A majority of Mohs surgeons have adopted telemedicine during the COVID-19 pandemic, a new survey finds, but only half expressed interest in making it a permanent part of their practices.

A variety of factors combine to make it “very difficult for surgeons to make long-term plans for implementing telemedicine in their practices,” said Mario Maruthur, MD, who presented the findings at the annual meeting of the American College of Mohs Surgery. “Telemedicine likely has a role in Mohs practices, particularly with postop follow-up visits. However, postpandemic reimbursement and regulatory issues need to be formally laid out before Mohs surgeons are able to incorporate it into their permanent work flow.”

Dr. Maruthur, a Mohs surgery and dermatologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues sent a survey to ACMS members in September and October 2020. “We saw first-hand in our surgical practice that telemedicine quickly became an important tool when the pandemic surged in the spring of 2020,” he said. Considering that surgical practices are highly dependent on in-person visits, the impetus for this study was to assess to what degree Mohs practices from across the spectrum, including academic and private practices, embraced telemedicine during the pandemic, and “what these surgical practices used telemedicine for, how it was received by their patients, which telemedicine platforms were most often utilized, and lastly, what are their plans if any for incorporating telemedicine into their surgical practices after the pandemic subsides.”

The researchers received responses from 115 surgeons representing all regions of the country (40% Northeast, 21% South, 21% Midwest, and 18% West). Half practiced in urban areas (37%) and large cities (13%), and 40% were in an academic setting versus 36% in a single-specialty private practice.

More than 70% of the respondents said their case load fell by at least 75% during the initial surge of the pandemic; 80% turned to telemedicine, compared with just 23% who relied on the technology prior to the pandemic. The most commonly used telemedicine technologies were FaceTime, Zoom, Doximity, and Epic.

Mohs surgeons reported most commonly using telemedicine for postsurgery management (77% of the total 115 responses). “Telemedicine is a great fit for this category of visits as they allow the surgeon to view the surgical site and answer any questions they patient may have,” Dr. Maruthur said. “If the surgeon does suspect a postop infection or other concern based on a patient’s signs or symptoms, they can easily schedule the patient for an in-person assessment. We suspect that postop follow-up visits may be the best candidate for long-term use of telemedicine in Mohs surgery practices.”

Surgeons also reported using telemedicine for “spot checks” (61%) and surgical consultations (59%).

However, Dr. Maruther noted that preoperative assessments and spot checks can be difficult to perform using telemedicine. “The quality of the video image is not always great, patients can have a difficult time pointing the camera at the right spot and at the right distance. Even appreciating the actual size of the lesion are all difficult over a video encounter. And there is a lot of information gleaned from in-person physical examination, such as whether the lesion is fixed to a deeper structure and whether there are any nearby scars or other suspicious lesions.”

Nearly three-quarters of the surgeons using the technology said most or all patients were receptive to telemedicine.

However, the surgeons reported multiple barriers to the use of telemedicine: Limitations when compared with physical exams (88%), fitting it into the work flow (58%), patient response and training (57%), reimbursement concerns (50%), implementation of the technology (37%), regulations such as HIPAA (24%), training of staff (17%), and licensing (8%).

In an interview, Sumaira Z. Aasi, MD, director of Mohs and dermatologic surgery, Stanford University, agreed that there are many obstacles to routine use of telemedicine by Mohs surgeons. “As surgeons, we rely on the physical and tactile exam to get a sense of the size and extent of the cancer and characteristics such as the laxity of the surrounding tissue whether the tumor is fixed,” she said. “It is very difficult to access this on a telemedicine visit.”

In addition, she said, “many of our patients are in the elderly population, and some may not be comfortable using this technology. Also, it’s not a work flow that we are comfortable or familiar with. And I think that the technology has to improve to allow for better resolution of images as we ‘examine’ patients through a telemedicine visit.”

She added that “another con is there is a reliance on having the patient point out lesions of concern. Many cancers are picked by a careful in-person examination by a qualified physician/dermatologist/Mohs surgeon when the lesion is quite small or subtle and not even noticed by the patient themselves. This approach invariably leads to earlier biopsies and earlier treatments that can prevent morbidity and save health care money.”

On the other hand, she said, telemedicine “may save patients some time and money in terms of the effort and cost of transportation to come in for simpler postoperative medical visits that are often short in their very nature, such as postop check-ups.”

Most of the surgeons surveyed (69%) said telemedicine probably or definitely deserves a place in the practice Mohs surgery, but only 50% said they’d like to or would definitely pursue giving telemedicine a role in their practices once the pandemic is over.

“At the start of the pandemic, many regulations in areas such as HIPAA were eased, and reimbursements were increased, which allowed telemedicine to be quickly adopted,” Dr. Maruther said. “The government and payers have yet to decide which regulations and reimbursements will be in place after the pandemic. That makes it very difficult for surgeons to make long-term plans for implementing telemedicine in their practices.”

Dr. Aasi predicted that telemedicine will become more appealing to patients and physicians as it its technology and usability improves. More familiarity with its use will also be helpful, she said, and surgeons will be more receptive as it’s incorporated into efficient daily work flow.

The study was funded in part by the National Institutes of Health.

A majority of Mohs surgeons have adopted telemedicine during the COVID-19 pandemic, a new survey finds, but only half expressed interest in making it a permanent part of their practices.

A variety of factors combine to make it “very difficult for surgeons to make long-term plans for implementing telemedicine in their practices,” said Mario Maruthur, MD, who presented the findings at the annual meeting of the American College of Mohs Surgery. “Telemedicine likely has a role in Mohs practices, particularly with postop follow-up visits. However, postpandemic reimbursement and regulatory issues need to be formally laid out before Mohs surgeons are able to incorporate it into their permanent work flow.”

Dr. Maruthur, a Mohs surgery and dermatologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues sent a survey to ACMS members in September and October 2020. “We saw first-hand in our surgical practice that telemedicine quickly became an important tool when the pandemic surged in the spring of 2020,” he said. Considering that surgical practices are highly dependent on in-person visits, the impetus for this study was to assess to what degree Mohs practices from across the spectrum, including academic and private practices, embraced telemedicine during the pandemic, and “what these surgical practices used telemedicine for, how it was received by their patients, which telemedicine platforms were most often utilized, and lastly, what are their plans if any for incorporating telemedicine into their surgical practices after the pandemic subsides.”

The researchers received responses from 115 surgeons representing all regions of the country (40% Northeast, 21% South, 21% Midwest, and 18% West). Half practiced in urban areas (37%) and large cities (13%), and 40% were in an academic setting versus 36% in a single-specialty private practice.

More than 70% of the respondents said their case load fell by at least 75% during the initial surge of the pandemic; 80% turned to telemedicine, compared with just 23% who relied on the technology prior to the pandemic. The most commonly used telemedicine technologies were FaceTime, Zoom, Doximity, and Epic.

Mohs surgeons reported most commonly using telemedicine for postsurgery management (77% of the total 115 responses). “Telemedicine is a great fit for this category of visits as they allow the surgeon to view the surgical site and answer any questions they patient may have,” Dr. Maruthur said. “If the surgeon does suspect a postop infection or other concern based on a patient’s signs or symptoms, they can easily schedule the patient for an in-person assessment. We suspect that postop follow-up visits may be the best candidate for long-term use of telemedicine in Mohs surgery practices.”

Surgeons also reported using telemedicine for “spot checks” (61%) and surgical consultations (59%).

However, Dr. Maruther noted that preoperative assessments and spot checks can be difficult to perform using telemedicine. “The quality of the video image is not always great, patients can have a difficult time pointing the camera at the right spot and at the right distance. Even appreciating the actual size of the lesion are all difficult over a video encounter. And there is a lot of information gleaned from in-person physical examination, such as whether the lesion is fixed to a deeper structure and whether there are any nearby scars or other suspicious lesions.”

Nearly three-quarters of the surgeons using the technology said most or all patients were receptive to telemedicine.

However, the surgeons reported multiple barriers to the use of telemedicine: Limitations when compared with physical exams (88%), fitting it into the work flow (58%), patient response and training (57%), reimbursement concerns (50%), implementation of the technology (37%), regulations such as HIPAA (24%), training of staff (17%), and licensing (8%).

In an interview, Sumaira Z. Aasi, MD, director of Mohs and dermatologic surgery, Stanford University, agreed that there are many obstacles to routine use of telemedicine by Mohs surgeons. “As surgeons, we rely on the physical and tactile exam to get a sense of the size and extent of the cancer and characteristics such as the laxity of the surrounding tissue whether the tumor is fixed,” she said. “It is very difficult to access this on a telemedicine visit.”

In addition, she said, “many of our patients are in the elderly population, and some may not be comfortable using this technology. Also, it’s not a work flow that we are comfortable or familiar with. And I think that the technology has to improve to allow for better resolution of images as we ‘examine’ patients through a telemedicine visit.”

