we see significant differences in 6MWD, hemodynamics, and risk factors. Overall, I think the benefit is greater than the risk” it may pose to patients through potential adverse effects, commented Julia Grapsa, MD, PhD, a cardiologist at St. Thomas Hospital in London, and another discussant at the meeting.

“The results are impressive” and “encouraging,” and “suggest that sotatercept may represent a new and clinically consequential addition to current medications for PAH,” wrote three clinicians from Canyons Region Intermountain Medical Center in Murray, Utah, in an editorial that accompanied the published report.

But the authors of the editorial also raised several cautions and concerns. They questioned the generalizability of the findings, noting that the patients with PAH enrolled in the study were all adults who were clinically stable and an average of more than 8 years out from their initial PAH diagnosis, and more than 90% were on stable treatment for PAH with two or three agents specific for treating the disorder. The study cohort also had a disproportionately high enrollment of patients with idiopathic (59%) or heritable (18%) forms of PAH, and the 15% of patients in the trial with connective tissue disease represented a disproportionately low prevalence of this PAH subtype.

The editorialists also called for “ongoing vigilance” for adverse effects from sotatercept treatment, although they acknowledged that the adverse effects reported to date from sotatercept are “largely reassuring.”
 

Death or clinical worsening cut by 84%

STELLAR randomized 323 patients at 91 sites in 21 countries with WHO Group 1 PAH and with WHO functional class II or III disease to receive either sotatercept or placebo for 24 weeks, with an option for treatment to continue beyond that until the last patient in the study reached 24 weeks on treatment, resulting in an overall median treatment duration of nearly 33 weeks.

In addition to the significant result for the primary endpoint, the 163 patients who received sotatercept had significant improvements, compared with 160 placebo-treated patients, for eight of nine secondary endpoints. The only secondary endpoint with a neutral result was for a measure of cognitive and emotional wellbeing, a parameter that was already at a normal level at baseline in most enrolled patients, Dr. Hoeper explained.

The incidence of either death or an event indicative of clinical worsening during the overall median follow-up of almost 33 weeks was 26.3% among the control patients and 5.5% among those who received sotatercept. This translated into a significant reduction for this endpoint of 84% with sotatercept treatment, compared with placebo.

The rates of treatment-emergent adverse events leading to discontinuation were roughly the same in the control and sotatercept arms, and the incidence of severe or serious treatment-emergent adverse events was higher among the control patients.

The most common adverse event on sotatercept was bleeding events, which occurred in 32% of those on sotatercept and in 16% of the control patients, but the events in the sotatercept arm were “mostly mild,” said Dr. Hoeper. The next most frequent adverse event during sotatercept treatment was appearance of telangiectasias, which occurred in 14% of those on sotatercept and in 4% of control patients.

“It’s an uncommon adverse event profile, but not unexpected for a drug with its mechanism of action,” he said.

Drug binds activin, a pathologic driver of PAH

Sotatercept is an engineered molecule that combines a section of a human immunoglobulin G molecule with a portion of the receptor for activin. This structure allows sotatercept to bind free activin molecules in a patient’s blood, thereby removing a key driver of the pulmonary vascular wall remodeling that is at the pathologic root of PAH.

“Hyperproliferation of blood vessel–wall cells” caused by activin signaling “is perhaps the most important driver of PAH,” Dr. Hoeper said. “Sotatercept allows us for the first time to target the underlying mechanism behind PAH.”

Still ongoing are the HYPERION and ZENITH phase 3 trials of sotatercept. HYPERION is enrolling patients with newly diagnosed or high-risk PAH and is expected to complete in 2028. ZENITH is enrolling patients with more advanced PAH and a higher mortality risk, with results expected in 2026.

Sotatercept has received “Breakthrough Therapy” designation and “Orphan Drug” designation by the Food and Drug Administration, and “Priority Medicines” designation and “Orphan Drug” designation by the European Medicines Agency for the treatment of PAH. One recent review estimated a worldwide PAH prevalence of about 3-4 cases/100,000, which for the United States translates into a total prevalence of perhaps 10,000-15,000 affected people.

STELLAR was funded by Acceleron Pharma, a subsidiary of Merck. Dr. Hoeper is a consultant to Acceleron. Dr. Cooper-DeHoff, Dr. Grapsa, and the authors of the editorial on STELLAR have no relevant disclosures.

