Those who run Taylor Swift’s Eras Tour have something in common with those who run ERAS, the Electronic Residency Application Service. They cause agita to the people they purport to serve.

Most medical students won’t see Taylor Swift perform her hit song “Cruel Summer,” but they will spend thousands of dollars on ERAS as they prepare for the 2024 residency match. Medical students applying for residency tend to be as stressed out as Swifties trying to score concert tickets. Aside from the expenses of residency applications, students also face an increasingly complex application process: a match algorithm many of them do not understand and major changes to the application process that most learn about right before the application cycle begins.

I have gone through two matches myself, one for internal medicine and one for neurology, and I have also guided students through the process for almost a decade as a dean of student affairs at a medical school. Every summer, the application process is filled with numerous changes, often with little, if any, warning for the students. One year, for example, a specialty required additional essays tailored to each program. Though this requirement may have helped programs discern which students are most enthusiastic about their programs, it also disadvantaged students working on busier rotations, strapped for time to write as many as 70 additional essays in a matter of weeks.

Other recent changes have included “signaling” programs, selecting preferred regions, and preinterview recordings for some specialties. In 2023, students cannot include more than 10 activities on their ERAS application. I have spoken to students at numerous medical schools concerned about the difficulty of selecting 10 activities out of dozens of meaningful pursuits throughout their journeys; this challenge is particularly acute for students who had other careers before entering medical school.

The stress continues to mount even after residency applications have been submitted. Students often feel tied to their phones because offers for residency interviews roll in day and night by email, and if they wait more than a few hours to respond, they’re often moved to a waiting list for their preferred interview date. One year, while we were rounding on patients, a student stepped away to schedule an interview; while doing so, he missed out on managing a patient who developed a neurologic emergency. Thankfully, many but not all specialties have put rules in place to allow students more time to think through interview offers. Having more time to think, even if it’s just 48 hours, may decrease stress, limit the negative impacts on medical education, and promote informed decisions during interview season.

To be sure, most changes are being made in an effort to improve the experience of the students and programs. But as with anything, the result has been a mix of good and bad. The transition to virtual interviews allowed students to apply more broadly to programs without worrying about travel costs. The move also benefits students with disabilities who face accessibility and other challenges with traveling. However, virtual interviews came with several downsides, including but not limited to an increased number of applications submitted (recall that this was also a benefit), interview hoarding, and challenges of connecting personally via virtual platform. Despite the virtual format, applicants increasingly are doing in-person second looks, which some worry may give those applicants an additional advantage over applicants who do not have the time or financial resources to travel for a second look. Despite these shortcomings, it is important that virtual interviews remain an option for those applicants who need it.

Another change, which has been extensively debated in medical education in recent years, was the switch to pass/fail on the USMLE Step 1 exam. Though this move decreased the stress students experienced in the first 2 years of medical school, it has resulted in a new challenge as many residency programs put more emphasis on USMLE Step 2. Many medical students feel they do not have a good gauge of their competitiveness until a few weeks before they submit their application, particularly those applicants attending medical schools that do not provide them with information regarding their class standing until right before they submit their applications.

By the time Swift’s Eras Tour ends in the summer of 2024, medical students will already have matched and started their residency programs. At the same time, a new batch of students will be entering the next year’s match. Though the number of anticipated changes may not reach the level of seismic activity caused by the Swifties at her Seattle concert, many medical students fear that the changes may be just like tectonic plates shifting the match process away from its original purpose: to provide an orderly and fair mechanism for matching the preferences of applicants for U.S. residency positions with the preferences of residency program directors.

Dr. Etienne is with WMCHealth Good Samaritan Hospital, New York, and New York Medical College. He disclosed no relevant conflicts of interest.

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

Those who run Taylor Swift’s Eras Tour have something in common with those who run ERAS, the Electronic Residency Application Service. They cause agita to the people they purport to serve.

Most medical students won’t see Taylor Swift perform her hit song “Cruel Summer,” but they will spend thousands of dollars on ERAS as they prepare for the 2024 residency match. Medical students applying for residency tend to be as stressed out as Swifties trying to score concert tickets. Aside from the expenses of residency applications, students also face an increasingly complex application process: a match algorithm many of them do not understand and major changes to the application process that most learn about right before the application cycle begins.

I have gone through two matches myself, one for internal medicine and one for neurology, and I have also guided students through the process for almost a decade as a dean of student affairs at a medical school. Every summer, the application process is filled with numerous changes, often with little, if any, warning for the students. One year, for example, a specialty required additional essays tailored to each program. Though this requirement may have helped programs discern which students are most enthusiastic about their programs, it also disadvantaged students working on busier rotations, strapped for time to write as many as 70 additional essays in a matter of weeks.

Other recent changes have included “signaling” programs, selecting preferred regions, and preinterview recordings for some specialties. In 2023, students cannot include more than 10 activities on their ERAS application. I have spoken to students at numerous medical schools concerned about the difficulty of selecting 10 activities out of dozens of meaningful pursuits throughout their journeys; this challenge is particularly acute for students who had other careers before entering medical school.

The stress continues to mount even after residency applications have been submitted. Students often feel tied to their phones because offers for residency interviews roll in day and night by email, and if they wait more than a few hours to respond, they’re often moved to a waiting list for their preferred interview date. One year, while we were rounding on patients, a student stepped away to schedule an interview; while doing so, he missed out on managing a patient who developed a neurologic emergency. Thankfully, many but not all specialties have put rules in place to allow students more time to think through interview offers. Having more time to think, even if it’s just 48 hours, may decrease stress, limit the negative impacts on medical education, and promote informed decisions during interview season.

To be sure, most changes are being made in an effort to improve the experience of the students and programs. But as with anything, the result has been a mix of good and bad. The transition to virtual interviews allowed students to apply more broadly to programs without worrying about travel costs. The move also benefits students with disabilities who face accessibility and other challenges with traveling. However, virtual interviews came with several downsides, including but not limited to an increased number of applications submitted (recall that this was also a benefit), interview hoarding, and challenges of connecting personally via virtual platform. Despite the virtual format, applicants increasingly are doing in-person second looks, which some worry may give those applicants an additional advantage over applicants who do not have the time or financial resources to travel for a second look. Despite these shortcomings, it is important that virtual interviews remain an option for those applicants who need it.

Another change, which has been extensively debated in medical education in recent years, was the switch to pass/fail on the USMLE Step 1 exam. Though this move decreased the stress students experienced in the first 2 years of medical school, it has resulted in a new challenge as many residency programs put more emphasis on USMLE Step 2. Many medical students feel they do not have a good gauge of their competitiveness until a few weeks before they submit their application, particularly those applicants attending medical schools that do not provide them with information regarding their class standing until right before they submit their applications.

By the time Swift’s Eras Tour ends in the summer of 2024, medical students will already have matched and started their residency programs. At the same time, a new batch of students will be entering the next year’s match. Though the number of anticipated changes may not reach the level of seismic activity caused by the Swifties at her Seattle concert, many medical students fear that the changes may be just like tectonic plates shifting the match process away from its original purpose: to provide an orderly and fair mechanism for matching the preferences of applicants for U.S. residency positions with the preferences of residency program directors.

Dr. Etienne is with WMCHealth Good Samaritan Hospital, New York, and New York Medical College. He disclosed no relevant conflicts of interest.

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

Those who run Taylor Swift’s Eras Tour have something in common with those who run ERAS, the Electronic Residency Application Service. They cause agita to the people they purport to serve.

Most medical students won’t see Taylor Swift perform her hit song “Cruel Summer,” but they will spend thousands of dollars on ERAS as they prepare for the 2024 residency match. Medical students applying for residency tend to be as stressed out as Swifties trying to score concert tickets. Aside from the expenses of residency applications, students also face an increasingly complex application process: a match algorithm many of them do not understand and major changes to the application process that most learn about right before the application cycle begins.

I have gone through two matches myself, one for internal medicine and one for neurology, and I have also guided students through the process for almost a decade as a dean of student affairs at a medical school. Every summer, the application process is filled with numerous changes, often with little, if any, warning for the students. One year, for example, a specialty required additional essays tailored to each program. Though this requirement may have helped programs discern which students are most enthusiastic about their programs, it also disadvantaged students working on busier rotations, strapped for time to write as many as 70 additional essays in a matter of weeks.

Other recent changes have included “signaling” programs, selecting preferred regions, and preinterview recordings for some specialties. In 2023, students cannot include more than 10 activities on their ERAS application. I have spoken to students at numerous medical schools concerned about the difficulty of selecting 10 activities out of dozens of meaningful pursuits throughout their journeys; this challenge is particularly acute for students who had other careers before entering medical school.

The stress continues to mount even after residency applications have been submitted. Students often feel tied to their phones because offers for residency interviews roll in day and night by email, and if they wait more than a few hours to respond, they’re often moved to a waiting list for their preferred interview date. One year, while we were rounding on patients, a student stepped away to schedule an interview; while doing so, he missed out on managing a patient who developed a neurologic emergency. Thankfully, many but not all specialties have put rules in place to allow students more time to think through interview offers. Having more time to think, even if it’s just 48 hours, may decrease stress, limit the negative impacts on medical education, and promote informed decisions during interview season.

To be sure, most changes are being made in an effort to improve the experience of the students and programs. But as with anything, the result has been a mix of good and bad. The transition to virtual interviews allowed students to apply more broadly to programs without worrying about travel costs. The move also benefits students with disabilities who face accessibility and other challenges with traveling. However, virtual interviews came with several downsides, including but not limited to an increased number of applications submitted (recall that this was also a benefit), interview hoarding, and challenges of connecting personally via virtual platform. Despite the virtual format, applicants increasingly are doing in-person second looks, which some worry may give those applicants an additional advantage over applicants who do not have the time or financial resources to travel for a second look. Despite these shortcomings, it is important that virtual interviews remain an option for those applicants who need it.

Another change, which has been extensively debated in medical education in recent years, was the switch to pass/fail on the USMLE Step 1 exam. Though this move decreased the stress students experienced in the first 2 years of medical school, it has resulted in a new challenge as many residency programs put more emphasis on USMLE Step 2. Many medical students feel they do not have a good gauge of their competitiveness until a few weeks before they submit their application, particularly those applicants attending medical schools that do not provide them with information regarding their class standing until right before they submit their applications.

By the time Swift’s Eras Tour ends in the summer of 2024, medical students will already have matched and started their residency programs. At the same time, a new batch of students will be entering the next year’s match. Though the number of anticipated changes may not reach the level of seismic activity caused by the Swifties at her Seattle concert, many medical students fear that the changes may be just like tectonic plates shifting the match process away from its original purpose: to provide an orderly and fair mechanism for matching the preferences of applicants for U.S. residency positions with the preferences of residency program directors.

Dr. Etienne is with WMCHealth Good Samaritan Hospital, New York, and New York Medical College. He disclosed no relevant conflicts of interest.

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

A lot of businesses benefit from being in private equity funds.

Health care isn’t one of them, and a recent report found that private equity buyouts of medical practices resulted in higher consumer prices.

This really shouldn’t surprise anyone. Such funds may offer glittering phrases like “improved technology” and “greater efficiency” but the bottom line is that they’re run by – and for – the shareholders. The majority of them aren’t going to be medical people or realize that you can’t run a medical practice like it’s a clothing retailer or electronic car manufacturer.

I’m not saying medicine isn’t a business – it is. I depend on my little practice to support three families, so keeping it in the black is important. But it also needs to run well to do that. Measures to increase revenue, like cutting my staff down (there are only two of them) or overbooking patients would seriously impact me effectively doing my part, which is playing doctor.

You can predict pretty accurately how long it will take to put a motor and bumper assembly on a specific model of car, but you can’t do that in medicine because people aren’t standardized. Even if you control variables such as same sex, age, and diagnosis, personalities vary widely, as do treatment decisions, questions they’ll have, and the “oh, another thing” factor.

That doesn’t happen at a bottling plant.

In the business model of health care, you’re hoping revenue will pay overhead and a reasonable salary for everyone. But when you add a private equity firm in, the shareholders also expect to be paid. Which means either revenue has to go up significantly, or costs have to be cut (layoffs, short staffing, reduced benefits, etc.), or a combination of both.

Regardless of which option is chosen, it isn’t good for the medical staff or the patients. Increasing the number of people seen in a given amount of time per doctor may be good for the shareholders, but it’s not good for the doctor or the person being cared for. Think of Lucy and Ethyl at the chocolate factory.

Even in an auto factory, if you speed up the rate of cars going through the assembly line, sooner or later mistakes will be made. Humans can’t keep up, and even robots will make errors if things aren’t aligned correctly, or are a few seconds ahead or behind the program. This is why they (hopefully) have quality control, to try and catch those things before they’re on the road.

Of course, cars are more easily fixable. When the mistake is found you repair or replace the part. You can’t do that as easily in people, and when serious mistakes happen it’s the doctor who’s held at fault – not the shareholders who pressured him or her to see patients faster and with less support.

Unfortunately, this is the way the current trend is going. The more people who are involved in the practice of medicine, in person or behind the scenes, the smaller each slice of the pie gets.

That’s not good for the patient, who’s the person at the center of it all and the reason why we’re here.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

A lot of businesses benefit from being in private equity funds.

Health care isn’t one of them, and a recent report found that private equity buyouts of medical practices resulted in higher consumer prices.

This really shouldn’t surprise anyone. Such funds may offer glittering phrases like “improved technology” and “greater efficiency” but the bottom line is that they’re run by – and for – the shareholders. The majority of them aren’t going to be medical people or realize that you can’t run a medical practice like it’s a clothing retailer or electronic car manufacturer.

I’m not saying medicine isn’t a business – it is. I depend on my little practice to support three families, so keeping it in the black is important. But it also needs to run well to do that. Measures to increase revenue, like cutting my staff down (there are only two of them) or overbooking patients would seriously impact me effectively doing my part, which is playing doctor.

You can predict pretty accurately how long it will take to put a motor and bumper assembly on a specific model of car, but you can’t do that in medicine because people aren’t standardized. Even if you control variables such as same sex, age, and diagnosis, personalities vary widely, as do treatment decisions, questions they’ll have, and the “oh, another thing” factor.

That doesn’t happen at a bottling plant.

In the business model of health care, you’re hoping revenue will pay overhead and a reasonable salary for everyone. But when you add a private equity firm in, the shareholders also expect to be paid. Which means either revenue has to go up significantly, or costs have to be cut (layoffs, short staffing, reduced benefits, etc.), or a combination of both.

Regardless of which option is chosen, it isn’t good for the medical staff or the patients. Increasing the number of people seen in a given amount of time per doctor may be good for the shareholders, but it’s not good for the doctor or the person being cared for. Think of Lucy and Ethyl at the chocolate factory.

Even in an auto factory, if you speed up the rate of cars going through the assembly line, sooner or later mistakes will be made. Humans can’t keep up, and even robots will make errors if things aren’t aligned correctly, or are a few seconds ahead or behind the program. This is why they (hopefully) have quality control, to try and catch those things before they’re on the road.

Of course, cars are more easily fixable. When the mistake is found you repair or replace the part. You can’t do that as easily in people, and when serious mistakes happen it’s the doctor who’s held at fault – not the shareholders who pressured him or her to see patients faster and with less support.

Unfortunately, this is the way the current trend is going. The more people who are involved in the practice of medicine, in person or behind the scenes, the smaller each slice of the pie gets.

That’s not good for the patient, who’s the person at the center of it all and the reason why we’re here.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

A lot of businesses benefit from being in private equity funds.

Health care isn’t one of them, and a recent report found that private equity buyouts of medical practices resulted in higher consumer prices.

This really shouldn’t surprise anyone. Such funds may offer glittering phrases like “improved technology” and “greater efficiency” but the bottom line is that they’re run by – and for – the shareholders. The majority of them aren’t going to be medical people or realize that you can’t run a medical practice like it’s a clothing retailer or electronic car manufacturer.

I’m not saying medicine isn’t a business – it is. I depend on my little practice to support three families, so keeping it in the black is important. But it also needs to run well to do that. Measures to increase revenue, like cutting my staff down (there are only two of them) or overbooking patients would seriously impact me effectively doing my part, which is playing doctor.

You can predict pretty accurately how long it will take to put a motor and bumper assembly on a specific model of car, but you can’t do that in medicine because people aren’t standardized. Even if you control variables such as same sex, age, and diagnosis, personalities vary widely, as do treatment decisions, questions they’ll have, and the “oh, another thing” factor.

That doesn’t happen at a bottling plant.