She added that “another con is there is a reliance on having the patient point out lesions of concern. Many cancers are picked by a careful in-person examination by a qualified physician/dermatologist/Mohs surgeon when the lesion is quite small or subtle and not even noticed by the patient themselves. This approach invariably leads to earlier biopsies and earlier treatments that can prevent morbidity and save health care money.”

On the other hand, she said, telemedicine “may save patients some time and money in terms of the effort and cost of transportation to come in for simpler postoperative medical visits that are often short in their very nature, such as postop check-ups.”

Most of the surgeons surveyed (69%) said telemedicine probably or definitely deserves a place in the practice Mohs surgery, but only 50% said they’d like to or would definitely pursue giving telemedicine a role in their practices once the pandemic is over.

“At the start of the pandemic, many regulations in areas such as HIPAA were eased, and reimbursements were increased, which allowed telemedicine to be quickly adopted,” Dr. Maruther said. “The government and payers have yet to decide which regulations and reimbursements will be in place after the pandemic. That makes it very difficult for surgeons to make long-term plans for implementing telemedicine in their practices.”

Dr. Aasi predicted that telemedicine will become more appealing to patients and physicians as it its technology and usability improves. More familiarity with its use will also be helpful, she said, and surgeons will be more receptive as it’s incorporated into efficient daily work flow.

The study was funded in part by the National Institutes of Health.

A majority of Mohs surgeons have adopted telemedicine during the COVID-19 pandemic, a new survey finds, but only half expressed interest in making it a permanent part of their practices.

A variety of factors combine to make it “very difficult for surgeons to make long-term plans for implementing telemedicine in their practices,” said Mario Maruthur, MD, who presented the findings at the annual meeting of the American College of Mohs Surgery. “Telemedicine likely has a role in Mohs practices, particularly with postop follow-up visits. However, postpandemic reimbursement and regulatory issues need to be formally laid out before Mohs surgeons are able to incorporate it into their permanent work flow.”

Dr. Maruthur, a Mohs surgery and dermatologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues sent a survey to ACMS members in September and October 2020. “We saw first-hand in our surgical practice that telemedicine quickly became an important tool when the pandemic surged in the spring of 2020,” he said. Considering that surgical practices are highly dependent on in-person visits, the impetus for this study was to assess to what degree Mohs practices from across the spectrum, including academic and private practices, embraced telemedicine during the pandemic, and “what these surgical practices used telemedicine for, how it was received by their patients, which telemedicine platforms were most often utilized, and lastly, what are their plans if any for incorporating telemedicine into their surgical practices after the pandemic subsides.”

The researchers received responses from 115 surgeons representing all regions of the country (40% Northeast, 21% South, 21% Midwest, and 18% West). Half practiced in urban areas (37%) and large cities (13%), and 40% were in an academic setting versus 36% in a single-specialty private practice.

More than 70% of the respondents said their case load fell by at least 75% during the initial surge of the pandemic; 80% turned to telemedicine, compared with just 23% who relied on the technology prior to the pandemic. The most commonly used telemedicine technologies were FaceTime, Zoom, Doximity, and Epic.

Mohs surgeons reported most commonly using telemedicine for postsurgery management (77% of the total 115 responses). “Telemedicine is a great fit for this category of visits as they allow the surgeon to view the surgical site and answer any questions they patient may have,” Dr. Maruthur said. “If the surgeon does suspect a postop infection or other concern based on a patient’s signs or symptoms, they can easily schedule the patient for an in-person assessment. We suspect that postop follow-up visits may be the best candidate for long-term use of telemedicine in Mohs surgery practices.”

Surgeons also reported using telemedicine for “spot checks” (61%) and surgical consultations (59%).

However, Dr. Maruther noted that preoperative assessments and spot checks can be difficult to perform using telemedicine. “The quality of the video image is not always great, patients can have a difficult time pointing the camera at the right spot and at the right distance. Even appreciating the actual size of the lesion are all difficult over a video encounter. And there is a lot of information gleaned from in-person physical examination, such as whether the lesion is fixed to a deeper structure and whether there are any nearby scars or other suspicious lesions.”

Nearly three-quarters of the surgeons using the technology said most or all patients were receptive to telemedicine.

However, the surgeons reported multiple barriers to the use of telemedicine: Limitations when compared with physical exams (88%), fitting it into the work flow (58%), patient response and training (57%), reimbursement concerns (50%), implementation of the technology (37%), regulations such as HIPAA (24%), training of staff (17%), and licensing (8%).

In an interview, Sumaira Z. Aasi, MD, director of Mohs and dermatologic surgery, Stanford University, agreed that there are many obstacles to routine use of telemedicine by Mohs surgeons. “As surgeons, we rely on the physical and tactile exam to get a sense of the size and extent of the cancer and characteristics such as the laxity of the surrounding tissue whether the tumor is fixed,” she said. “It is very difficult to access this on a telemedicine visit.”

In addition, she said, “many of our patients are in the elderly population, and some may not be comfortable using this technology. Also, it’s not a work flow that we are comfortable or familiar with. And I think that the technology has to improve to allow for better resolution of images as we ‘examine’ patients through a telemedicine visit.”

She added that “another con is there is a reliance on having the patient point out lesions of concern. Many cancers are picked by a careful in-person examination by a qualified physician/dermatologist/Mohs surgeon when the lesion is quite small or subtle and not even noticed by the patient themselves. This approach invariably leads to earlier biopsies and earlier treatments that can prevent morbidity and save health care money.”

On the other hand, she said, telemedicine “may save patients some time and money in terms of the effort and cost of transportation to come in for simpler postoperative medical visits that are often short in their very nature, such as postop check-ups.”

Most of the surgeons surveyed (69%) said telemedicine probably or definitely deserves a place in the practice Mohs surgery, but only 50% said they’d like to or would definitely pursue giving telemedicine a role in their practices once the pandemic is over.

“At the start of the pandemic, many regulations in areas such as HIPAA were eased, and reimbursements were increased, which allowed telemedicine to be quickly adopted,” Dr. Maruther said. “The government and payers have yet to decide which regulations and reimbursements will be in place after the pandemic. That makes it very difficult for surgeons to make long-term plans for implementing telemedicine in their practices.”

Dr. Aasi predicted that telemedicine will become more appealing to patients and physicians as it its technology and usability improves. More familiarity with its use will also be helpful, she said, and surgeons will be more receptive as it’s incorporated into efficient daily work flow.

The study was funded in part by the National Institutes of Health.

The average income for pediatricians declined slightly from 2019 to 2020, according to the Medscape Pediatrician Compensation Report 2021.

The report, which was conducted between October 2020 and February 2021, found that the average pediatrician income was down $11,000 – from $232,000 in 2019 to $221,000 in 2020, with 48% of pediatricians reporting at least some decline in compensation.

The specialty also earned the least amount of money in 2020, compared with all of the other specialties, which isn’t surprising since pediatricians have been among the lowest-paid physician specialties since 2013. The highest-earning specialty was plastic surgery with an average income of $526,000 annually.

Most pediatricians who saw a drop in income cited pandemic-related issues such as job loss, fewer hours, and fewer patients.

Jesse Hackell, MD, vice president and chief operating officer of Ponoma Pediatrics in New York, said in an interview the reduced wages pediatricians saw in 2020 didn’t surprise him because many pediatric offices saw a huge drop in visits that were not urgent.

“[The report] shows that procedural specialties tended to do a lot better than the nonprocedural specialties,” Dr. Hackell said. “That’s because, during the shutdown, if you broke your leg, you still needed the orthopedist. And even though the hospitals weren’t doing elective surgeries, they were certainly doing the emergency stuff.”

Meanwhile, in pediatrician offices, where Dr. Hackell said office visits dropped 70%-80% at the beginning of the pandemic, “parents weren’t going to bring a healthy kid out for routine visits and they weren’t going to bring a kid out for minor illnesses and expose them to possibly communicable diseases in the office.”

About 52% of pediatricians who lost income because of the pandemic believe their income levels will return to normal in 2-3 years. Meanwhile 30% of pediatricians expect their income to return to normal within a year, and 8% believe it will take 4 years for them to bounce back.

Physician work hours generally declined for some time during the pandemic, according to the report. However, most pediatricians are working about the same number of hours as they did before the pandemic, which is 47 hours per week.

Despite working the same number of hours per week that they did prepandemic, they are seeing fewer patients. They are currently seeing on average 64 patients per week, compared with the 78 patients they used to see weekly before the pandemic.

Dr. Hackell said that might be because pediatric offices are trying to make up the loss of revenue during the beginning of the pandemic, from the reduced number of well visits and immunizations, in the second half of the year with outreach.

“Since about June 2020, we’ve been making concerted efforts to remind parents that preventing other infectious diseases is critically important,” Dr. Hackell explained. “And so actually, for the second half of the year, many of us saw more well visits and immunization volume than in 2019 as we sought to make up the gap. It wasn’t that we were seeing more overall, but we’re trying to make up the gap that happened from March, April, May, [and] June.”