It’s Oscars weekend, so for the second annual Meddy Awards – a very self-congratulatory and very tongue-in-cheek version of the Oscars – we celebrate outstanding medical performances and events in motion pictures throughout history. Without further ado (or comedy skits or musical numbers or extended tributes or commercials), the Meddys go to ...

Best depiction of emergency medicine’s rollercoaster

M*A*S*H (1970)

The original film, not the TV show, jumps from Frank Burns being hauled away in a straitjacket to a soldier’s spurting neck wound. Hawkeye Pierce calmly steps in and we see the entire sequence of him applying pressure, then stepping back to gown-and-glove (“it’s going to spurt a bit”), then jumping back in with arterial sutures, quipping, “Baby, we’re gonna see some stitchin’ like you never saw before.” After that, cocktail hour. Yes, medicine in Hollywood can be overdramatized and even inaccurate, but Robert Altman’s take on the novel by former U.S. Army surgeon Richard Hooker still stands tall for just how crazy emergency medicine can be.

Best ‘is there a doctor in the house?’ moment

Field of Dreams (1989)

When Ray Kinsella’s daughter gets knocked off the back of the bleachers, everything stops. No one knows what to do … except Doc “Moonlight” Graham, who gives up his life’s (and afterlife’s) dream to step off the field and save the girl from choking to death. Burt Lancaster, in his final movie role, embodies everything people wish a doctor to be: Calm, kind, and able to offer a quick, effective solution to a crisis. “Hey rookie! You were good.” Yes, he sure was.

Most unethical doctor

Elvis (2022)

No doctor wants to be remembered as the guy who killed Elvis. But that legacy clings to Dr. George Nichopoulos, Elvis’s personal physician in the 1970s. In Elvis, Dr. Nichopoulos, played by Tony Nixon, hovers in the background, enabling the King’s worsening addictions. Taking late-night calls for narcotics and injecting the unconscious star with stimulants, “unethical” is an understatement for the fictional “Dr. Nick.” The real Dr. Nichopoulos was acquitted of wrongdoing in Elvis’ death, although there is little doubt that the thousands of medication doses he prescribed played a role. When his license was finally revoked for overprescribing in the 1990s, the obliging doc reportedly claimed, “I cared too much.”

Best self-use of a defibrillator

Casino Royale (2006)

We expect backlash in the post-award press conference since James Bond technically only attempted to self-defibrillate in the passenger seat of his car. He never attached the device to the leads. Vesper Lynd had to pick up his slack and save the day. Also, supporters of fellow self-defibrillating nominee Jason Statham in Crank will no doubt raise a stink on Twitter. But we stand by our choice because it was such an, ahem, heart-stopper of a scene.

Best worst patient lying about an injury

Tár (2022)

Love it or hate it, few recent movies have been as polarizing as Tár. Cate Blanchett’s portrayal of a musical genius might be toweringly brilliant or outrageously offensive (or both) depending on whom you ask. But clearly the character has a loose relationship with facts. More than a few doctors might have raised an eyebrow had Lydia Tár appeared with injuries to her face, claiming to have been attacked in a mugging. In reality, Lydia tripped and fell while pursuing an attractive young cellist into a hazardous basement. Did she lie to protect her image, preserve her marriage, or – like many patients – avoid a lecture on unhealthy behavior? We pick D, all of the above.

Best therapy for a speech disorder

The King’s Speech (2010)

Public speaking might cause anxiety for many of us, but how about doing it in front of a global radio audience while wrestling with a speech disorder? Based on a true story, The King’s Speech revealed that terrifying experience for England’s King George VI. Enter Lionel Logue, played by Geoffrey Rush. Irreverent, unconventional, and untrained, the Australian pioneer in speech and language therapy uses a range of strategies – some of which are still used today – to help the royal find his voice. But when singing, shouting swear words, and provoking rage don’t do the trick, Mr. Logue turns to psychotherapy to unearth the childhood traumas at the root of the king’s disability. Experience, as Mr. Logue tells his patient, matters just as much as “letters after your name.”

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

It’s Oscars weekend, so for the second annual Meddy Awards – a very self-congratulatory and very tongue-in-cheek version of the Oscars – we celebrate outstanding medical performances and events in motion pictures throughout history. Without further ado (or comedy skits or musical numbers or extended tributes or commercials), the Meddys go to ...