In the business model of health care, you’re hoping revenue will pay overhead and a reasonable salary for everyone. But when you add a private equity firm in, the shareholders also expect to be paid. Which means either revenue has to go up significantly, or costs have to be cut (layoffs, short staffing, reduced benefits, etc.), or a combination of both.

Regardless of which option is chosen, it isn’t good for the medical staff or the patients. Increasing the number of people seen in a given amount of time per doctor may be good for the shareholders, but it’s not good for the doctor or the person being cared for. Think of Lucy and Ethyl at the chocolate factory.

Even in an auto factory, if you speed up the rate of cars going through the assembly line, sooner or later mistakes will be made. Humans can’t keep up, and even robots will make errors if things aren’t aligned correctly, or are a few seconds ahead or behind the program. This is why they (hopefully) have quality control, to try and catch those things before they’re on the road.

Of course, cars are more easily fixable. When the mistake is found you repair or replace the part. You can’t do that as easily in people, and when serious mistakes happen it’s the doctor who’s held at fault – not the shareholders who pressured him or her to see patients faster and with less support.

Unfortunately, this is the way the current trend is going. The more people who are involved in the practice of medicine, in person or behind the scenes, the smaller each slice of the pie gets.

That’s not good for the patient, who’s the person at the center of it all and the reason why we’re here.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

The patient was having a flare of pemphigus vulgaris (PV), a rare and sometimes life-threatening acquired autoimmune blistering disease that affects the skin and/or mucosa. Ashkenazi Jewish patients and patients from Mediterranean and Middle Eastern countries are more likely to be affected.

In PV, acquired autoantibodies target the desmosomes that connect epithelial cells together, weakening the intercellular adhesion. It can affect skin, mucosa, or both. Patients present with fragile bullae or ulcers. The connections between the cells are often so damaged that rubbing on the skin creates a new blister called “Nikolsky sign.” In the mouth, bullae erode rapidly. Look for disease affecting the ocular conjunctiva or sclera, as well. PV can also occasionally affect the nasopharynx and esophagus, usually manifesting as hemoptysis, dysphagia, and nosebleeds with ulcer seen on endoscopy or otolaryngoscopy.

Although PV is often severe (and can warrant hospitalization when significant body surface area is involved), some patients may have few active lesions and can be managed safely as outpatients.

The diagnosis requires 2 biopsies and serum for indirect immunofluorescence. One biopsy (either by punch or shave to the upper dermis) is taken from the edge of a bulla or ulcer. Another biopsy (by punch or shave) is taken from nearby normal-looking skin or mucosa for testing the direct immunofluorescence pattern. In the mucosa, a punch biopsy may be left open or closed with absorbable sutures. A serum sample is taken for indirect immunofluorescence to differentiate pemphigus vulgaris from other forms of pemphigus.¹

PV is treated by suppressing the immune system. Focal disease may be treated with super-potent topical steroids, including clobetasol 0.05% ointment. Even in the mouth, topical clobetasol 0.05% may be used off-label twice daily until control is achieved. When topical treatment is used in the mouth, advise patients to apply the clobetasol ointment to a piece of gauze and place the gauze (ointment side down) over affected areas for 20 to 30 minutes twice daily.

Patients with widespread or severe disease should be hospitalized. In severe cases, supportive wound care is provided, and treatment is aimed at immunosuppression. Systemic options include high-dose prednisone 0.5 to 1 mg/kg daily until clear, a steroid-sparing immunosuppressant such as mycophenolate mofetil up to 1000 mg bid, or rituximab in 1 of several regimens.

Three years prior to this patient’s visit, she had been successfully treated for PV with a course of rituximab. To treat the current flare, she was started on prednisone 60 mg/d. In addition, the plan was for her to complete 2 infusions of 1000 mg rituximab 2 weeks apart.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, Maine.

The patient was having a flare of pemphigus vulgaris (PV), a rare and sometimes life-threatening acquired autoimmune blistering disease that affects the skin and/or mucosa. Ashkenazi Jewish patients and patients from Mediterranean and Middle Eastern countries are more likely to be affected.

In PV, acquired autoantibodies target the desmosomes that connect epithelial cells together, weakening the intercellular adhesion. It can affect skin, mucosa, or both. Patients present with fragile bullae or ulcers. The connections between the cells are often so damaged that rubbing on the skin creates a new blister called “Nikolsky sign.” In the mouth, bullae erode rapidly. Look for disease affecting the ocular conjunctiva or sclera, as well. PV can also occasionally affect the nasopharynx and esophagus, usually manifesting as hemoptysis, dysphagia, and nosebleeds with ulcer seen on endoscopy or otolaryngoscopy.

Although PV is often severe (and can warrant hospitalization when significant body surface area is involved), some patients may have few active lesions and can be managed safely as outpatients.

The diagnosis requires 2 biopsies and serum for indirect immunofluorescence. One biopsy (either by punch or shave to the upper dermis) is taken from the edge of a bulla or ulcer. Another biopsy (by punch or shave) is taken from nearby normal-looking skin or mucosa for testing the direct immunofluorescence pattern. In the mucosa, a punch biopsy may be left open or closed with absorbable sutures. A serum sample is taken for indirect immunofluorescence to differentiate pemphigus vulgaris from other forms of pemphigus.¹

PV is treated by suppressing the immune system. Focal disease may be treated with super-potent topical steroids, including clobetasol 0.05% ointment. Even in the mouth, topical clobetasol 0.05% may be used off-label twice daily until control is achieved. When topical treatment is used in the mouth, advise patients to apply the clobetasol ointment to a piece of gauze and place the gauze (ointment side down) over affected areas for 20 to 30 minutes twice daily.

Patients with widespread or severe disease should be hospitalized. In severe cases, supportive wound care is provided, and treatment is aimed at immunosuppression. Systemic options include high-dose prednisone 0.5 to 1 mg/kg daily until clear, a steroid-sparing immunosuppressant such as mycophenolate mofetil up to 1000 mg bid, or rituximab in 1 of several regimens.

Three years prior to this patient’s visit, she had been successfully treated for PV with a course of rituximab. To treat the current flare, she was started on prednisone 60 mg/d. In addition, the plan was for her to complete 2 infusions of 1000 mg rituximab 2 weeks apart.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, Maine.

The patient was having a flare of pemphigus vulgaris (PV), a rare and sometimes life-threatening acquired autoimmune blistering disease that affects the skin and/or mucosa. Ashkenazi Jewish patients and patients from Mediterranean and Middle Eastern countries are more likely to be affected.

In PV, acquired autoantibodies target the desmosomes that connect epithelial cells together, weakening the intercellular adhesion. It can affect skin, mucosa, or both. Patients present with fragile bullae or ulcers. The connections between the cells are often so damaged that rubbing on the skin creates a new blister called “Nikolsky sign.” In the mouth, bullae erode rapidly. Look for disease affecting the ocular conjunctiva or sclera, as well. PV can also occasionally affect the nasopharynx and esophagus, usually manifesting as hemoptysis, dysphagia, and nosebleeds with ulcer seen on endoscopy or otolaryngoscopy.

Although PV is often severe (and can warrant hospitalization when significant body surface area is involved), some patients may have few active lesions and can be managed safely as outpatients.

The diagnosis requires 2 biopsies and serum for indirect immunofluorescence. One biopsy (either by punch or shave to the upper dermis) is taken from the edge of a bulla or ulcer. Another biopsy (by punch or shave) is taken from nearby normal-looking skin or mucosa for testing the direct immunofluorescence pattern. In the mucosa, a punch biopsy may be left open or closed with absorbable sutures. A serum sample is taken for indirect immunofluorescence to differentiate pemphigus vulgaris from other forms of pemphigus.¹

PV is treated by suppressing the immune system. Focal disease may be treated with super-potent topical steroids, including clobetasol 0.05% ointment. Even in the mouth, topical clobetasol 0.05% may be used off-label twice daily until control is achieved. When topical treatment is used in the mouth, advise patients to apply the clobetasol ointment to a piece of gauze and place the gauze (ointment side down) over affected areas for 20 to 30 minutes twice daily.

Patients with widespread or severe disease should be hospitalized. In severe cases, supportive wound care is provided, and treatment is aimed at immunosuppression. Systemic options include high-dose prednisone 0.5 to 1 mg/kg daily until clear, a steroid-sparing immunosuppressant such as mycophenolate mofetil up to 1000 mg bid, or rituximab in 1 of several regimens.

Three years prior to this patient’s visit, she had been successfully treated for PV with a course of rituximab. To treat the current flare, she was started on prednisone 60 mg/d. In addition, the plan was for her to complete 2 infusions of 1000 mg rituximab 2 weeks apart.

‌

Photos and text for Photo Rounds Friday courtesy of Jonathan Karnes, MD (copyright retained). Dr. Karnes is the medical director of MDFMR Dermatology Services, Augusta, Maine.

AMSTERDAM – Intravenous iron supplementation showed modest benefits in recently hospitalized patients with heart failure and iron deficiency in the HEART-FID trial, but the study failed to meet the specified more rigorous definition of significance (P = .01) on the primary hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.

The trial, which investigated intravenous ferric carboxymaltose treatment vs. placebo, also showed no statistical difference in the main secondary endpoint: time to cardiovascular death or first heart failure hospitalization.

It was hoped that HEART-FID, the largest study to date to look at intravenous iron supplementation in heart failure, would confirm benefits suggested in previous smaller studies, but its modest results seem to have, if anything, caused more uncertainly on whether supplementing iron is actually worthwhile.

The HEART-FID trial was presented at the annual congress of the European Society of Cardiology and simultaneously published online in the New England Journal of Medicine.

Another presentation at the ESC Congress reported a pooled meta-analysis of all the intravenous iron supplementation studies, including HEART-FID. This showed a significant reduction in one coprimary endpoint (cardiovascular hospitalization/CV death) but not in the other (heart failure hospitalization/CV death), which is the more traditional and well-recognized endpoint in heart failure trials.

The meta-analysis was also published online in the European Heart Journal.

HEART-FID lead investigator, Robert J. Mentz, MD, Duke University, Durham, N.C., said the totality of the evidence showed clinical benefits of intravenous iron supplementation with intravenous ferric carboxymaltose.

“I worry that people will focus on a P value rather than the actual clinical benefits seen across all the studies,” Dr. Mentz said in an interview. “Technically, this study was neutral in respect to the primary endpoint, but when we look at all the evidence with respect to ferric carboxymaltose, including this new pooled analysis, this does support clinical benefits.”

Comoderator of the ESC Hotline session at which the trial was presented, John McMurray, MD, University of Glasgow (Scotland), thought the trial had “muddied the waters a bit” on the issue of iron supplementation in heart failure.

“I would say we are in a less clear position on iron supplementation now than we were a few months ago. Those clinicians who have believed that checking iron levels and supplementing iron in those who are low is the right thing to do may now be wondering about that,” he told this news organization.  

Dr. McMurray noted that initial impressions of the data from both HEART-FID and the meta-analysis suggested some benefit of intravenous iron on CV death/heart failure hospitalization in the first year, but on longer term follow-up, that benefit was less evident.

“We need to look further into why there is that discrepancy,” he said. “This could be a statistical phenomenon or could be something to do with the frequency of redosing over the longer term.”

He explained that several previous studies of intravenous iron supplementation in heart failure have reported apparent convincing benefits on quality of life and functional capacity, but there has been some uncertainty on this because of the difficulty in producing a placebo for intravenous iron.

“So, it would have been great to have some additional confirmation of these benefits and on harder endpoints,” he said, “but even in HEART-FID, there was only a small nonsignificant benefit in walking distance.”
 

HEART-FID

The HEART-FID trial randomly assigned 3,065 ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency to intravenous ferric carboxymaltose or placebo, given every 6 months as needed on the basis of iron indexes and hemoglobin levels, in addition to standard therapy for heart failure.

The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at .01.

Results showed that death by month 12 occurred in 8.6% of the ferric carboxymaltose group and 10.3% of the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean change from baseline to 6 months in the 6-minute walk distance was 8 meters in the ferric carboxymaltose group and 4 meters with placebo. The P value for the primary composite was .02.

The trial also used another method (unmatched win ratio) to analyze the hierarchical composite outcome in the ferric carboxymaltose group as compared with the placebo group that gave a result of 1.10 (99% confidence interval, 0.99-1.23).

During the follow-up period, CV death or hospitalization for heart failure (the main secondary outcome) occurred in 31.0% of the ferric carboxymaltose group and in 32.2% of the placebo group (hazard ratio, 0.93; 96% CI, 0.81-1.06).

Repeated dosing of ferric carboxymaltose appeared to be safe, with an acceptable adverse-event profile in most patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (27.0% in the ferric carboxymaltose group and 26.2% in the placebo group).
 

‘It’s hard to argue that we are not disappointed’

Designated discussant of the HEART-FID study at the ESC HOTLINE session, Scott Solomon, MD, Brigham and Women’s Hospital, Boston, described HEART-FID as “an extremely important and well-conducted trial.”

He noted that iron deficiency is extremely common in patients with heart failure, affecting at least about a third of patients, and is associated with reduced New York Heart Association class and reduced survival. Previous smaller studies have suggested benefit but have narrowly missed their primary endpoints. HEART-FID was a larger and sufficiently well-powered trial to test the hypothesis that iron supplementation can improve harder clinical endpoints.

Dr. Solomon said that the primary endpoint could be difficult to interpret, with a hierarchical composite, and a win ratio. “But I think it’s fair to say that the results are modest at best,” he added.

“When we look at the traditional cardiovascular death/heart failure hospitalization endpoint, one of the hard endpoints that we care about most in heart failure, it’s hard to argue that we are not disappointed,” he commented.

Referring to the P value of .01 threshold set for significance, which is based on new U.S. Food and Drug Administration regulatory standards, Dr. Solomon noted, “If they had used a standard P = .05 threshold, then they would be able to claim that this trial had met its primary endpoint. But, nevertheless, whatever threshold for significance we look at, the benefit was clearly modest.”

“As with all trials that show modest results, it will be useful to look at subgroups that are most likely to respond to the greatest extent to this therapy, and I look forward to learning more on this from further analyses,” Dr. Solomon concluded.

In an accompanying editorial in the New England Journal of Medicine, Pieter Martens, MD, and Wilfried Mullens, MD, PhD, Ziekenhuis Oost-Limburg, Genk, Belgium, and Hasselt (Belgium) University, point out that analyses from previous trials have suggested that intravenous iron did not have a treatment effect in patients with a transferrin saturation of more than 20%.

They note that, in the ferric carboxymaltose group in the HEART-FID trial, the mean transferrin saturation was 23.9% at baseline, higher than in previous studies.

Future analyses should assess the importance of the transferrin saturation value at baseline, which “could help redefine the definition of iron deficiency in patients with heart failure and, we hope, help clinicians determine which patients might benefit from intravenous iron supplementation,” they write.
 

Meta-analysis of trials

The meta-analysis of intravenous iron supplementation trials in heart failure was presented by Piotr Ponikowski, MD, Medical University Wroclaw (Poland).

The analysis pooled individual patient data from three double-blind, placebo-controlled trials – CONFIRM-HF 2, AFFIRM-AHF 3, and HEART-FID – giving a total of 4,475 patients, with 2,241 receiving ferric carboxymaltose and 2,234 receiving placebo.

The two prespecified composite primary endpoints were CV hospitalizations/CV death and heart failure hospitalizations/CV death.

These showed similar 13%-14% relative risk reductions with ferric carboxymaltose, but only the former was statistically significant.

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

AMSTERDAM – Intravenous iron supplementation showed modest benefits in recently hospitalized patients with heart failure and iron deficiency in the HEART-FID trial, but the study failed to meet the specified more rigorous definition of significance (P = .01) on the primary hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.

The trial, which investigated intravenous ferric carboxymaltose treatment vs. placebo, also showed no statistical difference in the main secondary endpoint: time to cardiovascular death or first heart failure hospitalization.

It was hoped that HEART-FID, the largest study to date to look at intravenous iron supplementation in heart failure, would confirm benefits suggested in previous smaller studies, but its modest results seem to have, if anything, caused more uncertainly on whether supplementing iron is actually worthwhile.

The HEART-FID trial was presented at the annual congress of the European Society of Cardiology and simultaneously published online in the New England Journal of Medicine.

Another presentation at the ESC Congress reported a pooled meta-analysis of all the intravenous iron supplementation studies, including HEART-FID. This showed a significant reduction in one coprimary endpoint (cardiovascular hospitalization/CV death) but not in the other (heart failure hospitalization/CV death), which is the more traditional and well-recognized endpoint in heart failure trials.

The meta-analysis was also published online in the European Heart Journal.

HEART-FID lead investigator, Robert J. Mentz, MD, Duke University, Durham, N.C., said the totality of the evidence showed clinical benefits of intravenous iron supplementation with intravenous ferric carboxymaltose.