Most pediatricians find their work rewarding. One-third say the most rewarding part of their job is gratitude from and relationships with their patients. Meanwhile, 31% of pediatricians said knowing they are making the world a better place was a rewarding part of their job. Only 8% of them said making money was a rewarding part of their job.

Dr. Hackell said he did not go into pediatrics to make money, it was because he found it stimulating and has “no complaints.”

“I’ve been a pediatrician for 40 years and I wouldn’t do anything else,” Dr. Hackell said. “I don’t know that there’s anything that I would find as rewarding as the relationships that I’ve had over 40 years with my patients. You know, getting invited to weddings of kids who I saw when they were newborns is pretty impressive. It’s the gratification of having ongoing relationships with families.”

Furthermore, the report revealed that 77% of pediatricians said they would pick medicine again if they had a choice, and 82% said they would choose the same specialty.

The experts disclosed no relevant financial interests.

*This story was updated on 5/18/2021.

The average income for pediatricians declined slightly from 2019 to 2020, according to the Medscape Pediatrician Compensation Report 2021.

The report, which was conducted between October 2020 and February 2021, found that the average pediatrician income was down $11,000 – from $232,000 in 2019 to $221,000 in 2020, with 48% of pediatricians reporting at least some decline in compensation.

The specialty also earned the least amount of money in 2020, compared with all of the other specialties, which isn’t surprising since pediatricians have been among the lowest-paid physician specialties since 2013. The highest-earning specialty was plastic surgery with an average income of $526,000 annually.

Most pediatricians who saw a drop in income cited pandemic-related issues such as job loss, fewer hours, and fewer patients.

Jesse Hackell, MD, vice president and chief operating officer of Ponoma Pediatrics in New York, said in an interview the reduced wages pediatricians saw in 2020 didn’t surprise him because many pediatric offices saw a huge drop in visits that were not urgent.

“[The report] shows that procedural specialties tended to do a lot better than the nonprocedural specialties,” Dr. Hackell said. “That’s because, during the shutdown, if you broke your leg, you still needed the orthopedist. And even though the hospitals weren’t doing elective surgeries, they were certainly doing the emergency stuff.”

Meanwhile, in pediatrician offices, where Dr. Hackell said office visits dropped 70%-80% at the beginning of the pandemic, “parents weren’t going to bring a healthy kid out for routine visits and they weren’t going to bring a kid out for minor illnesses and expose them to possibly communicable diseases in the office.”

About 52% of pediatricians who lost income because of the pandemic believe their income levels will return to normal in 2-3 years. Meanwhile 30% of pediatricians expect their income to return to normal within a year, and 8% believe it will take 4 years for them to bounce back.

Physician work hours generally declined for some time during the pandemic, according to the report. However, most pediatricians are working about the same number of hours as they did before the pandemic, which is 47 hours per week.

Despite working the same number of hours per week that they did prepandemic, they are seeing fewer patients. They are currently seeing on average 64 patients per week, compared with the 78 patients they used to see weekly before the pandemic.

Dr. Hackell said that might be because pediatric offices are trying to make up the loss of revenue during the beginning of the pandemic, from the reduced number of well visits and immunizations, in the second half of the year with outreach.

“Since about June 2020, we’ve been making concerted efforts to remind parents that preventing other infectious diseases is critically important,” Dr. Hackell explained. “And so actually, for the second half of the year, many of us saw more well visits and immunization volume than in 2019 as we sought to make up the gap. It wasn’t that we were seeing more overall, but we’re trying to make up the gap that happened from March, April, May, [and] June.”

Most pediatricians find their work rewarding. One-third say the most rewarding part of their job is gratitude from and relationships with their patients. Meanwhile, 31% of pediatricians said knowing they are making the world a better place was a rewarding part of their job. Only 8% of them said making money was a rewarding part of their job.

Dr. Hackell said he did not go into pediatrics to make money, it was because he found it stimulating and has “no complaints.”

“I’ve been a pediatrician for 40 years and I wouldn’t do anything else,” Dr. Hackell said. “I don’t know that there’s anything that I would find as rewarding as the relationships that I’ve had over 40 years with my patients. You know, getting invited to weddings of kids who I saw when they were newborns is pretty impressive. It’s the gratification of having ongoing relationships with families.”

Furthermore, the report revealed that 77% of pediatricians said they would pick medicine again if they had a choice, and 82% said they would choose the same specialty.

The experts disclosed no relevant financial interests.

*This story was updated on 5/18/2021.

The average income for pediatricians declined slightly from 2019 to 2020, according to the Medscape Pediatrician Compensation Report 2021.

The report, which was conducted between October 2020 and February 2021, found that the average pediatrician income was down $11,000 – from $232,000 in 2019 to $221,000 in 2020, with 48% of pediatricians reporting at least some decline in compensation.

The specialty also earned the least amount of money in 2020, compared with all of the other specialties, which isn’t surprising since pediatricians have been among the lowest-paid physician specialties since 2013. The highest-earning specialty was plastic surgery with an average income of $526,000 annually.

Most pediatricians who saw a drop in income cited pandemic-related issues such as job loss, fewer hours, and fewer patients.

Jesse Hackell, MD, vice president and chief operating officer of Ponoma Pediatrics in New York, said in an interview the reduced wages pediatricians saw in 2020 didn’t surprise him because many pediatric offices saw a huge drop in visits that were not urgent.

“[The report] shows that procedural specialties tended to do a lot better than the nonprocedural specialties,” Dr. Hackell said. “That’s because, during the shutdown, if you broke your leg, you still needed the orthopedist. And even though the hospitals weren’t doing elective surgeries, they were certainly doing the emergency stuff.”

Meanwhile, in pediatrician offices, where Dr. Hackell said office visits dropped 70%-80% at the beginning of the pandemic, “parents weren’t going to bring a healthy kid out for routine visits and they weren’t going to bring a kid out for minor illnesses and expose them to possibly communicable diseases in the office.”

About 52% of pediatricians who lost income because of the pandemic believe their income levels will return to normal in 2-3 years. Meanwhile 30% of pediatricians expect their income to return to normal within a year, and 8% believe it will take 4 years for them to bounce back.

Physician work hours generally declined for some time during the pandemic, according to the report. However, most pediatricians are working about the same number of hours as they did before the pandemic, which is 47 hours per week.

Despite working the same number of hours per week that they did prepandemic, they are seeing fewer patients. They are currently seeing on average 64 patients per week, compared with the 78 patients they used to see weekly before the pandemic.

Dr. Hackell said that might be because pediatric offices are trying to make up the loss of revenue during the beginning of the pandemic, from the reduced number of well visits and immunizations, in the second half of the year with outreach.

“Since about June 2020, we’ve been making concerted efforts to remind parents that preventing other infectious diseases is critically important,” Dr. Hackell explained. “And so actually, for the second half of the year, many of us saw more well visits and immunization volume than in 2019 as we sought to make up the gap. It wasn’t that we were seeing more overall, but we’re trying to make up the gap that happened from March, April, May, [and] June.”

Most pediatricians find their work rewarding. One-third say the most rewarding part of their job is gratitude from and relationships with their patients. Meanwhile, 31% of pediatricians said knowing they are making the world a better place was a rewarding part of their job. Only 8% of them said making money was a rewarding part of their job.

Dr. Hackell said he did not go into pediatrics to make money, it was because he found it stimulating and has “no complaints.”

“I’ve been a pediatrician for 40 years and I wouldn’t do anything else,” Dr. Hackell said. “I don’t know that there’s anything that I would find as rewarding as the relationships that I’ve had over 40 years with my patients. You know, getting invited to weddings of kids who I saw when they were newborns is pretty impressive. It’s the gratification of having ongoing relationships with families.”

Furthermore, the report revealed that 77% of pediatricians said they would pick medicine again if they had a choice, and 82% said they would choose the same specialty.

The experts disclosed no relevant financial interests.

*This story was updated on 5/18/2021.

Jon Hislop, MD, PhD, hadn’t been in practice very long before patients began coming to him with requests to order tests that their naturopaths had recommended.

The family physician in North Vancouver, British Columbia, knew little about naturopathy but began researching it.

“I was finding that some of what the naturopaths were telling them was a little odd. Some of the tests they were asking for were unnecessary,” Dr. Hislop said.

The more he learned about naturopathy, the more appalled he became. He eventually took to Twitter, where he wages a campaign against naturopathy and alternative medicine.

“There is no alternative medicine,” he said. “There’s medicine and there’s other stuff. We need to stick to medicine and stay away from the other stuff.”

Dr. Hislop is not alone in his criticism of naturopathic medicine. Professional medical societies almost universally oppose naturopathy, but that has not stopped its spread or prevented it from becoming part of some health care systems.