Best depiction of emergency medicine’s rollercoaster

M*A*S*H (1970)

The original film, not the TV show, jumps from Frank Burns being hauled away in a straitjacket to a soldier’s spurting neck wound. Hawkeye Pierce calmly steps in and we see the entire sequence of him applying pressure, then stepping back to gown-and-glove (“it’s going to spurt a bit”), then jumping back in with arterial sutures, quipping, “Baby, we’re gonna see some stitchin’ like you never saw before.” After that, cocktail hour. Yes, medicine in Hollywood can be overdramatized and even inaccurate, but Robert Altman’s take on the novel by former U.S. Army surgeon Richard Hooker still stands tall for just how crazy emergency medicine can be.

Best ‘is there a doctor in the house?’ moment

Field of Dreams (1989)

When Ray Kinsella’s daughter gets knocked off the back of the bleachers, everything stops. No one knows what to do … except Doc “Moonlight” Graham, who gives up his life’s (and afterlife’s) dream to step off the field and save the girl from choking to death. Burt Lancaster, in his final movie role, embodies everything people wish a doctor to be: Calm, kind, and able to offer a quick, effective solution to a crisis. “Hey rookie! You were good.” Yes, he sure was.

Most unethical doctor

Elvis (2022)

No doctor wants to be remembered as the guy who killed Elvis. But that legacy clings to Dr. George Nichopoulos, Elvis’s personal physician in the 1970s. In Elvis, Dr. Nichopoulos, played by Tony Nixon, hovers in the background, enabling the King’s worsening addictions. Taking late-night calls for narcotics and injecting the unconscious star with stimulants, “unethical” is an understatement for the fictional “Dr. Nick.” The real Dr. Nichopoulos was acquitted of wrongdoing in Elvis’ death, although there is little doubt that the thousands of medication doses he prescribed played a role. When his license was finally revoked for overprescribing in the 1990s, the obliging doc reportedly claimed, “I cared too much.”

Best self-use of a defibrillator

Casino Royale (2006)

We expect backlash in the post-award press conference since James Bond technically only attempted to self-defibrillate in the passenger seat of his car. He never attached the device to the leads. Vesper Lynd had to pick up his slack and save the day. Also, supporters of fellow self-defibrillating nominee Jason Statham in Crank will no doubt raise a stink on Twitter. But we stand by our choice because it was such an, ahem, heart-stopper of a scene.

Best worst patient lying about an injury

Tár (2022)

Love it or hate it, few recent movies have been as polarizing as Tár. Cate Blanchett’s portrayal of a musical genius might be toweringly brilliant or outrageously offensive (or both) depending on whom you ask. But clearly the character has a loose relationship with facts. More than a few doctors might have raised an eyebrow had Lydia Tár appeared with injuries to her face, claiming to have been attacked in a mugging. In reality, Lydia tripped and fell while pursuing an attractive young cellist into a hazardous basement. Did she lie to protect her image, preserve her marriage, or – like many patients – avoid a lecture on unhealthy behavior? We pick D, all of the above.

Best therapy for a speech disorder

The King’s Speech (2010)

Public speaking might cause anxiety for many of us, but how about doing it in front of a global radio audience while wrestling with a speech disorder? Based on a true story, The King’s Speech revealed that terrifying experience for England’s King George VI. Enter Lionel Logue, played by Geoffrey Rush. Irreverent, unconventional, and untrained, the Australian pioneer in speech and language therapy uses a range of strategies – some of which are still used today – to help the royal find his voice. But when singing, shouting swear words, and provoking rage don’t do the trick, Mr. Logue turns to psychotherapy to unearth the childhood traumas at the root of the king’s disability. Experience, as Mr. Logue tells his patient, matters just as much as “letters after your name.”

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

It’s Oscars weekend, so for the second annual Meddy Awards – a very self-congratulatory and very tongue-in-cheek version of the Oscars – we celebrate outstanding medical performances and events in motion pictures throughout history. Without further ado (or comedy skits or musical numbers or extended tributes or commercials), the Meddys go to ...

Best depiction of emergency medicine’s rollercoaster

M*A*S*H (1970)

The original film, not the TV show, jumps from Frank Burns being hauled away in a straitjacket to a soldier’s spurting neck wound. Hawkeye Pierce calmly steps in and we see the entire sequence of him applying pressure, then stepping back to gown-and-glove (“it’s going to spurt a bit”), then jumping back in with arterial sutures, quipping, “Baby, we’re gonna see some stitchin’ like you never saw before.” After that, cocktail hour. Yes, medicine in Hollywood can be overdramatized and even inaccurate, but Robert Altman’s take on the novel by former U.S. Army surgeon Richard Hooker still stands tall for just how crazy emergency medicine can be.