“I worry that people will focus on a P value rather than the actual clinical benefits seen across all the studies,” Dr. Mentz said in an interview. “Technically, this study was neutral in respect to the primary endpoint, but when we look at all the evidence with respect to ferric carboxymaltose, including this new pooled analysis, this does support clinical benefits.”

Comoderator of the ESC Hotline session at which the trial was presented, John McMurray, MD, University of Glasgow (Scotland), thought the trial had “muddied the waters a bit” on the issue of iron supplementation in heart failure.

“I would say we are in a less clear position on iron supplementation now than we were a few months ago. Those clinicians who have believed that checking iron levels and supplementing iron in those who are low is the right thing to do may now be wondering about that,” he told this news organization.  

Dr. McMurray noted that initial impressions of the data from both HEART-FID and the meta-analysis suggested some benefit of intravenous iron on CV death/heart failure hospitalization in the first year, but on longer term follow-up, that benefit was less evident.

“We need to look further into why there is that discrepancy,” he said. “This could be a statistical phenomenon or could be something to do with the frequency of redosing over the longer term.”

He explained that several previous studies of intravenous iron supplementation in heart failure have reported apparent convincing benefits on quality of life and functional capacity, but there has been some uncertainty on this because of the difficulty in producing a placebo for intravenous iron.

“So, it would have been great to have some additional confirmation of these benefits and on harder endpoints,” he said, “but even in HEART-FID, there was only a small nonsignificant benefit in walking distance.”
 

HEART-FID

The HEART-FID trial randomly assigned 3,065 ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency to intravenous ferric carboxymaltose or placebo, given every 6 months as needed on the basis of iron indexes and hemoglobin levels, in addition to standard therapy for heart failure.

The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at .01.

Results showed that death by month 12 occurred in 8.6% of the ferric carboxymaltose group and 10.3% of the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean change from baseline to 6 months in the 6-minute walk distance was 8 meters in the ferric carboxymaltose group and 4 meters with placebo. The P value for the primary composite was .02.

The trial also used another method (unmatched win ratio) to analyze the hierarchical composite outcome in the ferric carboxymaltose group as compared with the placebo group that gave a result of 1.10 (99% confidence interval, 0.99-1.23).

During the follow-up period, CV death or hospitalization for heart failure (the main secondary outcome) occurred in 31.0% of the ferric carboxymaltose group and in 32.2% of the placebo group (hazard ratio, 0.93; 96% CI, 0.81-1.06).

Repeated dosing of ferric carboxymaltose appeared to be safe, with an acceptable adverse-event profile in most patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (27.0% in the ferric carboxymaltose group and 26.2% in the placebo group).
 

‘It’s hard to argue that we are not disappointed’

Designated discussant of the HEART-FID study at the ESC HOTLINE session, Scott Solomon, MD, Brigham and Women’s Hospital, Boston, described HEART-FID as “an extremely important and well-conducted trial.”

He noted that iron deficiency is extremely common in patients with heart failure, affecting at least about a third of patients, and is associated with reduced New York Heart Association class and reduced survival. Previous smaller studies have suggested benefit but have narrowly missed their primary endpoints. HEART-FID was a larger and sufficiently well-powered trial to test the hypothesis that iron supplementation can improve harder clinical endpoints.

Dr. Solomon said that the primary endpoint could be difficult to interpret, with a hierarchical composite, and a win ratio. “But I think it’s fair to say that the results are modest at best,” he added.

“When we look at the traditional cardiovascular death/heart failure hospitalization endpoint, one of the hard endpoints that we care about most in heart failure, it’s hard to argue that we are not disappointed,” he commented.

Referring to the P value of .01 threshold set for significance, which is based on new U.S. Food and Drug Administration regulatory standards, Dr. Solomon noted, “If they had used a standard P = .05 threshold, then they would be able to claim that this trial had met its primary endpoint. But, nevertheless, whatever threshold for significance we look at, the benefit was clearly modest.”

“As with all trials that show modest results, it will be useful to look at subgroups that are most likely to respond to the greatest extent to this therapy, and I look forward to learning more on this from further analyses,” Dr. Solomon concluded.

In an accompanying editorial in the New England Journal of Medicine, Pieter Martens, MD, and Wilfried Mullens, MD, PhD, Ziekenhuis Oost-Limburg, Genk, Belgium, and Hasselt (Belgium) University, point out that analyses from previous trials have suggested that intravenous iron did not have a treatment effect in patients with a transferrin saturation of more than 20%.

They note that, in the ferric carboxymaltose group in the HEART-FID trial, the mean transferrin saturation was 23.9% at baseline, higher than in previous studies.

Future analyses should assess the importance of the transferrin saturation value at baseline, which “could help redefine the definition of iron deficiency in patients with heart failure and, we hope, help clinicians determine which patients might benefit from intravenous iron supplementation,” they write.
 

Meta-analysis of trials

The meta-analysis of intravenous iron supplementation trials in heart failure was presented by Piotr Ponikowski, MD, Medical University Wroclaw (Poland).

The analysis pooled individual patient data from three double-blind, placebo-controlled trials – CONFIRM-HF 2, AFFIRM-AHF 3, and HEART-FID – giving a total of 4,475 patients, with 2,241 receiving ferric carboxymaltose and 2,234 receiving placebo.

The two prespecified composite primary endpoints were CV hospitalizations/CV death and heart failure hospitalizations/CV death.

These showed similar 13%-14% relative risk reductions with ferric carboxymaltose, but only the former was statistically significant.

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

AMSTERDAM – Intravenous iron supplementation showed modest benefits in recently hospitalized patients with heart failure and iron deficiency in the HEART-FID trial, but the study failed to meet the specified more rigorous definition of significance (P = .01) on the primary hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.

The trial, which investigated intravenous ferric carboxymaltose treatment vs. placebo, also showed no statistical difference in the main secondary endpoint: time to cardiovascular death or first heart failure hospitalization.

It was hoped that HEART-FID, the largest study to date to look at intravenous iron supplementation in heart failure, would confirm benefits suggested in previous smaller studies, but its modest results seem to have, if anything, caused more uncertainly on whether supplementing iron is actually worthwhile.

The HEART-FID trial was presented at the annual congress of the European Society of Cardiology and simultaneously published online in the New England Journal of Medicine.

Another presentation at the ESC Congress reported a pooled meta-analysis of all the intravenous iron supplementation studies, including HEART-FID. This showed a significant reduction in one coprimary endpoint (cardiovascular hospitalization/CV death) but not in the other (heart failure hospitalization/CV death), which is the more traditional and well-recognized endpoint in heart failure trials.

The meta-analysis was also published online in the European Heart Journal.

HEART-FID lead investigator, Robert J. Mentz, MD, Duke University, Durham, N.C., said the totality of the evidence showed clinical benefits of intravenous iron supplementation with intravenous ferric carboxymaltose.

“I worry that people will focus on a P value rather than the actual clinical benefits seen across all the studies,” Dr. Mentz said in an interview. “Technically, this study was neutral in respect to the primary endpoint, but when we look at all the evidence with respect to ferric carboxymaltose, including this new pooled analysis, this does support clinical benefits.”

Comoderator of the ESC Hotline session at which the trial was presented, John McMurray, MD, University of Glasgow (Scotland), thought the trial had “muddied the waters a bit” on the issue of iron supplementation in heart failure.

“I would say we are in a less clear position on iron supplementation now than we were a few months ago. Those clinicians who have believed that checking iron levels and supplementing iron in those who are low is the right thing to do may now be wondering about that,” he told this news organization.  

Dr. McMurray noted that initial impressions of the data from both HEART-FID and the meta-analysis suggested some benefit of intravenous iron on CV death/heart failure hospitalization in the first year, but on longer term follow-up, that benefit was less evident.

“We need to look further into why there is that discrepancy,” he said. “This could be a statistical phenomenon or could be something to do with the frequency of redosing over the longer term.”

He explained that several previous studies of intravenous iron supplementation in heart failure have reported apparent convincing benefits on quality of life and functional capacity, but there has been some uncertainty on this because of the difficulty in producing a placebo for intravenous iron.

“So, it would have been great to have some additional confirmation of these benefits and on harder endpoints,” he said, “but even in HEART-FID, there was only a small nonsignificant benefit in walking distance.”
 

HEART-FID

The HEART-FID trial randomly assigned 3,065 ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency to intravenous ferric carboxymaltose or placebo, given every 6 months as needed on the basis of iron indexes and hemoglobin levels, in addition to standard therapy for heart failure.

The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at .01.

Results showed that death by month 12 occurred in 8.6% of the ferric carboxymaltose group and 10.3% of the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean change from baseline to 6 months in the 6-minute walk distance was 8 meters in the ferric carboxymaltose group and 4 meters with placebo. The P value for the primary composite was .02.

The trial also used another method (unmatched win ratio) to analyze the hierarchical composite outcome in the ferric carboxymaltose group as compared with the placebo group that gave a result of 1.10 (99% confidence interval, 0.99-1.23).

During the follow-up period, CV death or hospitalization for heart failure (the main secondary outcome) occurred in 31.0% of the ferric carboxymaltose group and in 32.2% of the placebo group (hazard ratio, 0.93; 96% CI, 0.81-1.06).

Repeated dosing of ferric carboxymaltose appeared to be safe, with an acceptable adverse-event profile in most patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (27.0% in the ferric carboxymaltose group and 26.2% in the placebo group).
 

‘It’s hard to argue that we are not disappointed’

Designated discussant of the HEART-FID study at the ESC HOTLINE session, Scott Solomon, MD, Brigham and Women’s Hospital, Boston, described HEART-FID as “an extremely important and well-conducted trial.”

He noted that iron deficiency is extremely common in patients with heart failure, affecting at least about a third of patients, and is associated with reduced New York Heart Association class and reduced survival. Previous smaller studies have suggested benefit but have narrowly missed their primary endpoints. HEART-FID was a larger and sufficiently well-powered trial to test the hypothesis that iron supplementation can improve harder clinical endpoints.

Dr. Solomon said that the primary endpoint could be difficult to interpret, with a hierarchical composite, and a win ratio. “But I think it’s fair to say that the results are modest at best,” he added.

“When we look at the traditional cardiovascular death/heart failure hospitalization endpoint, one of the hard endpoints that we care about most in heart failure, it’s hard to argue that we are not disappointed,” he commented.

Referring to the P value of .01 threshold set for significance, which is based on new U.S. Food and Drug Administration regulatory standards, Dr. Solomon noted, “If they had used a standard P = .05 threshold, then they would be able to claim that this trial had met its primary endpoint. But, nevertheless, whatever threshold for significance we look at, the benefit was clearly modest.”

“As with all trials that show modest results, it will be useful to look at subgroups that are most likely to respond to the greatest extent to this therapy, and I look forward to learning more on this from further analyses,” Dr. Solomon concluded.

In an accompanying editorial in the New England Journal of Medicine, Pieter Martens, MD, and Wilfried Mullens, MD, PhD, Ziekenhuis Oost-Limburg, Genk, Belgium, and Hasselt (Belgium) University, point out that analyses from previous trials have suggested that intravenous iron did not have a treatment effect in patients with a transferrin saturation of more than 20%.

They note that, in the ferric carboxymaltose group in the HEART-FID trial, the mean transferrin saturation was 23.9% at baseline, higher than in previous studies.

Future analyses should assess the importance of the transferrin saturation value at baseline, which “could help redefine the definition of iron deficiency in patients with heart failure and, we hope, help clinicians determine which patients might benefit from intravenous iron supplementation,” they write.
 

Meta-analysis of trials

The meta-analysis of intravenous iron supplementation trials in heart failure was presented by Piotr Ponikowski, MD, Medical University Wroclaw (Poland).

The analysis pooled individual patient data from three double-blind, placebo-controlled trials – CONFIRM-HF 2, AFFIRM-AHF 3, and HEART-FID – giving a total of 4,475 patients, with 2,241 receiving ferric carboxymaltose and 2,234 receiving placebo.

The two prespecified composite primary endpoints were CV hospitalizations/CV death and heart failure hospitalizations/CV death.

These showed similar 13%-14% relative risk reductions with ferric carboxymaltose, but only the former was statistically significant.

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

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.

By the end of August 2022, overall use of mental health services was almost 40% higher than before the COVID-19 pandemic, while spending increased by 54%, according to a new study by researchers at the RAND Corporation.

During the early phase of the pandemic, from mid-March to mid-December 2020, before the vaccine was available, in-person visits decreased by 40%, while telehealth visits increased by 1,000%, reported Jonathan H. Cantor, PhD, and colleagues at RAND, and at Castlight Health, a benefit coordination provider, in a paper published online in JAMA Health Forum.

Between December 2020 and August 2022, telehealth visits stayed stable, but in-person visits creeped back up, eventually reaching 80% of prepandemic levels. However, “total utilization was higher than before the pandemic,” Dr. Cantor, a policy researcher at RAND, told this news organization. 

“It could be that it’s easier for individuals to receive care via telehealth, but it could also just be that there’s a greater demand or need since the pandemic,” said Dr. Cantor. “We’ll just need more research to actually unpack what’s going on,” he said.

Initial per capita spending increased by about a third and was up overall by more than half. But it’s not clear how much of that is due to utilization or to price of services, said Dr. Cantor. Spending for telehealth services remained stable in the post-vaccine period, while spending on in-person visits returned to prepandemic levels.

Dr. Cantor and his colleagues were not able to determine whether utilization was by new or existing patients, but he said that would be good data to have. “It would be really important to know whether or not folks are initiating care because telehealth is making it easier,” he said.

The authors analyzed about 1.5 million claims for anxiety disorders, major depressive disorder, bipolar disorder, schizophrenia, and posttraumatic stress disorder, out of claims submitted by 7 million commercially insured adults whose self-insured employers used the Castlight benefit.

Dr. Cantor noted that this is just a small subset of the U.S. population. He said he’d like to have data from Medicare and Medicaid to fully assess the impact of the COVID-19 pandemic on mental health and of telehealth visits.

“This is a still-burgeoning field,” he said about telehealth. “We’re still trying to get a handle on how things are operating, given that there’s been so much change so rapidly.”

Meanwhile, 152 major employers responding to a large national survey this summer said that they’ve been grappling with how COVID-19 has affected workers. The employers include 72 Fortune 100 companies and provide health coverage for more than 60 million workers, retirees, and their families.

Seventy-seven percent said they are currently seeing an increase in depression, anxiety, and substance use disorders as a result of the pandemic, according to the Business Group on Health’s survey. That’s up from 44% in 2022.

Going forward, employers will focus on increasing access to mental health services, the survey reported.

“Our survey found that in 2024 and for the near future, employers will be acutely focused on addressing employees’ mental health needs while ensuring access and lowering cost barriers,” Ellen Kelsay, president and CEO of Business Group on Health, said in a statement.

The study was supported by grants from the National Institute of Mental Health and the National Institute on Aging. Coauthor Dena Bravata, MD, a Castlight employee, reported receiving personal fees from Castlight Health during the conduct of the study. Coauthor Christopher M. Whaley, a RAND employee, reported receiving personal fees from Castlight Health outside the submitted work.

A version of this article appeared on Medscape.com.

By the end of August 2022, overall use of mental health services was almost 40% higher than before the COVID-19 pandemic, while spending increased by 54%, according to a new study by researchers at the RAND Corporation.

During the early phase of the pandemic, from mid-March to mid-December 2020, before the vaccine was available, in-person visits decreased by 40%, while telehealth visits increased by 1,000%, reported Jonathan H. Cantor, PhD, and colleagues at RAND, and at Castlight Health, a benefit coordination provider, in a paper published online in JAMA Health Forum.

Between December 2020 and August 2022, telehealth visits stayed stable, but in-person visits creeped back up, eventually reaching 80% of prepandemic levels. However, “total utilization was higher than before the pandemic,” Dr. Cantor, a policy researcher at RAND, told this news organization. 

“It could be that it’s easier for individuals to receive care via telehealth, but it could also just be that there’s a greater demand or need since the pandemic,” said Dr. Cantor. “We’ll just need more research to actually unpack what’s going on,” he said.

Initial per capita spending increased by about a third and was up overall by more than half. But it’s not clear how much of that is due to utilization or to price of services, said Dr. Cantor. Spending for telehealth services remained stable in the post-vaccine period, while spending on in-person visits returned to prepandemic levels.

Dr. Cantor and his colleagues were not able to determine whether utilization was by new or existing patients, but he said that would be good data to have. “It would be really important to know whether or not folks are initiating care because telehealth is making it easier,” he said.