Americans spent $30.2 billion on out-of-pocket complementary health care, according to a 2016 report from the National Institutes of Health. That includes everything from herbal supplements and massage therapy to chiropractic care.
 

What is naturopathic medicine?

Naturopathy came to the United States from Germany in the 1800s, but some of its practices are thousands of years old. Naturopathic treatments include homeopathy, IV vitamin infusions, acupuncture, Reiki, and herbal supplements.

Naturopathy is based on the belief that the body has an innate ability to heal itself. It discourages drugs and surgery in favor of supplements, herbs, and other so-called natural treatments. Much of it centers around addressing lifestyle issues and counseling patients to improve their diets, quit smoking, exercise more, lose weight, etc., in order to address the root causes of some health problems.

Practitioners are critical of Western medicine for what they regard as an over-reliance on drugs and technology and for treating symptoms rather than the causes of disease.

“We get a lot of people who are at the end of their ropes, people with hard-to-diagnose diseases who know they are sick but whose labs are normal,” said Jaquel Patterson, ND, former president of the American Association of Naturopathic Physicians (AANP) and medical director of a naturopathic practice in Connecticut.
 

Separate training and licensing

There are major differences among naturopaths.

At one extreme are unlicensed, self-taught “healers,” who can embrace everything from homeopathy to aromatherapy.

At the other end are naturopathic doctors (NDs), who are more likely to become part of health care systems. These caregivers are trained and licensed, though not by the same institutions as traditional physicians.

To be licensed, NDs must graduate from one of seven accredited naturopathic medical schools in the United States and Canada. In addition to a standard medical curriculum, schools require graduates to complete 4 years of training in clinical nutrition, acupuncture, homeopathic medicine, botanical medicine, physical medicine, and counseling. Medical students intern in clinical settings for 2 years.

NDs are eager to distinguish themselves from their uncredentialed counterparts.

“Some people go to a weekend class and call themselves naturopaths. That’s very concerning. I don’t want those people to be licensed either,” said Hallie Armstrong, ND, who practices in Michigan.

In the United States, there are 6,000 practicing NDs and an unknown number of unlicensed naturopathic healers.
 

Can naturopaths call themselves ‘physicians’?

Twenty-two states, the District of Columbia, Puerto Rico, and the U.S. Virgin Islands have licensing or registration laws for naturopathic doctors. Three states – South Carolina, Tennessee, and Florida – prohibit practicing naturopathic medicine without a license, according to the AANP.

States that license NDs differ in what they permit them to do.

Nine states allow licensed NDs to use the term “physician,” although this is prohibited in seven states. Most licensed states allow naturopathic practitioners some prescribing authority, including the prescribing of many controlled substances, although only a few states permit full prescribing rights. Most states that license NDs allow them to prescribe and administer nonprescription therapeutic substances, drugs, and therapies.

Twelve states and the District of Columbia allow licensed naturopathic doctors to perform some minor procedures, such as stitching up wounds. Additionally, 13 states allow NDs to order diagnostic tests.

Although the AANP lobbies to get licensure in more states and to expand the activities that NDs can perform, the medical establishment in those states nearly always opposes the legislation, as do national organizations, such as the American Academy of Family Physicians and the American College of Physicians.

“They absolutely will not stop until they get licenses. They’ve done a really good job of selling themselves as legitimate health care professionals to state legislatures,” said David Gorski, MD, PhD, FACS, a surgical oncologist and managing editor of Science-Based Medicine, a blog that attacks unproven medical claims and defends traditional medicine. Naturopathy is a favorite target.
 

Are naturopaths gaining ground anyway?

Despite the opposition of the medical establishment and many individual health care professionals, a growing number of health care systems are adopting alternative medicine.

In 2018, the AANP stated that 28 prominent health systems, hospitals, and cancer treatment centers had one or more licensed NDs on staff. Among them were Cancer Treatment Centers of America, Cedars-Sinai, Columbia University’s Herbert Irving Comprehensive Cancer Center, and the Fred Hutchinson Cancer Research Center.

Other health care systems may not have NDs on staff but provide naturopathic treatments, usually under the heading of “complementary medicine” or “integrative medicine.” For example, the Cleveland Clinic’s Center for Integrative and Lifestyle Medicine offers acupuncture, Chinese herbal medicine, Reiki, yoga, and culinary medicine.

Critics find this appalling.

“I think it’s a mistake to integrate that kind of practice into a science-based health care setting. If we learned anything over the past year, it’s that medicine based on magical thinking is dangerous,” said Timothy Caulfield, LLM, FCAHS, research director at the Health Law Institute of the University of Alberta, Edmonton.

Dr. Gorski added: “I’m not exactly sure why doctors who should know better have become more accepting of practices that aren’t science-based or are outright quackery.”
 

Becoming part of the system

Beaumont Health, Michigan’s largest health care system, added integrative medicine in 2006 and hired its first naturopathic practitioners a year later.

The integrative practitioners began in oncology, offering such things as massage therapy, acupuncture, guided imagery, and Reiki. “Very quickly, people outside oncology began saying, ‘I’ve got a cardiology patient who would really benefit from this ... I’ve got a GI patient who could benefit from this...,’” said Maureen Anderson, MD, medical director of Beaumont Integrative Medicine.

Beaumont now offers integrative medicine at three locations. They average 20,000 visits a year and work with 50 to 60 practitioners, many of whom work part-time.

Because Michigan does not license NDs, their scope of practice at Beaumont is limited. They take patient histories, provide advice on nutrition, diet, and exercise, and prescribe herbs and supplements. Beaumont operates its own herbal and supplement pharmacy.

NDs work under the medical supervision of Dr. Anderson, an emergency medicine physician who became interested in naturopathy because she thought traditional medicine doesn’t do a good job of providing care for chronic conditions. Any initial skepticism on the part of the medical staff has been overcome by seeing the benefits naturopathy provides, Dr. Anderson said. The claim is echoed by Mr. Armstrong, an ND who works in the system part-time: “As soon as [doctors] understand our schooling and where we’re coming from and understand that we want to do the same things, then they’re very accepting.”

The University of California, Irvine, health care system has one of the largest naturopathic medicine programs in the country, the result of a $200 million donation in 2017 from a couple who champion alternative medicine. The Susan Samueli Integrative Health Institute includes 28 health care professionals, including MDs, NDs, RNs, acupuncturists, dietitians, yoga instructors, and others. It includes a research arm, which is focused primarily on acupuncture.

The alternative medicine offerings benefit the system, said Kim Hecht, DO, medical director of inpatient and ambulatory services at the Samueli Institute.

“I’m not against traditional medicine, because I think everything has a time and a place,” Dr. Hecht said. However, she rejects the idea that MDs can offer the same holistic approach as NDs.

“Medical science likes to say we’re interested in treating the whole person, but if you look at medical school courses, that’s not what’s being taught,” she said.

The chance to work within a traditional health care system was attractive to Arvin Jenab, ND, medical director of naturopathic medicine at the institute.

“It offers the opportunity to refine our medicine and trim the things that aren’t necessary or are controversial and concentrate on the things at the core of what we do,” he said.

UCI Health practices a conservative model of naturopathy that supports traditional practitioners, Mr. Jenab said.
 

Is there any harm?

Some patients clearly want what naturopathy offers. So what’s the harm?

Health care systems that integrate alternative medicine legitimize it and lower the overall standard of care, Mr. Caulfield said. Most naturopathy claims are not backed by evidence, and making it available to patients amounts to deceiving them, he said.

“If there’s good science behind it, it’s not going to be alternative medicine; it’s going to be medicine,” Mr. Caulfield said.

Family physician Dr. Hislop said that refusing to order naturopath-recommended tests interferes with his relationships with patients and often requires lengthy conversations to explain the problems with naturopathy.

Naturopathic medicine can deter patients from seeking proven conventional treatments, which can put their health at risk, Dr. Gorski said.

Some naturopaths could potentially be harmful.

In 2017, a California woman died after receiving an IV preparation of curcumin, a chemical constituent in the Indian spice turmeric featured in alternative medicine. The U.S. Food and Drug Administration found that the treating ND mixed the curcumin emulsion product with ungraded castor oil that had a warning label stating: “CAUTION: For manufacturing or laboratory use only.”

Because naturopathic care is generally not covered by insurance, it can also be expensive for patients who pay out of pocket.

Ironically, the mainstream health care system helps create the environment in which naturopathic medicine thrives.

It offers patients a more relaxed and personal alternative to rushed visits with harried doctors scrambling to see the required number of patients in a day. By contrast, an initial visit with an ND might last a leisurely 60 minutes, with 30-minute follow-up appointments.

Mr. Caulfield acknowledged that the relaxed naturopathic approach can be more attractive to patients but said the answer is to reform the current system: “You don’t fix a broken arm by acupuncture.”