Best ‘is there a doctor in the house?’ moment

Field of Dreams (1989)

When Ray Kinsella’s daughter gets knocked off the back of the bleachers, everything stops. No one knows what to do … except Doc “Moonlight” Graham, who gives up his life’s (and afterlife’s) dream to step off the field and save the girl from choking to death. Burt Lancaster, in his final movie role, embodies everything people wish a doctor to be: Calm, kind, and able to offer a quick, effective solution to a crisis. “Hey rookie! You were good.” Yes, he sure was.

Most unethical doctor

Elvis (2022)

No doctor wants to be remembered as the guy who killed Elvis. But that legacy clings to Dr. George Nichopoulos, Elvis’s personal physician in the 1970s. In Elvis, Dr. Nichopoulos, played by Tony Nixon, hovers in the background, enabling the King’s worsening addictions. Taking late-night calls for narcotics and injecting the unconscious star with stimulants, “unethical” is an understatement for the fictional “Dr. Nick.” The real Dr. Nichopoulos was acquitted of wrongdoing in Elvis’ death, although there is little doubt that the thousands of medication doses he prescribed played a role. When his license was finally revoked for overprescribing in the 1990s, the obliging doc reportedly claimed, “I cared too much.”

Best self-use of a defibrillator

Casino Royale (2006)

We expect backlash in the post-award press conference since James Bond technically only attempted to self-defibrillate in the passenger seat of his car. He never attached the device to the leads. Vesper Lynd had to pick up his slack and save the day. Also, supporters of fellow self-defibrillating nominee Jason Statham in Crank will no doubt raise a stink on Twitter. But we stand by our choice because it was such an, ahem, heart-stopper of a scene.

Best worst patient lying about an injury

Tár (2022)

Love it or hate it, few recent movies have been as polarizing as Tár. Cate Blanchett’s portrayal of a musical genius might be toweringly brilliant or outrageously offensive (or both) depending on whom you ask. But clearly the character has a loose relationship with facts. More than a few doctors might have raised an eyebrow had Lydia Tár appeared with injuries to her face, claiming to have been attacked in a mugging. In reality, Lydia tripped and fell while pursuing an attractive young cellist into a hazardous basement. Did she lie to protect her image, preserve her marriage, or – like many patients – avoid a lecture on unhealthy behavior? We pick D, all of the above.

Best therapy for a speech disorder

The King’s Speech (2010)

Public speaking might cause anxiety for many of us, but how about doing it in front of a global radio audience while wrestling with a speech disorder? Based on a true story, The King’s Speech revealed that terrifying experience for England’s King George VI. Enter Lionel Logue, played by Geoffrey Rush. Irreverent, unconventional, and untrained, the Australian pioneer in speech and language therapy uses a range of strategies – some of which are still used today – to help the royal find his voice. But when singing, shouting swear words, and provoking rage don’t do the trick, Mr. Logue turns to psychotherapy to unearth the childhood traumas at the root of the king’s disability. Experience, as Mr. Logue tells his patient, matters just as much as “letters after your name.”

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

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

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

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

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

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

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

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.

NEW ORLEANS – In the international FREEDOM COVID trial that randomized non–critically ill hospitalized patients, a therapeutic dose of anticoagulation relative to a prophylactic dose significantly reduced death from COVID-19 at 30 days, even as a larger composite primary endpoint was missed.

The mortality reduction suggests therapeutic-dose anticoagulation “may improve outcomes in non–critically ill patients hospitalized with COVID-19 who are at increased risk for adverse events but do not yet require ICU-level of care,” reported Valentin Fuster, MD, PhD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.

Ted Bosworth/MDedge News

These data provide a suggestion rather than a demonstration of benefit because the primary composite endpoint of all-cause mortality, intubation requiring mechanical ventilation, systemic thromboembolism or ischemic stroke at 30 days was not met. Although this 30-day outcome was lower on the therapeutic dose (11.3% vs. 13.2%), the difference was only a trend (hazard ratio, 0.85; P = .11), said Dr. Fuster, physician-in-chief, Mount Sinai Hospital, New York.
 

Missed primary endpoint blamed on low events

The declining severity of more recent COVID-19 variants (the trial was conducted from August 2022 to September 2022) might be one explanation that the primary endpoint was not met, but the more likely explanation is the relatively good health status – and therefore a low risk of events – among patients randomized in India, 1 of 10 participating countries.