The authors analyzed about 1.5 million claims for anxiety disorders, major depressive disorder, bipolar disorder, schizophrenia, and posttraumatic stress disorder, out of claims submitted by 7 million commercially insured adults whose self-insured employers used the Castlight benefit.

Dr. Cantor noted that this is just a small subset of the U.S. population. He said he’d like to have data from Medicare and Medicaid to fully assess the impact of the COVID-19 pandemic on mental health and of telehealth visits.

“This is a still-burgeoning field,” he said about telehealth. “We’re still trying to get a handle on how things are operating, given that there’s been so much change so rapidly.”

Meanwhile, 152 major employers responding to a large national survey this summer said that they’ve been grappling with how COVID-19 has affected workers. The employers include 72 Fortune 100 companies and provide health coverage for more than 60 million workers, retirees, and their families.

Seventy-seven percent said they are currently seeing an increase in depression, anxiety, and substance use disorders as a result of the pandemic, according to the Business Group on Health’s survey. That’s up from 44% in 2022.

Going forward, employers will focus on increasing access to mental health services, the survey reported.

“Our survey found that in 2024 and for the near future, employers will be acutely focused on addressing employees’ mental health needs while ensuring access and lowering cost barriers,” Ellen Kelsay, president and CEO of Business Group on Health, said in a statement.

The study was supported by grants from the National Institute of Mental Health and the National Institute on Aging. Coauthor Dena Bravata, MD, a Castlight employee, reported receiving personal fees from Castlight Health during the conduct of the study. Coauthor Christopher M. Whaley, a RAND employee, reported receiving personal fees from Castlight Health outside the submitted work.

A version of this article appeared on Medscape.com.

By the end of August 2022, overall use of mental health services was almost 40% higher than before the COVID-19 pandemic, while spending increased by 54%, according to a new study by researchers at the RAND Corporation.

During the early phase of the pandemic, from mid-March to mid-December 2020, before the vaccine was available, in-person visits decreased by 40%, while telehealth visits increased by 1,000%, reported Jonathan H. Cantor, PhD, and colleagues at RAND, and at Castlight Health, a benefit coordination provider, in a paper published online in JAMA Health Forum.

Between December 2020 and August 2022, telehealth visits stayed stable, but in-person visits creeped back up, eventually reaching 80% of prepandemic levels. However, “total utilization was higher than before the pandemic,” Dr. Cantor, a policy researcher at RAND, told this news organization. 

“It could be that it’s easier for individuals to receive care via telehealth, but it could also just be that there’s a greater demand or need since the pandemic,” said Dr. Cantor. “We’ll just need more research to actually unpack what’s going on,” he said.

Initial per capita spending increased by about a third and was up overall by more than half. But it’s not clear how much of that is due to utilization or to price of services, said Dr. Cantor. Spending for telehealth services remained stable in the post-vaccine period, while spending on in-person visits returned to prepandemic levels.

Dr. Cantor and his colleagues were not able to determine whether utilization was by new or existing patients, but he said that would be good data to have. “It would be really important to know whether or not folks are initiating care because telehealth is making it easier,” he said.

The authors analyzed about 1.5 million claims for anxiety disorders, major depressive disorder, bipolar disorder, schizophrenia, and posttraumatic stress disorder, out of claims submitted by 7 million commercially insured adults whose self-insured employers used the Castlight benefit.

Dr. Cantor noted that this is just a small subset of the U.S. population. He said he’d like to have data from Medicare and Medicaid to fully assess the impact of the COVID-19 pandemic on mental health and of telehealth visits.

“This is a still-burgeoning field,” he said about telehealth. “We’re still trying to get a handle on how things are operating, given that there’s been so much change so rapidly.”

Meanwhile, 152 major employers responding to a large national survey this summer said that they’ve been grappling with how COVID-19 has affected workers. The employers include 72 Fortune 100 companies and provide health coverage for more than 60 million workers, retirees, and their families.

Seventy-seven percent said they are currently seeing an increase in depression, anxiety, and substance use disorders as a result of the pandemic, according to the Business Group on Health’s survey. That’s up from 44% in 2022.

Going forward, employers will focus on increasing access to mental health services, the survey reported.

“Our survey found that in 2024 and for the near future, employers will be acutely focused on addressing employees’ mental health needs while ensuring access and lowering cost barriers,” Ellen Kelsay, president and CEO of Business Group on Health, said in a statement.

The study was supported by grants from the National Institute of Mental Health and the National Institute on Aging. Coauthor Dena Bravata, MD, a Castlight employee, reported receiving personal fees from Castlight Health during the conduct of the study. Coauthor Christopher M. Whaley, a RAND employee, reported receiving personal fees from Castlight Health outside the submitted work.

A version of this article appeared on Medscape.com.

Clinical trials of treatments for rheumatologic conditions appear especially vulnerable to inadvertent unblinding, because of noticeable side effects of some drugs and subjective outcome measures, according to a new analysis.

Until more is known about the potential for unblinding, clinicians need to keep in mind that patients and physicians could often guess accurately who was getting placebo or active drug, first author Cody Bruggemeyer, MD, a resident at the Medical College of Wisconsin, Milwaukee, said in an interview.

Dr. Bruggemeyer

“It’s important that rheumatologists be aware of this potential issue and use their clinical reasoning and their ability to critically assess papers to evaluate the study design” of research on treatments, he said in an interview.

Dr. Bruggemeyer and coauthors at the Medical College of Wisconsin presented their assessment of the potential for unblinding in a Viewpoint article in The Lancet Rheumatology.
 

A sample of pivotal clinical trials

The authors selected a sample of pivotal studies of 14 commonly prescribed drugs for rheumatic conditions for which double-blind randomized controlled trials (RCTs) that compared the active ingredient with a placebo were available.

The 14 trials involved treatments classified as disease-modifying antirheumatic drugs (DMARDs), some of which were likely to produce side effects that placebos would not mimic, such as injection site and infusion reactions and difference in readings in lab reports, the authors wrote.

In their analysis, Dr. Bruggemeyer and colleagues evaluated discrepancies in the rates of adverse events reported between active drugs and placebos and classified the 14 studies as follows:

• High unblinding risk: Nine studies had a high estimated risk of unblinding, including trials of adalimumab with citrate (Humira), anakinra (Kineret), anifrolumab (Saphnelo), apremilast (Otezla), ixekizumab (Taltz), leflunomide (Arava), methotrexate, risankizumab (Skyrizi) and tofacitinib (Xeljanz).
• Moderate unblinding risk: Three studies had a moderate estimated risk of unblinding, including trials of azathioprine (Imuran), mycophenolate mofetil and tocilizumab (Actemra).
• Low unblinding risk: Two studies had a low estimated risk of unblinding. These involved tests of belimumab (Benlysta) and rituximab (Rituxan).

Many of the effectiveness measurements of treatments used in rheumatology depend on patients’ reports of relief of pain and other disease symptoms. For example, the widely used American College of Rheumatology 20% response for rheumatoid arthritis includes components that rely on patient and physician assessment of disease activity.
 

Unblinding risk to clinical trial validity

CTs are the highest level of evidence to establish efficacy, because the study design aims to mask whether the experimental treatment is a drug or placebo. In cases where patients and physicians are more likely to correctly detect use of an active drug, there can be biases that skew results toward reports of symptom improvement. Other patients’ views of their treatment may be distorted by accurate guesses that they have been given placebo, Dr. Bruggemeyer and coauthors wrote.

“The degree of these effects cannot be predicted, but they tend to erroneously inflate the perceived benefit of novel interventions,” they wrote.

The consequences of this unblinding may be minimal in cases where there’s a clear difference between the placebo and active drug, they said. As an example, they cited trials of interleukin-23 inhibitors for psoriasis, where skin clearance as measured by the Psoriatic Area and Severity Index 75 differed by more than 50% in absolute terms between the treatment and placebo groups.

But in other cases, there needs to be more attention paid to the potential role of unblinding, they wrote.

“Studies where effect sizes were small, contradictory, or dependent on subgroup analyses might be especially problematic, but commentary rarely reflects this issue or acknowledges the potential influence of unblinding,” they wrote.

In the paper, they call for more analysis of previous trials to look for unreported assessments of unblinding, while also asking that researchers consider surveying participants in future trials to evaluate the degree to which unblinding occurs.

“Advocacy from professional societies and the U.S. Food and Drug Administration itself might be necessary, but in the interim, rheumatologists should assume unblinding has occurred to some degree in most trials,” they wrote.
 

Unblinding measure needs validation

In an interview, Roy M. Fleischmann, MD, co–medical director of the Metroplex Clinical Research Center in Dallas, raised some objections to the paper. The paper addresses an interesting question about unblinding, but there should have been more work done, such as finding “a measure that is validated that can say whether you’ve been unblinded or not.”

He added that he was surprised the paper on unblinding in rheumatology trials was published in its current form.

“I would have sent it for a major rewrite” if asked to review this paper before publication, said Dr. Fleischmann, who as a reviewer for Lancet Rheumatology. “I would have said: ‘Okay, 90% of this paper is okay, but your gist is not correct.’ It should be: ‘Is this a problem?’ ”

Dr. Fleischmann said he would have recommended a different perspective to the paper. “That is, this could occur. Should we be looking at this, and how would we look at this?”

In the paper, the authors acknowledge their approach has not been validated, “but it highlights the potential effect of idiosyncratic adverse events,” they wrote.

There’s less funding in general for meta-research than for studies involving treatments, so researchers look for approaches that can be handled without requiring significant funding, and much of the research on the quality of research is conducted like this analysis of rheumatology trials, Michael Putman, MD, the corresponding author and is a rheumatologist and an assistant professor at the Medical College of Wisconsin, said in an interview.

“You’re mostly doing on a shoestring budget with yourself and trainees,” he said. Dr. Putman is an associate editor at the journal Rheumatology and also involved in meta-research, or efforts to understand how studies and trials answer questions about how medical treatments work.

In an Aug. 16 tweet, Dr. Putman said this issue of unintentional unblinding with rheumatology trials was something he’d “been ruminating about for awhile; took two all star trainees to push it over the top!”

One of the barriers to funding of meta-research is a tendency for major funding for medical studies to be focused on specific diseases or targets. With meta-research, it may be more difficult to explain how a specific project will advance efforts to treat or prevent a certain disease, Dr. Putman said.

“It’s a little more esoteric and maybe not quite as clear how these projects will move things forward,” Dr. Putman said.

In addition, the nature of meta-research is to question and often be critical of work that’s already been published, adding another hurdle in attempts to secure funding, he said.

Dr. Putman is supported by a Rheumatology Research Foundation Scientist Development Grant, receives research funding related to clinical trials by AbbVie and AstraZeneca, and consulting fees from Novartis. The other authors declared no competing interests.

Clinical trials of treatments for rheumatologic conditions appear especially vulnerable to inadvertent unblinding, because of noticeable side effects of some drugs and subjective outcome measures, according to a new analysis.

Until more is known about the potential for unblinding, clinicians need to keep in mind that patients and physicians could often guess accurately who was getting placebo or active drug, first author Cody Bruggemeyer, MD, a resident at the Medical College of Wisconsin, Milwaukee, said in an interview.

Dr. Bruggemeyer

“It’s important that rheumatologists be aware of this potential issue and use their clinical reasoning and their ability to critically assess papers to evaluate the study design” of research on treatments, he said in an interview.

Dr. Bruggemeyer and coauthors at the Medical College of Wisconsin presented their assessment of the potential for unblinding in a Viewpoint article in The Lancet Rheumatology.
 

A sample of pivotal clinical trials

The authors selected a sample of pivotal studies of 14 commonly prescribed drugs for rheumatic conditions for which double-blind randomized controlled trials (RCTs) that compared the active ingredient with a placebo were available.

The 14 trials involved treatments classified as disease-modifying antirheumatic drugs (DMARDs), some of which were likely to produce side effects that placebos would not mimic, such as injection site and infusion reactions and difference in readings in lab reports, the authors wrote.

In their analysis, Dr. Bruggemeyer and colleagues evaluated discrepancies in the rates of adverse events reported between active drugs and placebos and classified the 14 studies as follows:

• High unblinding risk: Nine studies had a high estimated risk of unblinding, including trials of adalimumab with citrate (Humira), anakinra (Kineret), anifrolumab (Saphnelo), apremilast (Otezla), ixekizumab (Taltz), leflunomide (Arava), methotrexate, risankizumab (Skyrizi) and tofacitinib (Xeljanz).
• Moderate unblinding risk: Three studies had a moderate estimated risk of unblinding, including trials of azathioprine (Imuran), mycophenolate mofetil and tocilizumab (Actemra).
• Low unblinding risk: Two studies had a low estimated risk of unblinding. These involved tests of belimumab (Benlysta) and rituximab (Rituxan).

Many of the effectiveness measurements of treatments used in rheumatology depend on patients’ reports of relief of pain and other disease symptoms. For example, the widely used American College of Rheumatology 20% response for rheumatoid arthritis includes components that rely on patient and physician assessment of disease activity.
 

Unblinding risk to clinical trial validity

CTs are the highest level of evidence to establish efficacy, because the study design aims to mask whether the experimental treatment is a drug or placebo. In cases where patients and physicians are more likely to correctly detect use of an active drug, there can be biases that skew results toward reports of symptom improvement. Other patients’ views of their treatment may be distorted by accurate guesses that they have been given placebo, Dr. Bruggemeyer and coauthors wrote.

“The degree of these effects cannot be predicted, but they tend to erroneously inflate the perceived benefit of novel interventions,” they wrote.

The consequences of this unblinding may be minimal in cases where there’s a clear difference between the placebo and active drug, they said. As an example, they cited trials of interleukin-23 inhibitors for psoriasis, where skin clearance as measured by the Psoriatic Area and Severity Index 75 differed by more than 50% in absolute terms between the treatment and placebo groups.

But in other cases, there needs to be more attention paid to the potential role of unblinding, they wrote.

“Studies where effect sizes were small, contradictory, or dependent on subgroup analyses might be especially problematic, but commentary rarely reflects this issue or acknowledges the potential influence of unblinding,” they wrote.

In the paper, they call for more analysis of previous trials to look for unreported assessments of unblinding, while also asking that researchers consider surveying participants in future trials to evaluate the degree to which unblinding occurs.

“Advocacy from professional societies and the U.S. Food and Drug Administration itself might be necessary, but in the interim, rheumatologists should assume unblinding has occurred to some degree in most trials,” they wrote.
 

Unblinding measure needs validation

In an interview, Roy M. Fleischmann, MD, co–medical director of the Metroplex Clinical Research Center in Dallas, raised some objections to the paper. The paper addresses an interesting question about unblinding, but there should have been more work done, such as finding “a measure that is validated that can say whether you’ve been unblinded or not.”

He added that he was surprised the paper on unblinding in rheumatology trials was published in its current form.

“I would have sent it for a major rewrite” if asked to review this paper before publication, said Dr. Fleischmann, who as a reviewer for Lancet Rheumatology. “I would have said: ‘Okay, 90% of this paper is okay, but your gist is not correct.’ It should be: ‘Is this a problem?’ ”

Dr. Fleischmann said he would have recommended a different perspective to the paper. “That is, this could occur. Should we be looking at this, and how would we look at this?”

In the paper, the authors acknowledge their approach has not been validated, “but it highlights the potential effect of idiosyncratic adverse events,” they wrote.

There’s less funding in general for meta-research than for studies involving treatments, so researchers look for approaches that can be handled without requiring significant funding, and much of the research on the quality of research is conducted like this analysis of rheumatology trials, Michael Putman, MD, the corresponding author and is a rheumatologist and an assistant professor at the Medical College of Wisconsin, said in an interview.

“You’re mostly doing on a shoestring budget with yourself and trainees,” he said. Dr. Putman is an associate editor at the journal Rheumatology and also involved in meta-research, or efforts to understand how studies and trials answer questions about how medical treatments work.

In an Aug. 16 tweet, Dr. Putman said this issue of unintentional unblinding with rheumatology trials was something he’d “been ruminating about for awhile; took two all star trainees to push it over the top!”

One of the barriers to funding of meta-research is a tendency for major funding for medical studies to be focused on specific diseases or targets. With meta-research, it may be more difficult to explain how a specific project will advance efforts to treat or prevent a certain disease, Dr. Putman said.

“It’s a little more esoteric and maybe not quite as clear how these projects will move things forward,” Dr. Putman said.

In addition, the nature of meta-research is to question and often be critical of work that’s already been published, adding another hurdle in attempts to secure funding, he said.

Dr. Putman is supported by a Rheumatology Research Foundation Scientist Development Grant, receives research funding related to clinical trials by AbbVie and AstraZeneca, and consulting fees from Novartis. The other authors declared no competing interests.