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

Jon Hislop, MD, PhD, hadn’t been in practice very long before patients began coming to him with requests to order tests that their naturopaths had recommended.

The family physician in North Vancouver, British Columbia, knew little about naturopathy but began researching it.

“I was finding that some of what the naturopaths were telling them was a little odd. Some of the tests they were asking for were unnecessary,” Dr. Hislop said.

The more he learned about naturopathy, the more appalled he became. He eventually took to Twitter, where he wages a campaign against naturopathy and alternative medicine.

“There is no alternative medicine,” he said. “There’s medicine and there’s other stuff. We need to stick to medicine and stay away from the other stuff.”

Dr. Hislop is not alone in his criticism of naturopathic medicine. Professional medical societies almost universally oppose naturopathy, but that has not stopped its spread or prevented it from becoming part of some health care systems.

Americans spent $30.2 billion on out-of-pocket complementary health care, according to a 2016 report from the National Institutes of Health. That includes everything from herbal supplements and massage therapy to chiropractic care.
 

What is naturopathic medicine?

Naturopathy came to the United States from Germany in the 1800s, but some of its practices are thousands of years old. Naturopathic treatments include homeopathy, IV vitamin infusions, acupuncture, Reiki, and herbal supplements.

Naturopathy is based on the belief that the body has an innate ability to heal itself. It discourages drugs and surgery in favor of supplements, herbs, and other so-called natural treatments. Much of it centers around addressing lifestyle issues and counseling patients to improve their diets, quit smoking, exercise more, lose weight, etc., in order to address the root causes of some health problems.

Practitioners are critical of Western medicine for what they regard as an over-reliance on drugs and technology and for treating symptoms rather than the causes of disease.

“We get a lot of people who are at the end of their ropes, people with hard-to-diagnose diseases who know they are sick but whose labs are normal,” said Jaquel Patterson, ND, former president of the American Association of Naturopathic Physicians (AANP) and medical director of a naturopathic practice in Connecticut.
 

Separate training and licensing

There are major differences among naturopaths.

At one extreme are unlicensed, self-taught “healers,” who can embrace everything from homeopathy to aromatherapy.

At the other end are naturopathic doctors (NDs), who are more likely to become part of health care systems. These caregivers are trained and licensed, though not by the same institutions as traditional physicians.

To be licensed, NDs must graduate from one of seven accredited naturopathic medical schools in the United States and Canada. In addition to a standard medical curriculum, schools require graduates to complete 4 years of training in clinical nutrition, acupuncture, homeopathic medicine, botanical medicine, physical medicine, and counseling. Medical students intern in clinical settings for 2 years.

NDs are eager to distinguish themselves from their uncredentialed counterparts.

“Some people go to a weekend class and call themselves naturopaths. That’s very concerning. I don’t want those people to be licensed either,” said Hallie Armstrong, ND, who practices in Michigan.

In the United States, there are 6,000 practicing NDs and an unknown number of unlicensed naturopathic healers.
 

Can naturopaths call themselves ‘physicians’?

Twenty-two states, the District of Columbia, Puerto Rico, and the U.S. Virgin Islands have licensing or registration laws for naturopathic doctors. Three states – South Carolina, Tennessee, and Florida – prohibit practicing naturopathic medicine without a license, according to the AANP.

States that license NDs differ in what they permit them to do.

Nine states allow licensed NDs to use the term “physician,” although this is prohibited in seven states. Most licensed states allow naturopathic practitioners some prescribing authority, including the prescribing of many controlled substances, although only a few states permit full prescribing rights. Most states that license NDs allow them to prescribe and administer nonprescription therapeutic substances, drugs, and therapies.

Twelve states and the District of Columbia allow licensed naturopathic doctors to perform some minor procedures, such as stitching up wounds. Additionally, 13 states allow NDs to order diagnostic tests.

Although the AANP lobbies to get licensure in more states and to expand the activities that NDs can perform, the medical establishment in those states nearly always opposes the legislation, as do national organizations, such as the American Academy of Family Physicians and the American College of Physicians.

“They absolutely will not stop until they get licenses. They’ve done a really good job of selling themselves as legitimate health care professionals to state legislatures,” said David Gorski, MD, PhD, FACS, a surgical oncologist and managing editor of Science-Based Medicine, a blog that attacks unproven medical claims and defends traditional medicine. Naturopathy is a favorite target.
 

Are naturopaths gaining ground anyway?

Despite the opposition of the medical establishment and many individual health care professionals, a growing number of health care systems are adopting alternative medicine.

In 2018, the AANP stated that 28 prominent health systems, hospitals, and cancer treatment centers had one or more licensed NDs on staff. Among them were Cancer Treatment Centers of America, Cedars-Sinai, Columbia University’s Herbert Irving Comprehensive Cancer Center, and the Fred Hutchinson Cancer Research Center.

Other health care systems may not have NDs on staff but provide naturopathic treatments, usually under the heading of “complementary medicine” or “integrative medicine.” For example, the Cleveland Clinic’s Center for Integrative and Lifestyle Medicine offers acupuncture, Chinese herbal medicine, Reiki, yoga, and culinary medicine.

Critics find this appalling.

“I think it’s a mistake to integrate that kind of practice into a science-based health care setting. If we learned anything over the past year, it’s that medicine based on magical thinking is dangerous,” said Timothy Caulfield, LLM, FCAHS, research director at the Health Law Institute of the University of Alberta, Edmonton.

Dr. Gorski added: “I’m not exactly sure why doctors who should know better have become more accepting of practices that aren’t science-based or are outright quackery.”
 

Becoming part of the system

Beaumont Health, Michigan’s largest health care system, added integrative medicine in 2006 and hired its first naturopathic practitioners a year later.

The integrative practitioners began in oncology, offering such things as massage therapy, acupuncture, guided imagery, and Reiki. “Very quickly, people outside oncology began saying, ‘I’ve got a cardiology patient who would really benefit from this ... I’ve got a GI patient who could benefit from this...,’” said Maureen Anderson, MD, medical director of Beaumont Integrative Medicine.

Beaumont now offers integrative medicine at three locations. They average 20,000 visits a year and work with 50 to 60 practitioners, many of whom work part-time.

Because Michigan does not license NDs, their scope of practice at Beaumont is limited. They take patient histories, provide advice on nutrition, diet, and exercise, and prescribe herbs and supplements. Beaumont operates its own herbal and supplement pharmacy.

NDs work under the medical supervision of Dr. Anderson, an emergency medicine physician who became interested in naturopathy because she thought traditional medicine doesn’t do a good job of providing care for chronic conditions. Any initial skepticism on the part of the medical staff has been overcome by seeing the benefits naturopathy provides, Dr. Anderson said. The claim is echoed by Mr. Armstrong, an ND who works in the system part-time: “As soon as [doctors] understand our schooling and where we’re coming from and understand that we want to do the same things, then they’re very accepting.”

The University of California, Irvine, health care system has one of the largest naturopathic medicine programs in the country, the result of a $200 million donation in 2017 from a couple who champion alternative medicine. The Susan Samueli Integrative Health Institute includes 28 health care professionals, including MDs, NDs, RNs, acupuncturists, dietitians, yoga instructors, and others. It includes a research arm, which is focused primarily on acupuncture.

The alternative medicine offerings benefit the system, said Kim Hecht, DO, medical director of inpatient and ambulatory services at the Samueli Institute.

“I’m not against traditional medicine, because I think everything has a time and a place,” Dr. Hecht said. However, she rejects the idea that MDs can offer the same holistic approach as NDs.

“Medical science likes to say we’re interested in treating the whole person, but if you look at medical school courses, that’s not what’s being taught,” she said.

The chance to work within a traditional health care system was attractive to Arvin Jenab, ND, medical director of naturopathic medicine at the institute.

“It offers the opportunity to refine our medicine and trim the things that aren’t necessary or are controversial and concentrate on the things at the core of what we do,” he said.

UCI Health practices a conservative model of naturopathy that supports traditional practitioners, Mr. Jenab said.
 

Is there any harm?

Some patients clearly want what naturopathy offers. So what’s the harm?

Health care systems that integrate alternative medicine legitimize it and lower the overall standard of care, Mr. Caulfield said. Most naturopathy claims are not backed by evidence, and making it available to patients amounts to deceiving them, he said.

“If there’s good science behind it, it’s not going to be alternative medicine; it’s going to be medicine,” Mr. Caulfield said.

Family physician Dr. Hislop said that refusing to order naturopath-recommended tests interferes with his relationships with patients and often requires lengthy conversations to explain the problems with naturopathy.

Naturopathic medicine can deter patients from seeking proven conventional treatments, which can put their health at risk, Dr. Gorski said.

Some naturopaths could potentially be harmful.

In 2017, a California woman died after receiving an IV preparation of curcumin, a chemical constituent in the Indian spice turmeric featured in alternative medicine. The U.S. Food and Drug Administration found that the treating ND mixed the curcumin emulsion product with ungraded castor oil that had a warning label stating: “CAUTION: For manufacturing or laboratory use only.”