India accounted for roughly 40% of the total number of 3,398 patients in the intention-to-treat population. In India, the rates of events were 0.7 and 1.3 in the prophylactic and therapeutic anticoagulation arms, respectively. In contrast, they were 17.5 and 9.5, respectively in the United States. In combined data from the other eight countries, the rates were 22.78 and 20.4, respectively.

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies” Dr. Fuster said.

In fact, the therapeutic anticoagulation was linked to a nonsignificant twofold increase in the risk of the primary outcome in India (HR, 2.01; 95% confidence interval, 0.57-7.13) when outcomes were stratified by country. In the United States, where there was a much higher incidence of events, therapeutic anticoagulation was associated with a nearly 50% reduction (HR, 0.53; 95% CI, 0.31-0.91).

In the remaining countries, which included those in Latin America and Europe as well as the city of Hong Kong, the primary outcome was reduced numerically but not statistically by therapeutic relative to prophylactic anticoagulation (HR, 0.89; 95% CI, 0.71-1.11).
 

Enoxaparin and apixaban are studied

In FREEDOM COVID, patients were randomized to a therapeutic dose of the low-molecular-weight heparin (LMWH) enoxaparin (1 mg/kg every 12 hours), a prophylactic dose of enoxaparin (40 mg once daily), or a therapeutic dose of the direct factor Xa inhibitor apixaban (5 mg every 12 hours). Lower doses of enoxaparin and apixaban were used for those with renal impairment, and lower doses of apixaban were employed for elderly patients (≥ 80 years) and those with low body weight (≤ 60 kg).

The major inclusion criteria were confirmed COVID-19 infection with symptomatic systemic involvement. The major exclusion criteria were need for ICU level of care or active bleeding.

The therapeutic anticoagulation arms performed similarly and were combined for comparison to the prophylactic arm. Despite the failure to show a difference in the primary outcome, the rate of 30-day mortality was substantially lower in the therapeutic arm (4.9% vs. 7.0%), translating into a 30% risk reduction (HR, 0.70; P = .01).

Therapeutic anticoagulation was also associated with a lower rate of intubation/mechanical ventilation (6.4% vs. 8.4%) that reached statistical significance (HR, 0.75; P = .03). The risk reduction was also significant for a combination of these endpoints (HR, 0.77; P = .03).

The lower proportion of patients who eventually required ICU-level of care (9.9% vs. 11.7%) showed a trend in favor of therapeutic anticoagulation (HR, 0.84; P = .11).
 

Bleeding rates did not differ between arms

Bleeding Academic Research Consortium major bleeding types 3 and 5 were slightly numerically higher in the group randomized to therapeutic enoxaparin (0.5%) than prophylactic enoxaparin (0.1%) and therapeutic apixaban (0.3%), but the differences between any groups were not significant.

Numerous anticoagulation trials in patients with COVID-19 have been published previously. One 2021 trial published in the New England Journal of Medicine also suggested benefit from a therapeutic relative to prophylactic anticoagulation. In that trial, which compared heparin to usual-care thromboprophylaxis, benefits were derived from a Bayesian analysis. Significant differences were not shown for death or other major outcome assessed individually.

Even though this more recent trial missed its primary endpoint, Gregg Stone, MD, a coauthor of this study and a colleague of Dr. Fuster at the Mount Sinai School of Medicine, New York, reiterated that these results support routine anticoagulation in hospitalized COVID-19 patients.

“These are robust reductions in mortality and intubation rates, which are the most serious outcomes,” said Dr. Stone, who is first author of the paper, which was published in the Journal of the American College of Cardiology immediately after Dr. Fuster’s presentation.

COVID-19 has proven to be a very thrombogenic virus, but the literature has not been wholly consistent on which anticoagulation treatment provides the best balance of benefits and risks, according to Julia Grapsa, MD, PhD, attending cardiologist, Guys and St. Thomas Hospital, London. She said that this randomized trial, despite its failure to meet the primary endpoint, is useful.

“This demonstrates that a therapeutic dose of enoxaparin is likely to improve outcomes over a prophylactic dose with a low risk of bleeding,” Dr. Grapsa said. On the basis of the randomized study, “I feel more confident with this approach.”

Dr. Fuster reported no potential conflicts of interest. Dr. Stone has financial relationships with more than 30 companies that make pharmaceuticals and medical devices. Dr. Grapsa reported no potential conflicts of interest.