Clinical trials of treatments for rheumatologic conditions appear especially vulnerable to inadvertent unblinding, because of noticeable side effects of some drugs and subjective outcome measures, according to a new analysis.

Until more is known about the potential for unblinding, clinicians need to keep in mind that patients and physicians could often guess accurately who was getting placebo or active drug, first author Cody Bruggemeyer, MD, a resident at the Medical College of Wisconsin, Milwaukee, said in an interview.

Dr. Bruggemeyer

“It’s important that rheumatologists be aware of this potential issue and use their clinical reasoning and their ability to critically assess papers to evaluate the study design” of research on treatments, he said in an interview.

Dr. Bruggemeyer and coauthors at the Medical College of Wisconsin presented their assessment of the potential for unblinding in a Viewpoint article in The Lancet Rheumatology.
 

A sample of pivotal clinical trials

The authors selected a sample of pivotal studies of 14 commonly prescribed drugs for rheumatic conditions for which double-blind randomized controlled trials (RCTs) that compared the active ingredient with a placebo were available.

The 14 trials involved treatments classified as disease-modifying antirheumatic drugs (DMARDs), some of which were likely to produce side effects that placebos would not mimic, such as injection site and infusion reactions and difference in readings in lab reports, the authors wrote.

In their analysis, Dr. Bruggemeyer and colleagues evaluated discrepancies in the rates of adverse events reported between active drugs and placebos and classified the 14 studies as follows:

• High unblinding risk: Nine studies had a high estimated risk of unblinding, including trials of adalimumab with citrate (Humira), anakinra (Kineret), anifrolumab (Saphnelo), apremilast (Otezla), ixekizumab (Taltz), leflunomide (Arava), methotrexate, risankizumab (Skyrizi) and tofacitinib (Xeljanz).
• Moderate unblinding risk: Three studies had a moderate estimated risk of unblinding, including trials of azathioprine (Imuran), mycophenolate mofetil and tocilizumab (Actemra).
• Low unblinding risk: Two studies had a low estimated risk of unblinding. These involved tests of belimumab (Benlysta) and rituximab (Rituxan).

Many of the effectiveness measurements of treatments used in rheumatology depend on patients’ reports of relief of pain and other disease symptoms. For example, the widely used American College of Rheumatology 20% response for rheumatoid arthritis includes components that rely on patient and physician assessment of disease activity.
 

Unblinding risk to clinical trial validity

CTs are the highest level of evidence to establish efficacy, because the study design aims to mask whether the experimental treatment is a drug or placebo. In cases where patients and physicians are more likely to correctly detect use of an active drug, there can be biases that skew results toward reports of symptom improvement. Other patients’ views of their treatment may be distorted by accurate guesses that they have been given placebo, Dr. Bruggemeyer and coauthors wrote.

“The degree of these effects cannot be predicted, but they tend to erroneously inflate the perceived benefit of novel interventions,” they wrote.

The consequences of this unblinding may be minimal in cases where there’s a clear difference between the placebo and active drug, they said. As an example, they cited trials of interleukin-23 inhibitors for psoriasis, where skin clearance as measured by the Psoriatic Area and Severity Index 75 differed by more than 50% in absolute terms between the treatment and placebo groups.

But in other cases, there needs to be more attention paid to the potential role of unblinding, they wrote.

“Studies where effect sizes were small, contradictory, or dependent on subgroup analyses might be especially problematic, but commentary rarely reflects this issue or acknowledges the potential influence of unblinding,” they wrote.

In the paper, they call for more analysis of previous trials to look for unreported assessments of unblinding, while also asking that researchers consider surveying participants in future trials to evaluate the degree to which unblinding occurs.

“Advocacy from professional societies and the U.S. Food and Drug Administration itself might be necessary, but in the interim, rheumatologists should assume unblinding has occurred to some degree in most trials,” they wrote.
 

Unblinding measure needs validation

In an interview, Roy M. Fleischmann, MD, co–medical director of the Metroplex Clinical Research Center in Dallas, raised some objections to the paper. The paper addresses an interesting question about unblinding, but there should have been more work done, such as finding “a measure that is validated that can say whether you’ve been unblinded or not.”

He added that he was surprised the paper on unblinding in rheumatology trials was published in its current form.

“I would have sent it for a major rewrite” if asked to review this paper before publication, said Dr. Fleischmann, who as a reviewer for Lancet Rheumatology. “I would have said: ‘Okay, 90% of this paper is okay, but your gist is not correct.’ It should be: ‘Is this a problem?’ ”

Dr. Fleischmann said he would have recommended a different perspective to the paper. “That is, this could occur. Should we be looking at this, and how would we look at this?”

In the paper, the authors acknowledge their approach has not been validated, “but it highlights the potential effect of idiosyncratic adverse events,” they wrote.

There’s less funding in general for meta-research than for studies involving treatments, so researchers look for approaches that can be handled without requiring significant funding, and much of the research on the quality of research is conducted like this analysis of rheumatology trials, Michael Putman, MD, the corresponding author and is a rheumatologist and an assistant professor at the Medical College of Wisconsin, said in an interview.

“You’re mostly doing on a shoestring budget with yourself and trainees,” he said. Dr. Putman is an associate editor at the journal Rheumatology and also involved in meta-research, or efforts to understand how studies and trials answer questions about how medical treatments work.

In an Aug. 16 tweet, Dr. Putman said this issue of unintentional unblinding with rheumatology trials was something he’d “been ruminating about for awhile; took two all star trainees to push it over the top!”

One of the barriers to funding of meta-research is a tendency for major funding for medical studies to be focused on specific diseases or targets. With meta-research, it may be more difficult to explain how a specific project will advance efforts to treat or prevent a certain disease, Dr. Putman said.

“It’s a little more esoteric and maybe not quite as clear how these projects will move things forward,” Dr. Putman said.

In addition, the nature of meta-research is to question and often be critical of work that’s already been published, adding another hurdle in attempts to secure funding, he said.

Dr. Putman is supported by a Rheumatology Research Foundation Scientist Development Grant, receives research funding related to clinical trials by AbbVie and AstraZeneca, and consulting fees from Novartis. The other authors declared no competing interests.

AMSTERDAM – Among patients with atrial high-rate episodes detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite outcome of cardiovascular death, stroke, or systemic embolism in comparison with placebo but was associated with a higher bleeding risk in the NOAH-AFNET 6 trial.

“These results tell us that patients with atrial high-rate episodes with clinical stroke risk factors – but who do not have clinically defined AF[ib] [atrial fibrillation – do not need blood thinners. They do not need to be anticoagulated. That is a relief,” the lead investigator of the trial, Paulus Kirchhof, MD, University Heart and Vascular Center Hamburg (Germany), said in an interview.

Dr. Kirchhof pointed out that this result was unexpected. “Many of us thought that because atrial high-rate episodes look like AF[ib] when they occur, then they are an indication for anticoagulation. But based on these results from the first-ever randomized trial on this population, there is no need for anticoagulation in these patients.”

Dr. Kirchhof presented the NOAH-AFNET 6 trial at the annual congress of the European Society of Cardiology. The study was also simultaneously published in the New England Journal of Medicine.

The trial recruited patients with implanted devices that enable continuous monitoring of atrial rhythm, such as pacemakers and defibrillators. “Because we can record the rhythm day and night with these devices, they pick up small abnormalities. About 20% of these patients experience these occasional atrial high-rate episodes – short episodes that look like AF[ib], but they are rare and brief,” Dr. Kirchhof noted.

He explained that whether the occurrence of these atrial high-rate episodes in patients without AFib, as documented on a conventional electrocardiogram, justifies the initiation of anticoagulants has been unclear. “But this trial tells us that these episodes are different to AF[ib] that is diagnosed on ECG,” he added.

Another finding in the trial was that among these patients, there was an unexpectedly low rate of stroke, despite the patients’ having a CHADSVASC score of 4.

“Based on the result of this trial, these occasional atrial high-rate episodes do not appear to be associated with stroke. It appears quite benign,” Dr. Kirchhof said.
 

Implications for wearable technology?

He said the results may also have implications for wearable devices that pick up abnormal heart rhythm, such as smartwatches.

“We don’t know exactly what these wearable technologies are picking up, but most likely it is these atrial high-rate episodes. But we need more research on the value of these wearable technologies; we need randomized trials in this particular patient population before we consider anticoagulation in these patients,” Dr. Kirchhof stated.

The NOAH-AFNET 6 study was an event-driven, double-blind, double-dummy, randomized trial involving 2,536 patients aged 65 years or older who had atrial high-rate episodes that lasted for at least 6 minutes and who had at least one additional risk factor for stroke.

Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding.

The mean age of the patients was 78 years, 37.4% were women, and the median duration of atrial high-rate episodes was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed.

Results showed that a primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval, 0.60-1.08; P = .15). The incidence of stroke was approximately 1% per patient-year in both groups.

A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (HR, 1.31; 95% CI, 1.02-1.67; P = .03).

ECG-diagnosed AFib developed in 462 of 2,536 patients (18.2% total, 8.7% per patient-year).

In the NEJM article, the authors wrote that the findings of this trial – the low incidence of stroke that was not further reduced by treatment with edoxaban – may make it appropriate to withhold anticoagulant therapy for patients with atrial high-rate episodes.

The main difference between the population studied in this trial and patients with AFib, as documented on an ECG, appears to be the paucity and brevity of atrial arrhythmias in patients with atrial high-rate episodes (termed low arrhythmia burden). Published reports show that a low arrhythmia burden contributes to a low incidence of stroke among patients with AFib, the study authors wrote.

They added that the low rate of stroke in this trial suggests that in addition to clinical risk prediction formulas for stroke, methods to improve the estimation of stroke risk among patients with infrequent atrial arrhythmias detected by long-term monitoring are needed to guide decision-making on the use of anticoagulation.

Commenting on the NOAH-AFNET 6 results, the comoderator of the ESC HOTLINE session at which they were presented, Barbara Casadei, MD, John Radcliffe Hospital, Oxford, England, said: “Finally we know what to with these patients. Before we just had a variety of opinions with no evidence. I think that the trial really highlights that patients who come to the doctor with symptoms of AF[ib] or who have ECG-documented AF[ib] have a much higher risk of cardioembolic stroke than patients in whom this presumed AF[ib] is picked up incidentally from implanted devices.”

She added: “The stroke rates are very low in this trial, so anticoagulation was never going to work. But this is an important finding. We know that anticoagulants are not a free lunch. There is a significant bleeding risk. These results suggest that unless a patient has clinical AF[ib] that shows up on an ECG then we need to more cautious in prescribing anticoagulation.”

Also commenting on the study, immediate past president of the American College of Cardiology Ed Fry, MD, Ascension Indiana St. Vincent Heart Center, Indianapolis, said the management of patients with implanted cardiac devices or personal wearable technology that has picked up an abnormal rhythm suggestive of AFib was a big question in clinical practice.

“These episodes could be AF[ib], which comes with an increased stroke risk, but it could also be something else like atrial tachycardia or supraventricular tachycardia, which do not confer an increased stroke risk,” he explained.

“This study shows that without a firm diagnosis of AF[ib] on an ECG or some sort of continuous AF[ib] monitoring device, we are going to be anticoagulating people who don’t need it. They were exposed to the risk of bleeding without getting the benefit of a reduction in stroke risk,” Dr. Fry noted.

“The important outcome from this trial is that it gives comfort in we can be more confident in withholding anticoagulation until we get a firm diagnosis of AF[ib]. If we have a high index of suspicion that this could be AF[ib], then we can arrange for a further testing,” he added.
 

Second trial reporting soon

A trial similar to NOAH-AFNET 6 is currently underway – the ARTESIA trial, which is expected to be reported later in 2023.

“We are in close contact with the leadership of that trial, and we hope to do some meta-analysis,” Dr. Kirchhof said. “But I think today we’ve gone from no evidence to one outcome-based trial which shows there is no reason to use anticoagulation in these patients with atrial high-rate episodes. I think this is reason to change practice now, but yes, of course we need to look at the data in totality once the second trial has reported.”

But the lead investigator of the ARTESIA trial, Stuart Connolly, MD, McMaster University, Hamilton, Ont., does not believe the NOAH-AFNET 6 trial should change practice at this time.

“This trial fails to adequately address the critical issue that drives clinical decision-making in these patients because it is underpowered for the most important endpoint of stroke,” he said in an interview.

“The key question is whether anticoagulation reduces stroke in these patients,” he added. “To answer that, a clinical trial needs to have a lot of strokes, and this trial had very few. The trial was stopped early and had way too few strokes to properly answer this key question.”

The NOAH-AFNET 6 trial was an investigator-initiated trial funded by the German Center for Cardiovascular Research and Daiichi Sankyo Europe. Dr. Kirchhof reported research support from several drug and device companies active in AFib. He is also listed as an inventor on two patents held by the University of Hamburg on AFib therapy and AFib markers.

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

AMSTERDAM – Among patients with atrial high-rate episodes detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite outcome of cardiovascular death, stroke, or systemic embolism in comparison with placebo but was associated with a higher bleeding risk in the NOAH-AFNET 6 trial.

“These results tell us that patients with atrial high-rate episodes with clinical stroke risk factors – but who do not have clinically defined AF[ib] [atrial fibrillation – do not need blood thinners. They do not need to be anticoagulated. That is a relief,” the lead investigator of the trial, Paulus Kirchhof, MD, University Heart and Vascular Center Hamburg (Germany), said in an interview.

Dr. Kirchhof pointed out that this result was unexpected. “Many of us thought that because atrial high-rate episodes look like AF[ib] when they occur, then they are an indication for anticoagulation. But based on these results from the first-ever randomized trial on this population, there is no need for anticoagulation in these patients.”

Dr. Kirchhof presented the NOAH-AFNET 6 trial at the annual congress of the European Society of Cardiology. The study was also simultaneously published in the New England Journal of Medicine.

The trial recruited patients with implanted devices that enable continuous monitoring of atrial rhythm, such as pacemakers and defibrillators. “Because we can record the rhythm day and night with these devices, they pick up small abnormalities. About 20% of these patients experience these occasional atrial high-rate episodes – short episodes that look like AF[ib], but they are rare and brief,” Dr. Kirchhof noted.

He explained that whether the occurrence of these atrial high-rate episodes in patients without AFib, as documented on a conventional electrocardiogram, justifies the initiation of anticoagulants has been unclear. “But this trial tells us that these episodes are different to AF[ib] that is diagnosed on ECG,” he added.

Another finding in the trial was that among these patients, there was an unexpectedly low rate of stroke, despite the patients’ having a CHADSVASC score of 4.

“Based on the result of this trial, these occasional atrial high-rate episodes do not appear to be associated with stroke. It appears quite benign,” Dr. Kirchhof said.
 

Implications for wearable technology?

He said the results may also have implications for wearable devices that pick up abnormal heart rhythm, such as smartwatches.

“We don’t know exactly what these wearable technologies are picking up, but most likely it is these atrial high-rate episodes. But we need more research on the value of these wearable technologies; we need randomized trials in this particular patient population before we consider anticoagulation in these patients,” Dr. Kirchhof stated.

The NOAH-AFNET 6 study was an event-driven, double-blind, double-dummy, randomized trial involving 2,536 patients aged 65 years or older who had atrial high-rate episodes that lasted for at least 6 minutes and who had at least one additional risk factor for stroke.

Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding.

The mean age of the patients was 78 years, 37.4% were women, and the median duration of atrial high-rate episodes was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed.

Results showed that a primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval, 0.60-1.08; P = .15). The incidence of stroke was approximately 1% per patient-year in both groups.

A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (HR, 1.31; 95% CI, 1.02-1.67; P = .03).

ECG-diagnosed AFib developed in 462 of 2,536 patients (18.2% total, 8.7% per patient-year).

In the NEJM article, the authors wrote that the findings of this trial – the low incidence of stroke that was not further reduced by treatment with edoxaban – may make it appropriate to withhold anticoagulant therapy for patients with atrial high-rate episodes.

The main difference between the population studied in this trial and patients with AFib, as documented on an ECG, appears to be the paucity and brevity of atrial arrhythmias in patients with atrial high-rate episodes (termed low arrhythmia burden). Published reports show that a low arrhythmia burden contributes to a low incidence of stroke among patients with AFib, the study authors wrote.

They added that the low rate of stroke in this trial suggests that in addition to clinical risk prediction formulas for stroke, methods to improve the estimation of stroke risk among patients with infrequent atrial arrhythmias detected by long-term monitoring are needed to guide decision-making on the use of anticoagulation.