Because naturopathic care is generally not covered by insurance, it can also be expensive for patients who pay out of pocket.

Ironically, the mainstream health care system helps create the environment in which naturopathic medicine thrives.

It offers patients a more relaxed and personal alternative to rushed visits with harried doctors scrambling to see the required number of patients in a day. By contrast, an initial visit with an ND might last a leisurely 60 minutes, with 30-minute follow-up appointments.

Mr. Caulfield acknowledged that the relaxed naturopathic approach can be more attractive to patients but said the answer is to reform the current system: “You don’t fix a broken arm by acupuncture.”

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

Jon Hislop, MD, PhD, hadn’t been in practice very long before patients began coming to him with requests to order tests that their naturopaths had recommended.

The family physician in North Vancouver, British Columbia, knew little about naturopathy but began researching it.

“I was finding that some of what the naturopaths were telling them was a little odd. Some of the tests they were asking for were unnecessary,” Dr. Hislop said.

The more he learned about naturopathy, the more appalled he became. He eventually took to Twitter, where he wages a campaign against naturopathy and alternative medicine.

“There is no alternative medicine,” he said. “There’s medicine and there’s other stuff. We need to stick to medicine and stay away from the other stuff.”

Dr. Hislop is not alone in his criticism of naturopathic medicine. Professional medical societies almost universally oppose naturopathy, but that has not stopped its spread or prevented it from becoming part of some health care systems.

Americans spent $30.2 billion on out-of-pocket complementary health care, according to a 2016 report from the National Institutes of Health. That includes everything from herbal supplements and massage therapy to chiropractic care.
 

What is naturopathic medicine?

Naturopathy came to the United States from Germany in the 1800s, but some of its practices are thousands of years old. Naturopathic treatments include homeopathy, IV vitamin infusions, acupuncture, Reiki, and herbal supplements.

Naturopathy is based on the belief that the body has an innate ability to heal itself. It discourages drugs and surgery in favor of supplements, herbs, and other so-called natural treatments. Much of it centers around addressing lifestyle issues and counseling patients to improve their diets, quit smoking, exercise more, lose weight, etc., in order to address the root causes of some health problems.

Practitioners are critical of Western medicine for what they regard as an over-reliance on drugs and technology and for treating symptoms rather than the causes of disease.

“We get a lot of people who are at the end of their ropes, people with hard-to-diagnose diseases who know they are sick but whose labs are normal,” said Jaquel Patterson, ND, former president of the American Association of Naturopathic Physicians (AANP) and medical director of a naturopathic practice in Connecticut.
 

Separate training and licensing

There are major differences among naturopaths.

At one extreme are unlicensed, self-taught “healers,” who can embrace everything from homeopathy to aromatherapy.

At the other end are naturopathic doctors (NDs), who are more likely to become part of health care systems. These caregivers are trained and licensed, though not by the same institutions as traditional physicians.

To be licensed, NDs must graduate from one of seven accredited naturopathic medical schools in the United States and Canada. In addition to a standard medical curriculum, schools require graduates to complete 4 years of training in clinical nutrition, acupuncture, homeopathic medicine, botanical medicine, physical medicine, and counseling. Medical students intern in clinical settings for 2 years.

NDs are eager to distinguish themselves from their uncredentialed counterparts.

“Some people go to a weekend class and call themselves naturopaths. That’s very concerning. I don’t want those people to be licensed either,” said Hallie Armstrong, ND, who practices in Michigan.

In the United States, there are 6,000 practicing NDs and an unknown number of unlicensed naturopathic healers.
 

Can naturopaths call themselves ‘physicians’?

Twenty-two states, the District of Columbia, Puerto Rico, and the U.S. Virgin Islands have licensing or registration laws for naturopathic doctors. Three states – South Carolina, Tennessee, and Florida – prohibit practicing naturopathic medicine without a license, according to the AANP.

States that license NDs differ in what they permit them to do.

Nine states allow licensed NDs to use the term “physician,” although this is prohibited in seven states. Most licensed states allow naturopathic practitioners some prescribing authority, including the prescribing of many controlled substances, although only a few states permit full prescribing rights. Most states that license NDs allow them to prescribe and administer nonprescription therapeutic substances, drugs, and therapies.

Twelve states and the District of Columbia allow licensed naturopathic doctors to perform some minor procedures, such as stitching up wounds. Additionally, 13 states allow NDs to order diagnostic tests.

Although the AANP lobbies to get licensure in more states and to expand the activities that NDs can perform, the medical establishment in those states nearly always opposes the legislation, as do national organizations, such as the American Academy of Family Physicians and the American College of Physicians.

“They absolutely will not stop until they get licenses. They’ve done a really good job of selling themselves as legitimate health care professionals to state legislatures,” said David Gorski, MD, PhD, FACS, a surgical oncologist and managing editor of Science-Based Medicine, a blog that attacks unproven medical claims and defends traditional medicine. Naturopathy is a favorite target.
 

Are naturopaths gaining ground anyway?

Despite the opposition of the medical establishment and many individual health care professionals, a growing number of health care systems are adopting alternative medicine.

In 2018, the AANP stated that 28 prominent health systems, hospitals, and cancer treatment centers had one or more licensed NDs on staff. Among them were Cancer Treatment Centers of America, Cedars-Sinai, Columbia University’s Herbert Irving Comprehensive Cancer Center, and the Fred Hutchinson Cancer Research Center.

Other health care systems may not have NDs on staff but provide naturopathic treatments, usually under the heading of “complementary medicine” or “integrative medicine.” For example, the Cleveland Clinic’s Center for Integrative and Lifestyle Medicine offers acupuncture, Chinese herbal medicine, Reiki, yoga, and culinary medicine.

Critics find this appalling.

“I think it’s a mistake to integrate that kind of practice into a science-based health care setting. If we learned anything over the past year, it’s that medicine based on magical thinking is dangerous,” said Timothy Caulfield, LLM, FCAHS, research director at the Health Law Institute of the University of Alberta, Edmonton.

Dr. Gorski added: “I’m not exactly sure why doctors who should know better have become more accepting of practices that aren’t science-based or are outright quackery.”
 

Becoming part of the system

Beaumont Health, Michigan’s largest health care system, added integrative medicine in 2006 and hired its first naturopathic practitioners a year later.

The integrative practitioners began in oncology, offering such things as massage therapy, acupuncture, guided imagery, and Reiki. “Very quickly, people outside oncology began saying, ‘I’ve got a cardiology patient who would really benefit from this ... I’ve got a GI patient who could benefit from this...,’” said Maureen Anderson, MD, medical director of Beaumont Integrative Medicine.

Beaumont now offers integrative medicine at three locations. They average 20,000 visits a year and work with 50 to 60 practitioners, many of whom work part-time.

Because Michigan does not license NDs, their scope of practice at Beaumont is limited. They take patient histories, provide advice on nutrition, diet, and exercise, and prescribe herbs and supplements. Beaumont operates its own herbal and supplement pharmacy.

NDs work under the medical supervision of Dr. Anderson, an emergency medicine physician who became interested in naturopathy because she thought traditional medicine doesn’t do a good job of providing care for chronic conditions. Any initial skepticism on the part of the medical staff has been overcome by seeing the benefits naturopathy provides, Dr. Anderson said. The claim is echoed by Mr. Armstrong, an ND who works in the system part-time: “As soon as [doctors] understand our schooling and where we’re coming from and understand that we want to do the same things, then they’re very accepting.”

The University of California, Irvine, health care system has one of the largest naturopathic medicine programs in the country, the result of a $200 million donation in 2017 from a couple who champion alternative medicine. The Susan Samueli Integrative Health Institute includes 28 health care professionals, including MDs, NDs, RNs, acupuncturists, dietitians, yoga instructors, and others. It includes a research arm, which is focused primarily on acupuncture.

The alternative medicine offerings benefit the system, said Kim Hecht, DO, medical director of inpatient and ambulatory services at the Samueli Institute.

“I’m not against traditional medicine, because I think everything has a time and a place,” Dr. Hecht said. However, she rejects the idea that MDs can offer the same holistic approach as NDs.

“Medical science likes to say we’re interested in treating the whole person, but if you look at medical school courses, that’s not what’s being taught,” she said.

The chance to work within a traditional health care system was attractive to Arvin Jenab, ND, medical director of naturopathic medicine at the institute.

“It offers the opportunity to refine our medicine and trim the things that aren’t necessary or are controversial and concentrate on the things at the core of what we do,” he said.

UCI Health practices a conservative model of naturopathy that supports traditional practitioners, Mr. Jenab said.
 

Is there any harm?

Some patients clearly want what naturopathy offers. So what’s the harm?

Health care systems that integrate alternative medicine legitimize it and lower the overall standard of care, Mr. Caulfield said. Most naturopathy claims are not backed by evidence, and making it available to patients amounts to deceiving them, he said.

“If there’s good science behind it, it’s not going to be alternative medicine; it’s going to be medicine,” Mr. Caulfield said.

Family physician Dr. Hislop said that refusing to order naturopath-recommended tests interferes with his relationships with patients and often requires lengthy conversations to explain the problems with naturopathy.

Naturopathic medicine can deter patients from seeking proven conventional treatments, which can put their health at risk, Dr. Gorski said.

Some naturopaths could potentially be harmful.

In 2017, a California woman died after receiving an IV preparation of curcumin, a chemical constituent in the Indian spice turmeric featured in alternative medicine. The U.S. Food and Drug Administration found that the treating ND mixed the curcumin emulsion product with ungraded castor oil that had a warning label stating: “CAUTION: For manufacturing or laboratory use only.”

Because naturopathic care is generally not covered by insurance, it can also be expensive for patients who pay out of pocket.

Ironically, the mainstream health care system helps create the environment in which naturopathic medicine thrives.

It offers patients a more relaxed and personal alternative to rushed visits with harried doctors scrambling to see the required number of patients in a day. By contrast, an initial visit with an ND might last a leisurely 60 minutes, with 30-minute follow-up appointments.

Mr. Caulfield acknowledged that the relaxed naturopathic approach can be more attractive to patients but said the answer is to reform the current system: “You don’t fix a broken arm by acupuncture.”

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Questions over the cardiovascular benefits shown in the REDUCE-IT trial with icosapent ethyl, a high-dose eicosapentaenoic acid (EPA) product, have been reignited with a new analysis from the STRENGTH trial showing no benefit of a high-dose combined omega-3 fatty acid product in patients who achieved the highest EPA levels and no harm in those with the highest levels of docosahexaenoic acid (DHA).

STRENGTH investigator Steven Nissen, MD, said these new results add to concerns about the positive result in the previously reported REDUCE-IT trial and suggest that “there is no strong evidence of a benefit of fish oil in preventing major cardiovascular events.”

But Dr. Nissen, who is chair of the department of cardiovascular medicine at the Cleveland Clinic in Ohio, pointed out evidence of harm, with both REDUCE-IT and STRENGTH showing an increase in atrial fibrillation with the high-dose omega-3 fatty acid products.

“Fish oils increase the risk of atrial fibrillation substantially, and there is no solid evidence that they help the heart in any way,” he stated.

The new STRENGTH analysis was presented at the annual scientific sessions of the American College of Cardiology. and was simultaneously published in JAMA Cardiology.

The REDUCE-IT trial showed a large 25% relative-risk reduction in cardiovascular events in patients taking icosapent ethyl (Vascepa, Amarin), a high-dose purified formulation of EPA, compared with patients taking a mineral oil placebo. But a similar trial, STRENGTH, showed no effect of a similar high dose of the mixed EPA/DHA product (Epanova, AstraZeneca), compared with a corn oil placebo.

The different results from these two studies have led to many questions about how the benefits seen in REDUCE-IT were brought about, and why they weren’t replicated in the STRENGTH study.

Dr. Nissen noted that several hypotheses have been proposed. These include a potential adverse effect of the mineral oil placebo in the REDUCE-IT trial, which may have elevated risk in the placebo treatment group and led to a false-positive result for icosapent ethyl. Another possibility is that the moderately higher plasma levels of EPA achieved in REDUCE-IT were responsible for the observed benefits or that the coadministration of DHA in STRENGTH may have counteracted the potential beneficial effects of EPA.

The current post hoc analysis of STRENGTH was conducted to address these latter two possibilities. It aimed to assess the association between cardiovascular outcomes and achieved levels of EPA, DHA, or changes in levels of these fatty acids.

“In our new analysis, among patients treated with fish oil, we found no evidence that EPA is beneficial or that DHA is harmful,” Dr. Nissen said.

Results of the new analysis showed an absence of a benefit from achieving high levels of EPA or harm from achieving high levels of DHA which, the authors say, “strengthens the concerns that the choice of comparator may have influenced the divergent results observed in the two trials.”

“Unlike corn oil, which is inert, mineral oil has major adverse effects, increasing LDL by 10.9% and CRP [C-reactive protein] by 32% in the REDUCE-IT trial,” Dr. Nissen said. “If you give a toxic placebo, then the active drug may falsely look really good.”  

The STRENGTH trial randomly assigned 13,078 individuals at high risk for major cardiovascular events to receive 4 g daily of the EPA/DHA combined product (omega-3 carboxylic acid) or corn oil as the placebo. Main results, reported previously, showed no difference between the two groups in terms of the primary outcome – a composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or unstable angina requiring hospitalization.

The current analysis, in 10,382 patients with available omega-3 fatty acid levels, looked at event rates according to tertiles of achieved EPA and DHA levels. The median plasma EPA level for patients taking the omega-3 product was 89 mcg/mL, with the top tertile achieving levels of 151 mcg/mL (a 443% increase). Dr. Nissen pointed out that this was higher than the median level of EPA reported in the REDUCE-IT trial (144 mcg/mL).

The median level of DHA was 91 mcg/mL, rising to 118 mcg/mL (a 68% increase) in the top tertile in the STRENGTH analysis.

Results showed no difference in the occurrence of the prespecified primary outcome among patients treated with omega-3 carboxylic acid who were in the top tertile of achieved EPA levels at 1 year (event rate, 11.3%), compared with patients treated with corn oil (11.0%), a nonsignificant difference (hazard ratio, 0.98; P = .81).

For DHA, patients in the top tertile of achieved DHA levels had an event rate of 11.4% vs. 11.0% in the corn oil group, also a nonsignificant difference (HR, 1.02; P = .85)    

Sensitivity analyses based on the highest tertile of change in EPA or DHA levels showed similarly neutral results.

Because plasma levels may not reflect tissue levels of EPA or DHA, additional analyses assessed red blood cell EPA and DHA levels, neither of which showed any evidence of benefit or harm.

“These findings suggest that supplementation of omega-3 fatty acids in high-risk cardiovascular patients is neutral even at the highest achieved levels,” Dr. Nissen said. “And, in the context of increased risk of atrial fibrillation in omega-3 trials, they cast uncertainty over whether there is net benefit or harm with any omega-3 preparation,” he concluded.

He suggested that the choice of placebo comparator may play an important role in determining outcome for trials of omega-3 products, adding that further research is needed with trials specifically designed to compare corn oil with mineral oil and compare purified EPA with other formulations of omega-3 fatty acids.

At an press conference, Dr. Nissen said he could not recommend use of omega-3 fatty acid products for cardiovascular risk reduction given the uncertainty over the benefit in REDUCE-IT.

“We need replication, and the problem is STRENGTH did not replicate REDUCE-IT,” he stated.

 REDUCE-IT investigator responds

The discussant of the STRENGTH analysis at the ACC presentation, Deepak L. Bhatt, MD, who was lead investigator of the REDUCE-IT trial, suggested that one conclusion could be that “an absence of a relationship in a negative trial doesn’t tell us that much other than that specific drug doesn’t work.”

Dr. Bhatt, who is executive director of interventional cardiovascular programs at Brigham and Women’s Hospital Heart & Vascular Center, Boston, said in an interview that comparisons should not be made between different trials using different products.  

“I commend the STRENGTH investigators on a well-conducted trial that provided a definitive answer about the specific drug they studied, finding no benefit. But in a completely negative trial, I wouldn’t necessarily expect to see a relationship between any biomarker and outcome,” he said.

“With respect to icosapent ethyl (pure EPA), every cardiovascular trial to date has been positive: REDUCE-IT (randomized, placebo-controlled), JELIS (randomized, no placebo), EVAPORATE (randomized, placebo-controlled), CHERRY (randomized, no placebo), and some smaller ones,” Dr. Bhatt added. “Both REDUCE-IT and JELIS found associations between higher levels of EPA and lower rates of cardiovascular events, suggesting that higher EPA levels attained specifically with icosapent ethyl are beneficial.”

Pointing out that all the glucagonlike peptide–1 agonists lower glucose, for example, but not all reduce cardiovascular events, Dr. Bhatt said it was best to focus on clinical trial results and not overly focus on biomarker changes.

“Yes, the drug in STRENGTH raised EPA (and raised DHA, as well as lowering triglycerides), but the drug in REDUCE-IT and JELIS raised EPA much more, without raising DHA – and more importantly, the increase in EPA was via a totally different drug, with many different properties,” he added.

In his discussion of the study at the ACC presentation, Dr. Bhatt pointed out that in the STRENGTH trial overall there was no reduction in major adverse cardiovascular events despite a 19% reduction in triglycerides, which he said was a “very interesting disconnect.” He asked Dr. Nissen what he thought the reason was for the observation in this analysis of no relationship between EPA or DHA level and triglyceride reduction. 