Commenting on the NOAH-AFNET 6 results, the comoderator of the ESC HOTLINE session at which they were presented, Barbara Casadei, MD, John Radcliffe Hospital, Oxford, England, said: “Finally we know what to with these patients. Before we just had a variety of opinions with no evidence. I think that the trial really highlights that patients who come to the doctor with symptoms of AF[ib] or who have ECG-documented AF[ib] have a much higher risk of cardioembolic stroke than patients in whom this presumed AF[ib] is picked up incidentally from implanted devices.”

She added: “The stroke rates are very low in this trial, so anticoagulation was never going to work. But this is an important finding. We know that anticoagulants are not a free lunch. There is a significant bleeding risk. These results suggest that unless a patient has clinical AF[ib] that shows up on an ECG then we need to more cautious in prescribing anticoagulation.”

Also commenting on the study, immediate past president of the American College of Cardiology Ed Fry, MD, Ascension Indiana St. Vincent Heart Center, Indianapolis, said the management of patients with implanted cardiac devices or personal wearable technology that has picked up an abnormal rhythm suggestive of AFib was a big question in clinical practice.

“These episodes could be AF[ib], which comes with an increased stroke risk, but it could also be something else like atrial tachycardia or supraventricular tachycardia, which do not confer an increased stroke risk,” he explained.

“This study shows that without a firm diagnosis of AF[ib] on an ECG or some sort of continuous AF[ib] monitoring device, we are going to be anticoagulating people who don’t need it. They were exposed to the risk of bleeding without getting the benefit of a reduction in stroke risk,” Dr. Fry noted.

“The important outcome from this trial is that it gives comfort in we can be more confident in withholding anticoagulation until we get a firm diagnosis of AF[ib]. If we have a high index of suspicion that this could be AF[ib], then we can arrange for a further testing,” he added.
 

Second trial reporting soon

A trial similar to NOAH-AFNET 6 is currently underway – the ARTESIA trial, which is expected to be reported later in 2023.

“We are in close contact with the leadership of that trial, and we hope to do some meta-analysis,” Dr. Kirchhof said. “But I think today we’ve gone from no evidence to one outcome-based trial which shows there is no reason to use anticoagulation in these patients with atrial high-rate episodes. I think this is reason to change practice now, but yes, of course we need to look at the data in totality once the second trial has reported.”

But the lead investigator of the ARTESIA trial, Stuart Connolly, MD, McMaster University, Hamilton, Ont., does not believe the NOAH-AFNET 6 trial should change practice at this time.

“This trial fails to adequately address the critical issue that drives clinical decision-making in these patients because it is underpowered for the most important endpoint of stroke,” he said in an interview.

“The key question is whether anticoagulation reduces stroke in these patients,” he added. “To answer that, a clinical trial needs to have a lot of strokes, and this trial had very few. The trial was stopped early and had way too few strokes to properly answer this key question.”

The NOAH-AFNET 6 trial was an investigator-initiated trial funded by the German Center for Cardiovascular Research and Daiichi Sankyo Europe. Dr. Kirchhof reported research support from several drug and device companies active in AFib. He is also listed as an inventor on two patents held by the University of Hamburg on AFib therapy and AFib markers.

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

AMSTERDAM – Among patients with atrial high-rate episodes detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite outcome of cardiovascular death, stroke, or systemic embolism in comparison with placebo but was associated with a higher bleeding risk in the NOAH-AFNET 6 trial.

“These results tell us that patients with atrial high-rate episodes with clinical stroke risk factors – but who do not have clinically defined AF[ib] [atrial fibrillation – do not need blood thinners. They do not need to be anticoagulated. That is a relief,” the lead investigator of the trial, Paulus Kirchhof, MD, University Heart and Vascular Center Hamburg (Germany), said in an interview.

Dr. Kirchhof pointed out that this result was unexpected. “Many of us thought that because atrial high-rate episodes look like AF[ib] when they occur, then they are an indication for anticoagulation. But based on these results from the first-ever randomized trial on this population, there is no need for anticoagulation in these patients.”

Dr. Kirchhof presented the NOAH-AFNET 6 trial at the annual congress of the European Society of Cardiology. The study was also simultaneously published in the New England Journal of Medicine.

The trial recruited patients with implanted devices that enable continuous monitoring of atrial rhythm, such as pacemakers and defibrillators. “Because we can record the rhythm day and night with these devices, they pick up small abnormalities. About 20% of these patients experience these occasional atrial high-rate episodes – short episodes that look like AF[ib], but they are rare and brief,” Dr. Kirchhof noted.

He explained that whether the occurrence of these atrial high-rate episodes in patients without AFib, as documented on a conventional electrocardiogram, justifies the initiation of anticoagulants has been unclear. “But this trial tells us that these episodes are different to AF[ib] that is diagnosed on ECG,” he added.

Another finding in the trial was that among these patients, there was an unexpectedly low rate of stroke, despite the patients’ having a CHADSVASC score of 4.

“Based on the result of this trial, these occasional atrial high-rate episodes do not appear to be associated with stroke. It appears quite benign,” Dr. Kirchhof said.
 

Implications for wearable technology?

He said the results may also have implications for wearable devices that pick up abnormal heart rhythm, such as smartwatches.

“We don’t know exactly what these wearable technologies are picking up, but most likely it is these atrial high-rate episodes. But we need more research on the value of these wearable technologies; we need randomized trials in this particular patient population before we consider anticoagulation in these patients,” Dr. Kirchhof stated.

The NOAH-AFNET 6 study was an event-driven, double-blind, double-dummy, randomized trial involving 2,536 patients aged 65 years or older who had atrial high-rate episodes that lasted for at least 6 minutes and who had at least one additional risk factor for stroke.

Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding.

The mean age of the patients was 78 years, 37.4% were women, and the median duration of atrial high-rate episodes was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed.

Results showed that a primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval, 0.60-1.08; P = .15). The incidence of stroke was approximately 1% per patient-year in both groups.

A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (HR, 1.31; 95% CI, 1.02-1.67; P = .03).

ECG-diagnosed AFib developed in 462 of 2,536 patients (18.2% total, 8.7% per patient-year).

In the NEJM article, the authors wrote that the findings of this trial – the low incidence of stroke that was not further reduced by treatment with edoxaban – may make it appropriate to withhold anticoagulant therapy for patients with atrial high-rate episodes.

The main difference between the population studied in this trial and patients with AFib, as documented on an ECG, appears to be the paucity and brevity of atrial arrhythmias in patients with atrial high-rate episodes (termed low arrhythmia burden). Published reports show that a low arrhythmia burden contributes to a low incidence of stroke among patients with AFib, the study authors wrote.

They added that the low rate of stroke in this trial suggests that in addition to clinical risk prediction formulas for stroke, methods to improve the estimation of stroke risk among patients with infrequent atrial arrhythmias detected by long-term monitoring are needed to guide decision-making on the use of anticoagulation.

Commenting on the NOAH-AFNET 6 results, the comoderator of the ESC HOTLINE session at which they were presented, Barbara Casadei, MD, John Radcliffe Hospital, Oxford, England, said: “Finally we know what to with these patients. Before we just had a variety of opinions with no evidence. I think that the trial really highlights that patients who come to the doctor with symptoms of AF[ib] or who have ECG-documented AF[ib] have a much higher risk of cardioembolic stroke than patients in whom this presumed AF[ib] is picked up incidentally from implanted devices.”

She added: “The stroke rates are very low in this trial, so anticoagulation was never going to work. But this is an important finding. We know that anticoagulants are not a free lunch. There is a significant bleeding risk. These results suggest that unless a patient has clinical AF[ib] that shows up on an ECG then we need to more cautious in prescribing anticoagulation.”

Also commenting on the study, immediate past president of the American College of Cardiology Ed Fry, MD, Ascension Indiana St. Vincent Heart Center, Indianapolis, said the management of patients with implanted cardiac devices or personal wearable technology that has picked up an abnormal rhythm suggestive of AFib was a big question in clinical practice.

“These episodes could be AF[ib], which comes with an increased stroke risk, but it could also be something else like atrial tachycardia or supraventricular tachycardia, which do not confer an increased stroke risk,” he explained.

“This study shows that without a firm diagnosis of AF[ib] on an ECG or some sort of continuous AF[ib] monitoring device, we are going to be anticoagulating people who don’t need it. They were exposed to the risk of bleeding without getting the benefit of a reduction in stroke risk,” Dr. Fry noted.

“The important outcome from this trial is that it gives comfort in we can be more confident in withholding anticoagulation until we get a firm diagnosis of AF[ib]. If we have a high index of suspicion that this could be AF[ib], then we can arrange for a further testing,” he added.
 

Second trial reporting soon

A trial similar to NOAH-AFNET 6 is currently underway – the ARTESIA trial, which is expected to be reported later in 2023.

“We are in close contact with the leadership of that trial, and we hope to do some meta-analysis,” Dr. Kirchhof said. “But I think today we’ve gone from no evidence to one outcome-based trial which shows there is no reason to use anticoagulation in these patients with atrial high-rate episodes. I think this is reason to change practice now, but yes, of course we need to look at the data in totality once the second trial has reported.”

But the lead investigator of the ARTESIA trial, Stuart Connolly, MD, McMaster University, Hamilton, Ont., does not believe the NOAH-AFNET 6 trial should change practice at this time.

“This trial fails to adequately address the critical issue that drives clinical decision-making in these patients because it is underpowered for the most important endpoint of stroke,” he said in an interview.

“The key question is whether anticoagulation reduces stroke in these patients,” he added. “To answer that, a clinical trial needs to have a lot of strokes, and this trial had very few. The trial was stopped early and had way too few strokes to properly answer this key question.”

The NOAH-AFNET 6 trial was an investigator-initiated trial funded by the German Center for Cardiovascular Research and Daiichi Sankyo Europe. Dr. Kirchhof reported research support from several drug and device companies active in AFib. He is also listed as an inventor on two patents held by the University of Hamburg on AFib therapy and AFib markers.

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

Survivors of out-of-hospital cardiac arrest (OHCA) without ST-segment elevation who were transported to the nearest hospital emergency department had outcomes similar to those of patients transported to specialist cardiac arrest centers, in the ARREST trial.

Both groups had the same 30-day survival, the primary outcome, as well as 3-month survival and neurologic outcomes.

“The take-home message is that this trial does not support transporting cardiac arrest patients direct to a cardiac arrest center in London; they would fare better going to their nearest emergency department,” senior author Simon R. Redwood, MD, principal investigator of ARREST, from Guy’s and St. Thomas’ NHS Trust Hospitals and King’s College, London, said during a press briefing. “These results may allow better resource allocation elsewhere.”

Importantly, this study excluded patients who clearly had myocardial infarction (MI), he stressed. Cardiac arrest can result from cardiac causes or from other events, including trauma, overdose, drowning, or electrocution, he noted.

On the other hand, patients with MI “will benefit from going straight to a heart attack center and having an attempt at reopening the artery,” he emphasized.

Tiffany Patterson, PhD, clinical lead of ARREST, with the same affiliations as Dr. Redwood, presented the trial findings at the annual congress of the European Society of Cardiology in Amsterdam, on Aug. 27. The study was simultaneously published online in The Lancet.

Observational studies of registry data suggest that postarrest care for patients resuscitated after cardiac arrest, without ST-segment elevation, may be best delivered in a specialized center, she noted.

The International Liaison Committee on Resuscitation called for a randomized clinical trial of patients resuscitated after cardiac arrest without ST-segment elevation to clarify this.

In the ARREST trial, among 800 patients with return of spontaneous circulation following OHCA without ST-segment elevation who were randomly assigned to be transported to specialized centers or an emergency department, there was no survival benefit, she summarized.

ARREST was “not simply a negative trial, but a new evidence-based starting point,” according to the trial discussant Lia Crotti, MD, PhD, IRCCS Istituto Auxologico Italiano and University Milano-Bicocca, Italy. 

She drew attention to two findings: First, among the 862 patients who were enrolled, whom paramedics judged as being without an obvious noncardiac cause of the cardiac arrest, “only 60% ended up having a cardiac cause for their cardiac arrest and only around one quarter of the total had coronary artery disease.”

The small number of patients who could have benefited from early access to a catheterization laboratory probably contributed to the negative result obtained in this trial, with the loss of statistical power, she said.

Second, London is a dense urban area with high-quality acute care hospitals, so the standard of care in the nearest emergency department may be not so different from that in cardiac arrest centers, she noted. Furthermore, four of the seven cardiac arrest centers have an emergency department, and some of the standard care patients may have been transported there.

“If the clinical trial would be extended to the entire country, including rural areas, maybe the result would be different,” she said.

The study authors acknowledge that the main limitation of this study was that “it was done across London with a dense population in a small geographic area,” and “the London Ambulance Service has rapid response times and short transit times and delivers high quality prehospital care, which could limit generalizability.”

Asked during the press conference here why the results were so different from the registry study findings, Dr. Redwood said, “We’ve seen time and time again that registry data think they are telling us the answer. They’re actually not.”

The session cochairs, Rudolf de Boer, MD, PhD, of Erasmus University Medical Centre, Rotterdam, the Netherlands, and Faiez Zannad, MD, PhD, from University of Lorraine–Vandoeuvre-lès-Nancy, France, each congratulated the researchers on a well-done study.

Dr. de Boer wanted to know whether, for example, 100% of these resuscitated OHCA patients without ST-segment elevation  had a cardiac cause, “Would results differ? Or is this just real life?” he asked. Dr. Patterson replied that the paramedics excluded obvious noncardiac causes and the findings were based on current facilities.

“Does this trial provide a definitive answer?” Dr. de Boer asked. Dr. Patterson replied that for the moment, subgroup analysis did not identify any subgroup that might benefit from expedited transport to a cardiac arrest center.

Dr. Zannad wanted to know how informed consent was obtained. Dr. Patterson noted that they have an excellent ethical committee that allowed them to undertake this research in vulnerable patients. Written informed consent was obtained from the patient once the initial emergency had passed if they had regained capacity.
 

Rationale and trial findings

“It’s very well established that early bystander CPR [cardiopulmonary resuscitation], early defibrillation, and advanced in-hospital care improves survival,” Dr. Redwood noted. “Despite this, only 1 in 10 survive to leave the hospital.”

Therefore, “a cardiac arrest center has been proposed as a way of improving outcome.” These centers have a catheterization laboratory, open 24 hours a day, 7 days a week, advanced critical care including advanced ventilation, temperature management of the patient, hemodynamic support, and neuroprognostication and rehab “because often these patients will have brain injury.

“There’s quite overwhelming registry data to suggest that these cardiac arrest centers improve outcome,” he said, “but these are limited by bias.”

Between January 2018 and December 2022, London Ambulance paramedics randomly assigned 862 patients who were successfully resuscitated and without a confirmed MI to be transported the nearest hospital emergency department or the catheterization laboratory in a cardiac arrest center.

Data were available for 822 participants. They had a mean age of 63 years, and 68% were male.

The primary endpoint, 30-day mortality, occurred in 258 (63%) of 411 participants in the cardiac arrest center group and in 258 (63%) of 412 in the standard care group (unadjusted risk ratio for survival, 1.00; 95% confidence interval [CI], 0.90-1.11; P = 0.96).

Mortality at 3 months was similar in both groups: 64% in the standard care group and 65% in the cardiac arrest center group.

Neurologic outcomes at discharge and 3 months were similar in both groups.

Eight (2%) of 414 patients in the cardiac arrest center group and three (1%) of 413 in the standard care group had serious adverse events, none of which were deemed related to the trial intervention.

A cardiac cause of arrest was identified in roughly 60% of patients in each group, and of these, roughly 42% were coronary causes, 33% were arrhythmia, and 17% were cardiomyopathy.

The median time from cardiac arrest to hospital arrival was 84 minutes in the cardiac arrest center group and 77 minutes in the standard care group.
 

“Surprising and important RCT evidence”

In an accompanying editorial, Carolina Malta Hansen, MD, PhD, University of Copenhagen, and colleagues wrote that “this study provides randomized trial evidence that in urban settings such as London, there is no survival advantage of a strategy of transporting patients who have been resuscitated to centres with specialty expertise in care of cardiac arrest.
“This result is surprising and important, since this complex and critically ill population would be expected to benefit from centres with more expertise.”

However, “it would be a mistake to conclude that the trial results apply to regions where local hospitals provide a lower quality of care than those in this trial,” they cautioned.

“Where does this leave the medical community, researchers, and society in general?” they asked rhetorically. “Prioritising a minimum standard of care at local hospitals caring for this population is at least as important as ensuring high-quality care or advanced treatment at tertiary centres.

“This trial also calls for more focus on the basics, including efforts to increase bystander cardiopulmonary resuscitation and early defibrillation, aspects of care that are currently being assessed in two ongoing clinical trials (NCT04660526 and NCT03835403) and are most strongly associated with improved survival, when coupled with high-quality prehospital care with trained staff and short response times,” they concluded.

The study was fully funded by the British Heart Foundation. The authors reported that they have no relevant financial disclosures. The financial disclosures of the editorialists are listed with the editorial.

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

Survivors of out-of-hospital cardiac arrest (OHCA) without ST-segment elevation who were transported to the nearest hospital emergency department had outcomes similar to those of patients transported to specialist cardiac arrest centers, in the ARREST trial.

Both groups had the same 30-day survival, the primary outcome, as well as 3-month survival and neurologic outcomes.

“The take-home message is that this trial does not support transporting cardiac arrest patients direct to a cardiac arrest center in London; they would fare better going to their nearest emergency department,” senior author Simon R. Redwood, MD, principal investigator of ARREST, from Guy’s and St. Thomas’ NHS Trust Hospitals and King’s College, London, said during a press briefing. “These results may allow better resource allocation elsewhere.”

Importantly, this study excluded patients who clearly had myocardial infarction (MI), he stressed. Cardiac arrest can result from cardiac causes or from other events, including trauma, overdose, drowning, or electrocution, he noted.

On the other hand, patients with MI “will benefit from going straight to a heart attack center and having an attempt at reopening the artery,” he emphasized.

Tiffany Patterson, PhD, clinical lead of ARREST, with the same affiliations as Dr. Redwood, presented the trial findings at the annual congress of the European Society of Cardiology in Amsterdam, on Aug. 27. The study was simultaneously published online in The Lancet.

Observational studies of registry data suggest that postarrest care for patients resuscitated after cardiac arrest, without ST-segment elevation, may be best delivered in a specialized center, she noted.

The International Liaison Committee on Resuscitation called for a randomized clinical trial of patients resuscitated after cardiac arrest without ST-segment elevation to clarify this.

In the ARREST trial, among 800 patients with return of spontaneous circulation following OHCA without ST-segment elevation who were randomly assigned to be transported to specialized centers or an emergency department, there was no survival benefit, she summarized.

ARREST was “not simply a negative trial, but a new evidence-based starting point,” according to the trial discussant Lia Crotti, MD, PhD, IRCCS Istituto Auxologico Italiano and University Milano-Bicocca, Italy. 

She drew attention to two findings: First, among the 862 patients who were enrolled, whom paramedics judged as being without an obvious noncardiac cause of the cardiac arrest, “only 60% ended up having a cardiac cause for their cardiac arrest and only around one quarter of the total had coronary artery disease.”

The small number of patients who could have benefited from early access to a catheterization laboratory probably contributed to the negative result obtained in this trial, with the loss of statistical power, she said.

Second, London is a dense urban area with high-quality acute care hospitals, so the standard of care in the nearest emergency department may be not so different from that in cardiac arrest centers, she noted. Furthermore, four of the seven cardiac arrest centers have an emergency department, and some of the standard care patients may have been transported there.

“If the clinical trial would be extended to the entire country, including rural areas, maybe the result would be different,” she said.

The study authors acknowledge that the main limitation of this study was that “it was done across London with a dense population in a small geographic area,” and “the London Ambulance Service has rapid response times and short transit times and delivers high quality prehospital care, which could limit generalizability.”

Asked during the press conference here why the results were so different from the registry study findings, Dr. Redwood said, “We’ve seen time and time again that registry data think they are telling us the answer. They’re actually not.”

The session cochairs, Rudolf de Boer, MD, PhD, of Erasmus University Medical Centre, Rotterdam, the Netherlands, and Faiez Zannad, MD, PhD, from University of Lorraine–Vandoeuvre-lès-Nancy, France, each congratulated the researchers on a well-done study.

Dr. de Boer wanted to know whether, for example, 100% of these resuscitated OHCA patients without ST-segment elevation  had a cardiac cause, “Would results differ? Or is this just real life?” he asked. Dr. Patterson replied that the paramedics excluded obvious noncardiac causes and the findings were based on current facilities.

“Does this trial provide a definitive answer?” Dr. de Boer asked. Dr. Patterson replied that for the moment, subgroup analysis did not identify any subgroup that might benefit from expedited transport to a cardiac arrest center.

Dr. Zannad wanted to know how informed consent was obtained. Dr. Patterson noted that they have an excellent ethical committee that allowed them to undertake this research in vulnerable patients. Written informed consent was obtained from the patient once the initial emergency had passed if they had regained capacity.
 

Rationale and trial findings

“It’s very well established that early bystander CPR [cardiopulmonary resuscitation], early defibrillation, and advanced in-hospital care improves survival,” Dr. Redwood noted. “Despite this, only 1 in 10 survive to leave the hospital.”

Therefore, “a cardiac arrest center has been proposed as a way of improving outcome.” These centers have a catheterization laboratory, open 24 hours a day, 7 days a week, advanced critical care including advanced ventilation, temperature management of the patient, hemodynamic support, and neuroprognostication and rehab “because often these patients will have brain injury.

“There’s quite overwhelming registry data to suggest that these cardiac arrest centers improve outcome,” he said, “but these are limited by bias.”

Between January 2018 and December 2022, London Ambulance paramedics randomly assigned 862 patients who were successfully resuscitated and without a confirmed MI to be transported the nearest hospital emergency department or the catheterization laboratory in a cardiac arrest center.

Data were available for 822 participants. They had a mean age of 63 years, and 68% were male.

The primary endpoint, 30-day mortality, occurred in 258 (63%) of 411 participants in the cardiac arrest center group and in 258 (63%) of 412 in the standard care group (unadjusted risk ratio for survival, 1.00; 95% confidence interval [CI], 0.90-1.11; P = 0.96).

Mortality at 3 months was similar in both groups: 64% in the standard care group and 65% in the cardiac arrest center group.

Neurologic outcomes at discharge and 3 months were similar in both groups.

Eight (2%) of 414 patients in the cardiac arrest center group and three (1%) of 413 in the standard care group had serious adverse events, none of which were deemed related to the trial intervention.

A cardiac cause of arrest was identified in roughly 60% of patients in each group, and of these, roughly 42% were coronary causes, 33% were arrhythmia, and 17% were cardiomyopathy.

The median time from cardiac arrest to hospital arrival was 84 minutes in the cardiac arrest center group and 77 minutes in the standard care group.
 

“Surprising and important RCT evidence”

In an accompanying editorial, Carolina Malta Hansen, MD, PhD, University of Copenhagen, and colleagues wrote that “this study provides randomized trial evidence that in urban settings such as London, there is no survival advantage of a strategy of transporting patients who have been resuscitated to centres with specialty expertise in care of cardiac arrest.
“This result is surprising and important, since this complex and critically ill population would be expected to benefit from centres with more expertise.”

However, “it would be a mistake to conclude that the trial results apply to regions where local hospitals provide a lower quality of care than those in this trial,” they cautioned.

“Where does this leave the medical community, researchers, and society in general?” they asked rhetorically. “Prioritising a minimum standard of care at local hospitals caring for this population is at least as important as ensuring high-quality care or advanced treatment at tertiary centres.

“This trial also calls for more focus on the basics, including efforts to increase bystander cardiopulmonary resuscitation and early defibrillation, aspects of care that are currently being assessed in two ongoing clinical trials (NCT04660526 and NCT03835403) and are most strongly associated with improved survival, when coupled with high-quality prehospital care with trained staff and short response times,” they concluded.

The study was fully funded by the British Heart Foundation. The authors reported that they have no relevant financial disclosures. The financial disclosures of the editorialists are listed with the editorial.

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

Survivors of out-of-hospital cardiac arrest (OHCA) without ST-segment elevation who were transported to the nearest hospital emergency department had outcomes similar to those of patients transported to specialist cardiac arrest centers, in the ARREST trial.

Both groups had the same 30-day survival, the primary outcome, as well as 3-month survival and neurologic outcomes.

“The take-home message is that this trial does not support transporting cardiac arrest patients direct to a cardiac arrest center in London; they would fare better going to their nearest emergency department,” senior author Simon R. Redwood, MD, principal investigator of ARREST, from Guy’s and St. Thomas’ NHS Trust Hospitals and King’s College, London, said during a press briefing. “These results may allow better resource allocation elsewhere.”

Importantly, this study excluded patients who clearly had myocardial infarction (MI), he stressed. Cardiac arrest can result from cardiac causes or from other events, including trauma, overdose, drowning, or electrocution, he noted.

On the other hand, patients with MI “will benefit from going straight to a heart attack center and having an attempt at reopening the artery,” he emphasized.

Tiffany Patterson, PhD, clinical lead of ARREST, with the same affiliations as Dr. Redwood, presented the trial findings at the annual congress of the European Society of Cardiology in Amsterdam, on Aug. 27. The study was simultaneously published online in The Lancet.

Observational studies of registry data suggest that postarrest care for patients resuscitated after cardiac arrest, without ST-segment elevation, may be best delivered in a specialized center, she noted.

The International Liaison Committee on Resuscitation called for a randomized clinical trial of patients resuscitated after cardiac arrest without ST-segment elevation to clarify this.

In the ARREST trial, among 800 patients with return of spontaneous circulation following OHCA without ST-segment elevation who were randomly assigned to be transported to specialized centers or an emergency department, there was no survival benefit, she summarized.

ARREST was “not simply a negative trial, but a new evidence-based starting point,” according to the trial discussant Lia Crotti, MD, PhD, IRCCS Istituto Auxologico Italiano and University Milano-Bicocca, Italy. 

She drew attention to two findings: First, among the 862 patients who were enrolled, whom paramedics judged as being without an obvious noncardiac cause of the cardiac arrest, “only 60% ended up having a cardiac cause for their cardiac arrest and only around one quarter of the total had coronary artery disease.”

The small number of patients who could have benefited from early access to a catheterization laboratory probably contributed to the negative result obtained in this trial, with the loss of statistical power, she said.

Second, London is a dense urban area with high-quality acute care hospitals, so the standard of care in the nearest emergency department may be not so different from that in cardiac arrest centers, she noted. Furthermore, four of the seven cardiac arrest centers have an emergency department, and some of the standard care patients may have been transported there.

“If the clinical trial would be extended to the entire country, including rural areas, maybe the result would be different,” she said.

The study authors acknowledge that the main limitation of this study was that “it was done across London with a dense population in a small geographic area,” and “the London Ambulance Service has rapid response times and short transit times and delivers high quality prehospital care, which could limit generalizability.”

Asked during the press conference here why the results were so different from the registry study findings, Dr. Redwood said, “We’ve seen time and time again that registry data think they are telling us the answer. They’re actually not.”

The session cochairs, Rudolf de Boer, MD, PhD, of Erasmus University Medical Centre, Rotterdam, the Netherlands, and Faiez Zannad, MD, PhD, from University of Lorraine–Vandoeuvre-lès-Nancy, France, each congratulated the researchers on a well-done study.

Dr. de Boer wanted to know whether, for example, 100% of these resuscitated OHCA patients without ST-segment elevation  had a cardiac cause, “Would results differ? Or is this just real life?” he asked. Dr. Patterson replied that the paramedics excluded obvious noncardiac causes and the findings were based on current facilities.

“Does this trial provide a definitive answer?” Dr. de Boer asked. Dr. Patterson replied that for the moment, subgroup analysis did not identify any subgroup that might benefit from expedited transport to a cardiac arrest center.

Dr. Zannad wanted to know how informed consent was obtained. Dr. Patterson noted that they have an excellent ethical committee that allowed them to undertake this research in vulnerable patients. Written informed consent was obtained from the patient once the initial emergency had passed if they had regained capacity.
 

Rationale and trial findings

“It’s very well established that early bystander CPR [cardiopulmonary resuscitation], early defibrillation, and advanced in-hospital care improves survival,” Dr. Redwood noted. “Despite this, only 1 in 10 survive to leave the hospital.”

Therefore, “a cardiac arrest center has been proposed as a way of improving outcome.” These centers have a catheterization laboratory, open 24 hours a day, 7 days a week, advanced critical care including advanced ventilation, temperature management of the patient, hemodynamic support, and neuroprognostication and rehab “because often these patients will have brain injury.

“There’s quite overwhelming registry data to suggest that these cardiac arrest centers improve outcome,” he said, “but these are limited by bias.”

Between January 2018 and December 2022, London Ambulance paramedics randomly assigned 862 patients who were successfully resuscitated and without a confirmed MI to be transported the nearest hospital emergency department or the catheterization laboratory in a cardiac arrest center.

Data were available for 822 participants. They had a mean age of 63 years, and 68% were male.

The primary endpoint, 30-day mortality, occurred in 258 (63%) of 411 participants in the cardiac arrest center group and in 258 (63%) of 412 in the standard care group (unadjusted risk ratio for survival, 1.00; 95% confidence interval [CI], 0.90-1.11; P = 0.96).

Mortality at 3 months was similar in both groups: 64% in the standard care group and 65% in the cardiac arrest center group.

Neurologic outcomes at discharge and 3 months were similar in both groups.

Eight (2%) of 414 patients in the cardiac arrest center group and three (1%) of 413 in the standard care group had serious adverse events, none of which were deemed related to the trial intervention.

A cardiac cause of arrest was identified in roughly 60% of patients in each group, and of these, roughly 42% were coronary causes, 33% were arrhythmia, and 17% were cardiomyopathy.

The median time from cardiac arrest to hospital arrival was 84 minutes in the cardiac arrest center group and 77 minutes in the standard care group.
 

“Surprising and important RCT evidence”

In an accompanying editorial, Carolina Malta Hansen, MD, PhD, University of Copenhagen, and colleagues wrote that “this study provides randomized trial evidence that in urban settings such as London, there is no survival advantage of a strategy of transporting patients who have been resuscitated to centres with specialty expertise in care of cardiac arrest.
“This result is surprising and important, since this complex and critically ill population would be expected to benefit from centres with more expertise.”

However, “it would be a mistake to conclude that the trial results apply to regions where local hospitals provide a lower quality of care than those in this trial,” they cautioned.

“Where does this leave the medical community, researchers, and society in general?” they asked rhetorically. “Prioritising a minimum standard of care at local hospitals caring for this population is at least as important as ensuring high-quality care or advanced treatment at tertiary centres.

“This trial also calls for more focus on the basics, including efforts to increase bystander cardiopulmonary resuscitation and early defibrillation, aspects of care that are currently being assessed in two ongoing clinical trials (NCT04660526 and NCT03835403) and are most strongly associated with improved survival, when coupled with high-quality prehospital care with trained staff and short response times,” they concluded.

The study was fully funded by the British Heart Foundation. The authors reported that they have no relevant financial disclosures. The financial disclosures of the editorialists are listed with the editorial.

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

A new trial testing perioperative treatment with colchicine has shown no significant benefit on the co-primary outcomes of clinically important atrial fibrillation (AFib) or myocardial injury after noncardiac surgery (MINS) in patients undergoing thoracic surgery.

Trends were seen with reductions in events, but these did not reach significance. However, benefit was seen in a post-hoc analysis looking at a composite of both of those endpoints, the researchers note, as well as a composite of vascular death, nonfatal MINS, nonfatal stroke, and clinically important perioperative AFib, the researchers report.

“We interpret that as there is a trend that is promising, a trend that needs to be further explored,” lead author David Conen, MD, Population Health Research Institute, Hamilton, Ont., said in an interview. “We think that further studies are needed to tease out which patients can benefit from colchicine and in what setting it can be used.”

Treatment was safe, with no effect on the risk for sepsis or infection, but it did cause an increase in noninfectious diarrhea. “These events were mostly benign and did not increase length of stay, and only one patient was readmitted because of diarrhea,” Dr. Conen noted.

Results of the COP-AF trial were presented at the annual congress of the European Society of Cardiology, Amsterdam, and published online  in The Lancet .
 

Inflammation and perioperative AFib

AFib and MINS are common complications in patients undergoing major thoracic surgery, Dr. Conen explained. The literature suggests AFib occurs in about 10% and MINS in about 20% of these patients, “and patients with these complications have a much higher risk of additional complications, such as stroke or MI [myocardial infarction],” Dr. Conen said.

Both disorders are associated with high levels of inflammatory biomarkers, so they set out to test colchicine, a well-known anti-inflammatory drug used in higher doses to treat common clinical disorders, such as gout and pericarditis. Small, randomized trials had shown it reduced the incidence of perioperative AFib after cardiac surgery, he noted.

Low-dose colchicine (LoDoCo, Agepha Pharma) was recently approved by the U.S. Food and Drug Administration to reduce the risk for MI, stroke, coronary revascularization, or death in patients with established atherosclerotic disease or multiple risk factors for cardiovascular disease. It was approved on the basis of the LoDoCo 2 trial in patients with stable coronary artery disease and the COLCOT trial in patients with recent MI.

COP-AF was a randomized trial, conducted at 45 sites in 11 countries, and enrolled 3,209 patients aged 55 years or older (51.6% male) undergoing major noncardiac thoracic surgery. Patients were excluded if they had previous AFib, had any contraindications to colchicine, or required colchicine on a clinical basis.

Patients were randomly assigned 1:1 to receive oral colchicine at a dose of 0.5 mg twice daily (1,608 patients) or placebo (1,601 patients). Treatment was begun within 4 hours before surgery and continued for 10 days. Health care providers and patients, as well as data collectors and adjudicators, were blinded to treatment assignment.

The co-primary outcomes were clinically important perioperative AFib or MINS over 14 days of follow-up. The trial was originally looking only at clinically important AFib, Dr. Conen noted, but after the publication of LoDoCo 2 and COLCOT, “MINS was added as an independent co-primary outcome,” requiring more patients to achieve adequate power.

The main safety outcomes were a composite of sepsis or infection, along with noninfectious diarrhea.

Clinically important AFib was defined as AFib that results in angina, heart failure, or symptomatic hypotension or required treatment with a rate-controlling drug, antiarrhythmic drug, or electrical cardioversion. “This definition was chosen because of its prognostic relevance, and to avoid adding short, asymptomatic AFib episodes of uncertain clinical relevance to the primary outcome,” Dr. Conen said during his presentation.

MINS was defined as an MI or any postoperative troponin elevation that was judged by an adjudication panel to be of ischemic origin.

At 14 days, there was no significant difference between groups on either of the co-primary end points.

Low-risk patients

Jean-Claude Tardif, MD, Montreal Heart Institute and Université de Montréal, was the invited discussant for the COP-AF presentation and congratulated the researchers on “a job well done.”

He made the point that the risk for perioperative AFib has decreased substantially with the greater use of thoracoscopic rather than open surgical approaches. The population of this trial was relatively young, with an average age of 68 years; the presence of concomitant CVD was low, at about 9%; by design, patients with previous AFib were excluded; and only about 20% of patients had surgery with an open approach.

“So that population of patients were probably at relatively low risk of atrial fibrillation, and sure enough, the incidence of perioperative AFib in that population at 7.5% was lower than the assumed rate in the statistical powering of the study at 9%,” Dr. Tardif noted.

The post-hoc analyses showed a “nominally significant effect on the composite of MINS and AFib; however, that combination is fairly difficult to justify given the different pathophysiology and clinical consequences of both outcomes,” he pointed out.

The incidence of postoperative MI as a secondary outcome was low, less than 1%, as was the incidence of postoperative stroke in that study, Dr. Tardif added. “Given the link between presence of blood in the pericardium as a trigger for AFib, it would be interesting to know the incidence of perioperative pericarditis in COP-AF.”

In conclusion, he said, “when trying to put these results into the bigger picture of colchicine in cardiovascular disease, I believe we need large, well-powered clinical trials to determine the value of colchicine to reduce the risk of AFib after cardiac surgery and after catheter ablation,” Dr. Tardif said.

“We all know that colchicine represents the first line of therapy for the treatment of acute and recurrent pericarditis, and finally, low-dose colchicine, at a lower dose than was used in COP-AF, 0.5 mg once daily, is the first anti-inflammatory agent approved by both U.S. FDA and Health Canada to reduce the risk of atherothombotic events in patients with ASCVD [atherosclerotic cardiovascular disease], I believe offering a new pillar of treatment for the prevention of ischemic events in such patients.”

Session co-moderator Franz Weidinger, MD, Landstrasse Clinic, Vienna, Austria, called the COP-AF results “very important” but also noted that they show “the challenge of doing well-powered randomized trials these days when we have patients so well treated for a wide array of cardiovascular disease.”

The study was supported by the Canadian Institutes of Health Research (CIHR); Accelerating Clinical Trials Consortium; Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario; Population Health Research Institute; Hamilton Health Sciences; Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong. Dr. Conen reports receiving research grants from CIHR, speaker fees from Servier outside the current study, and advisory board fees from Roche Diagnostics and Trimedics outside the current study.

A version of this article appeared on Medscape.com.

A new trial testing perioperative treatment with colchicine has shown no significant benefit on the co-primary outcomes of clinically important atrial fibrillation (AFib) or myocardial injury after noncardiac surgery (MINS) in patients undergoing thoracic surgery.

Trends were seen with reductions in events, but these did not reach significance. However, benefit was seen in a post-hoc analysis looking at a composite of both of those endpoints, the researchers note, as well as a composite of vascular death, nonfatal MINS, nonfatal stroke, and clinically important perioperative AFib, the researchers report.

“We interpret that as there is a trend that is promising, a trend that needs to be further explored,” lead author David Conen, MD, Population Health Research Institute, Hamilton, Ont., said in an interview. “We think that further studies are needed to tease out which patients can benefit from colchicine and in what setting it can be used.”

Treatment was safe, with no effect on the risk for sepsis or infection, but it did cause an increase in noninfectious diarrhea. “These events were mostly benign and did not increase length of stay, and only one patient was readmitted because of diarrhea,” Dr. Conen noted.

Results of the COP-AF trial were presented at the annual congress of the European Society of Cardiology, Amsterdam, and published online  in The Lancet .
 

Inflammation and perioperative AFib

AFib and MINS are common complications in patients undergoing major thoracic surgery, Dr. Conen explained. The literature suggests AFib occurs in about 10% and MINS in about 20% of these patients, “and patients with these complications have a much higher risk of additional complications, such as stroke or MI [myocardial infarction],” Dr. Conen said.

Both disorders are associated with high levels of inflammatory biomarkers, so they set out to test colchicine, a well-known anti-inflammatory drug used in higher doses to treat common clinical disorders, such as gout and pericarditis. Small, randomized trials had shown it reduced the incidence of perioperative AFib after cardiac surgery, he noted.

Low-dose colchicine (LoDoCo, Agepha Pharma) was recently approved by the U.S. Food and Drug Administration to reduce the risk for MI, stroke, coronary revascularization, or death in patients with established atherosclerotic disease or multiple risk factors for cardiovascular disease. It was approved on the basis of the LoDoCo 2 trial in patients with stable coronary artery disease and the COLCOT trial in patients with recent MI.

COP-AF was a randomized trial, conducted at 45 sites in 11 countries, and enrolled 3,209 patients aged 55 years or older (51.6% male) undergoing major noncardiac thoracic surgery. Patients were excluded if they had previous AFib, had any contraindications to colchicine, or required colchicine on a clinical basis.

Patients were randomly assigned 1:1 to receive oral colchicine at a dose of 0.5 mg twice daily (1,608 patients) or placebo (1,601 patients). Treatment was begun within 4 hours before surgery and continued for 10 days. Health care providers and patients, as well as data collectors and adjudicators, were blinded to treatment assignment.

The co-primary outcomes were clinically important perioperative AFib or MINS over 14 days of follow-up. The trial was originally looking only at clinically important AFib, Dr. Conen noted, but after the publication of LoDoCo 2 and COLCOT, “MINS was added as an independent co-primary outcome,” requiring more patients to achieve adequate power.

The main safety outcomes were a composite of sepsis or infection, along with noninfectious diarrhea.

Clinically important AFib was defined as AFib that results in angina, heart failure, or symptomatic hypotension or required treatment with a rate-controlling drug, antiarrhythmic drug, or electrical cardioversion. “This definition was chosen because of its prognostic relevance, and to avoid adding short, asymptomatic AFib episodes of uncertain clinical relevance to the primary outcome,” Dr. Conen said during his presentation.

MINS was defined as an MI or any postoperative troponin elevation that was judged by an adjudication panel to be of ischemic origin.

At 14 days, there was no significant difference between groups on either of the co-primary end points.

Low-risk patients

Jean-Claude Tardif, MD, Montreal Heart Institute and Université de Montréal, was the invited discussant for the COP-AF presentation and congratulated the researchers on “a job well done.”

He made the point that the risk for perioperative AFib has decreased substantially with the greater use of thoracoscopic rather than open surgical approaches. The population of this trial was relatively young, with an average age of 68 years; the presence of concomitant CVD was low, at about 9%; by design, patients with previous AFib were excluded; and only about 20% of patients had surgery with an open approach.

“So that population of patients were probably at relatively low risk of atrial fibrillation, and sure enough, the incidence of perioperative AFib in that population at 7.5% was lower than the assumed rate in the statistical powering of the study at 9%,” Dr. Tardif noted.

The post-hoc analyses showed a “nominally significant effect on the composite of MINS and AFib; however, that combination is fairly difficult to justify given the different pathophysiology and clinical consequences of both outcomes,” he pointed out.

The incidence of postoperative MI as a secondary outcome was low, less than 1%, as was the incidence of postoperative stroke in that study, Dr. Tardif added. “Given the link between presence of blood in the pericardium as a trigger for AFib, it would be interesting to know the incidence of perioperative pericarditis in COP-AF.”

In conclusion, he said, “when trying to put these results into the bigger picture of colchicine in cardiovascular disease, I believe we need large, well-powered clinical trials to determine the value of colchicine to reduce the risk of AFib after cardiac surgery and after catheter ablation,” Dr. Tardif said.

“We all know that colchicine represents the first line of therapy for the treatment of acute and recurrent pericarditis, and finally, low-dose colchicine, at a lower dose than was used in COP-AF, 0.5 mg once daily, is the first anti-inflammatory agent approved by both U.S. FDA and Health Canada to reduce the risk of atherothombotic events in patients with ASCVD [atherosclerotic cardiovascular disease], I believe offering a new pillar of treatment for the prevention of ischemic events in such patients.”

Session co-moderator Franz Weidinger, MD, Landstrasse Clinic, Vienna, Austria, called the COP-AF results “very important” but also noted that they show “the challenge of doing well-powered randomized trials these days when we have patients so well treated for a wide array of cardiovascular disease.”

The study was supported by the Canadian Institutes of Health Research (CIHR); Accelerating Clinical Trials Consortium; Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario; Population Health Research Institute; Hamilton Health Sciences; Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong. Dr. Conen reports receiving research grants from CIHR, speaker fees from Servier outside the current study, and advisory board fees from Roche Diagnostics and Trimedics outside the current study.

A version of this article appeared on Medscape.com.

A new trial testing perioperative treatment with colchicine has shown no significant benefit on the co-primary outcomes of clinically important atrial fibrillation (AFib) or myocardial injury after noncardiac surgery (MINS) in patients undergoing thoracic surgery.

Trends were seen with reductions in events, but these did not reach significance. However, benefit was seen in a post-hoc analysis looking at a composite of both of those endpoints, the researchers note, as well as a composite of vascular death, nonfatal MINS, nonfatal stroke, and clinically important perioperative AFib, the researchers report.

“We interpret that as there is a trend that is promising, a trend that needs to be further explored,” lead author David Conen, MD, Population Health Research Institute, Hamilton, Ont., said in an interview. “We think that further studies are needed to tease out which patients can benefit from colchicine and in what setting it can be used.”

Treatment was safe, with no effect on the risk for sepsis or infection, but it did cause an increase in noninfectious diarrhea. “These events were mostly benign and did not increase length of stay, and only one patient was readmitted because of diarrhea,” Dr. Conen noted.

Results of the COP-AF trial were presented at the annual congress of the European Society of Cardiology, Amsterdam, and published online  in The Lancet .
 

Inflammation and perioperative AFib

AFib and MINS are common complications in patients undergoing major thoracic surgery, Dr. Conen explained. The literature suggests AFib occurs in about 10% and MINS in about 20% of these patients, “and patients with these complications have a much higher risk of additional complications, such as stroke or MI [myocardial infarction],” Dr. Conen said.

Both disorders are associated with high levels of inflammatory biomarkers, so they set out to test colchicine, a well-known anti-inflammatory drug used in higher doses to treat common clinical disorders, such as gout and pericarditis. Small, randomized trials had shown it reduced the incidence of perioperative AFib after cardiac surgery, he noted.

Low-dose colchicine (LoDoCo, Agepha Pharma) was recently approved by the U.S. Food and Drug Administration to reduce the risk for MI, stroke, coronary revascularization, or death in patients with established atherosclerotic disease or multiple risk factors for cardiovascular disease. It was approved on the basis of the LoDoCo 2 trial in patients with stable coronary artery disease and the COLCOT trial in patients with recent MI.

COP-AF was a randomized trial, conducted at 45 sites in 11 countries, and enrolled 3,209 patients aged 55 years or older (51.6% male) undergoing major noncardiac thoracic surgery. Patients were excluded if they had previous AFib, had any contraindications to colchicine, or required colchicine on a clinical basis.

Patients were randomly assigned 1:1 to receive oral colchicine at a dose of 0.5 mg twice daily (1,608 patients) or placebo (1,601 patients). Treatment was begun within 4 hours before surgery and continued for 10 days. Health care providers and patients, as well as data collectors and adjudicators, were blinded to treatment assignment.

The co-primary outcomes were clinically important perioperative AFib or MINS over 14 days of follow-up. The trial was originally looking only at clinically important AFib, Dr. Conen noted, but after the publication of LoDoCo 2 and COLCOT, “MINS was added as an independent co-primary outcome,” requiring more patients to achieve adequate power.

The main safety outcomes were a composite of sepsis or infection, along with noninfectious diarrhea.

Clinically important AFib was defined as AFib that results in angina, heart failure, or symptomatic hypotension or required treatment with a rate-controlling drug, antiarrhythmic drug, or electrical cardioversion. “This definition was chosen because of its prognostic relevance, and to avoid adding short, asymptomatic AFib episodes of uncertain clinical relevance to the primary outcome,” Dr. Conen said during his presentation.

MINS was defined as an MI or any postoperative troponin elevation that was judged by an adjudication panel to be of ischemic origin.

At 14 days, there was no significant difference between groups on either of the co-primary end points.

Low-risk patients

Jean-Claude Tardif, MD, Montreal Heart Institute and Université de Montréal, was the invited discussant for the COP-AF presentation and congratulated the researchers on “a job well done.”

He made the point that the risk for perioperative AFib has decreased substantially with the greater use of thoracoscopic rather than open surgical approaches. The population of this trial was relatively young, with an average age of 68 years; the presence of concomitant CVD was low, at about 9%; by design, patients with previous AFib were excluded; and only about 20% of patients had surgery with an open approach.

“So that population of patients were probably at relatively low risk of atrial fibrillation, and sure enough, the incidence of perioperative AFib in that population at 7.5% was lower than the assumed rate in the statistical powering of the study at 9%,” Dr. Tardif noted.

The post-hoc analyses showed a “nominally significant effect on the composite of MINS and AFib; however, that combination is fairly difficult to justify given the different pathophysiology and clinical consequences of both outcomes,” he pointed out.

The incidence of postoperative MI as a secondary outcome was low, less than 1%, as was the incidence of postoperative stroke in that study, Dr. Tardif added. “Given the link between presence of blood in the pericardium as a trigger for AFib, it would be interesting to know the incidence of perioperative pericarditis in COP-AF.”

In conclusion, he said, “when trying to put these results into the bigger picture of colchicine in cardiovascular disease, I believe we need large, well-powered clinical trials to determine the value of colchicine to reduce the risk of AFib after cardiac surgery and after catheter ablation,” Dr. Tardif said.

“We all know that colchicine represents the first line of therapy for the treatment of acute and recurrent pericarditis, and finally, low-dose colchicine, at a lower dose than was used in COP-AF, 0.5 mg once daily, is the first anti-inflammatory agent approved by both U.S. FDA and Health Canada to reduce the risk of atherothombotic events in patients with ASCVD [atherosclerotic cardiovascular disease], I believe offering a new pillar of treatment for the prevention of ischemic events in such patients.”

Session co-moderator Franz Weidinger, MD, Landstrasse Clinic, Vienna, Austria, called the COP-AF results “very important” but also noted that they show “the challenge of doing well-powered randomized trials these days when we have patients so well treated for a wide array of cardiovascular disease.”

The study was supported by the Canadian Institutes of Health Research (CIHR); Accelerating Clinical Trials Consortium; Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario; Population Health Research Institute; Hamilton Health Sciences; Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong. Dr. Conen reports receiving research grants from CIHR, speaker fees from Servier outside the current study, and advisory board fees from Roche Diagnostics and Trimedics outside the current study.

A version of this article appeared on Medscape.com.