Dr. Nissen said that was an interesting point. “When we look at the two trials, they both reduced triglyceride levels by an almost identical amount, 19%, but we don’t see a relationship with that and EPA levels achieved.” He suggested this may be because of different threshold levels.

Dr. Bhatt also noted that high-intensity statin use was lower in the patients with higher EPA levels in the STRENGTH analysis, but Dr. Nissen countered: “I don’t think that was enough of a difference to explain the lack of an effect.”

Invited commentator on the new analysis at an ACC press conference, Eileen Handberg, PhD, said it was important to try to understand the reasons behind the different results of the STRENGTH and REDUCE-IT trials. “These new findings are important because they explain potentially why these outcomes are different,” she stated.

Dr. Handberg, who is professor of medicine at the University of Florida, Gainesville, said she hoped the additional research called for by Dr. Nissen would go ahead as a head-to-head study of the two omega-3 products or of the two different placebo oils.

The STRENGTH trial was sponsored by Astra Zeneca. Dr. Nissen reports research grants from AbbVie, Amgen, Astra Zeneca, Eli Lilly, Esperion Therapeutics, MEDTRONIC, MyoKardia, Novartis, Novo Nordisk, Pfizer, and Silence Therapeutics. Dr. Bhatt reports constant fees/honoraria from CellProthera, Elsevier Practice Update Cardiology, K2P, Level Ex, Medtelligence, MJH Life Sciences, and WebMD; data safety monitoring board activities with Contego; other roles with TobeSoft, Belvoir Publications, Cardax, Cereno Scientific, Clinical Cardiology, Elsevier, HMP Global, Janssen Pharmaceuticals, Journal of Invasive Cardiology, Medscape Cardiology, Merck, MyoKardia, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Slack Publications/Cardiology Research Foundation; and research grants from Abbott, Afimmune, Amarin, Amgen, Astra Zeneca, Bayer Healthcare Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals,  Bristol-Myers Squibb, Cardax, Chiesi, Eisai, Eli Lilly, Ethicon, FlowCo, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, MEDTRONIC, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, Takeda, and The Medicines Company.  

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

Renal denervation’s comeback as a potential treatment for patients with drug-resistant hypertension rolls on.

Renal denervation with ultrasound energy produced a significant, median 4.5–mm Hg incremental drop in daytime, ambulatory, systolic blood pressure, compared with sham-treatment after 2 months follow-up in a randomized study of 136 patients with drug-resistant hypertension maintained on a standardized, single-pill, triple-drug regimen during the study.

Courtesy American College of Cardiology

The results “confirm that ultrasound renal denervation can lower blood pressure across a spectrum of hypertension,” concluded Ajay J. Kirtane, MD, at the annual scientific sessions of the American College of Cardiology. Renal denervation procedures involve percutaneously placing an endovascular catheter bilaterally inside a patient’s renal arteries and using brief pulses of energy to ablate neurons involved in blood pressure regulation.

A former ‘hot concept’

“Renal denervation was a hot concept a number of years ago, but had been tested only in studies without a sham control,” and initial testing using sham controls failed to show a significant benefit from the intervention, noted Deepak L. Bhatt, MD, an interventional cardiologist and professor of medicine at Harvard Medical School in Boston who was not involved with the study. The significant reductions in systolic blood pressure reported with renal denervation, compared with control patients in this study, “are believable” because of inclusion of a true control cohort, he added. “This really exciting finding puts renal denervation squarely back on the map,” commented Dr. Bhatt during a press briefing.

Dr. Bhatt added that, while the median 4.5–mm Hg incremental reduction in daytime, ambulatory, systolic blood pressure, compared with control patients – the study’s primary endpoint – may seem modest, “in the world of hypertension it’s a meaningful reduction” that, if sustained over the long term, would be expected to produce meaningful cuts in adverse cardiovascular events such as heart failure, stroke, and MI.

“The question is whether the effects are durable,” highlighted Dr. Bhatt, who helped lead the first sham-controlled trial of renal denervation, SYMPLICITY HTN-3, which failed to show a significant blood pressure reduction, compared with controls using radiofrequency energy to ablate renal nerves. A more recent study that used a different radiofrequency catheter and sham controls showed a significant effect on reducing systolic blood pressure in the SPYRAL HTN-OFF MED Pivotal trial, which by design did not maintain patients on any antihypertensive medications following their renal denervation procedure.

Dr. Kirtane noted that, although the median systolic blood pressure reduction, compared with controls treated by a sham procedure, was 4.5 mm Hg, the total median systolic pressure reduction after 2 months in the actively treated patients was 8.0 mm Hg when compared with their baseline blood pressure.

Concurrently with his report the results also appeared in an article posted online (Lancet. 2021 May 16;doi: 10.1016/S0140-6736(21)00788-1).

Denervation coupled with a single, daily three-drug pill

The RADIANCE-HTN TRIO study ran at 53 centers in the United States and Europe, and randomized 136 adults with an office-measured blood pressure of at least 140/90 mm Hg despite being on a stable regimen of at least three antihypertensive drugs including a diuretic. The enrolled cohort averaged 52 years of age and had an average office-measured pressure of about 162/104 mm Hg despite being on an average of four agents, although only about a third of enrolled patients were on treatment with a mineralocorticoid-receptor antagonist (MRA) such as spironolactone.

At the time of enrollment and 4 weeks before their denervation procedure, all patients switched to a uniform drug regimen of a single, daily, oral pill containing the calcium channel blocker amlodipine, the angiotensin receptor blocker valsartan or olmesartan, and the diuretic hydrochlorothiazide with no other drug treatment allowed except for unusual, prespecified clinical circumstances. All patients remained on this drug regimen for the initial 2-month follow-up period unless their blood pressure exceeded 180/110 mm Hg during in-office measurement.

The denervation treatment was well tolerated, although patients reported brief, transient, and “minor” pain associated with the procedure that did not affect treatment blinding or have any lingering consequences, said Dr. Kirtane, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons in New York.

A reason to use energy delivery by ultrasound rather than by radiofrequency to ablate nerves in the renal arteries is that the ultrasound approach exerts a more uniform effect, allowing effective treatment delivery without need for catheter repositioning into more distal branches of the renal arteries, said Dr. Kirtane, who is also an interventional cardiologist at NewYork-Presbyterian/Columbia University Irving Medical Center.

But each method has its advantages, he added.

He also conceded that additional questions need to be addressed regarding which patients are most appropriate for renal denervation. “We need to figure out in which patients we can apply a device-based treatment,” Dr. Kirtane said during the press briefing. Patients with what appears to be drug-resistant hypertension often do not receive treatment with a MRA because of adverse effects, and many of these patients are not usually assessed for primary aldosteronism.

In SYMPLICITY HTN-3, “about half the patients who were seemingly eligible became ineligible” when they started treatment with a MRA, noted Dr. Bhatt. “A little spironolactone can go a long way” toward resolving treatment-resistant hypertension in many patients, he said.

RADIANCE-HTN TRIO was sponsored by ReCor Medical, the company developing the tested ultrasound catheter. Dr. Kirtane has received travel expenses and meals from ReCor Medical and several other companies, and Columbia has received research funding from ReCor Medical and several other companies related to research he has conducted. Dr. Bhatt has no relationship with ReCor Medical. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an advisor to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies.

[email protected]

Renal denervation’s comeback as a potential treatment for patients with drug-resistant hypertension rolls on.

Renal denervation with ultrasound energy produced a significant, median 4.5–mm Hg incremental drop in daytime, ambulatory, systolic blood pressure, compared with sham-treatment after 2 months follow-up in a randomized study of 136 patients with drug-resistant hypertension maintained on a standardized, single-pill, triple-drug regimen during the study.

Courtesy American College of Cardiology

The results “confirm that ultrasound renal denervation can lower blood pressure across a spectrum of hypertension,” concluded Ajay J. Kirtane, MD, at the annual scientific sessions of the American College of Cardiology. Renal denervation procedures involve percutaneously placing an endovascular catheter bilaterally inside a patient’s renal arteries and using brief pulses of energy to ablate neurons involved in blood pressure regulation.

A former ‘hot concept’

“Renal denervation was a hot concept a number of years ago, but had been tested only in studies without a sham control,” and initial testing using sham controls failed to show a significant benefit from the intervention, noted Deepak L. Bhatt, MD, an interventional cardiologist and professor of medicine at Harvard Medical School in Boston who was not involved with the study. The significant reductions in systolic blood pressure reported with renal denervation, compared with control patients in this study, “are believable” because of inclusion of a true control cohort, he added. “This really exciting finding puts renal denervation squarely back on the map,” commented Dr. Bhatt during a press briefing.

Dr. Bhatt added that, while the median 4.5–mm Hg incremental reduction in daytime, ambulatory, systolic blood pressure, compared with control patients – the study’s primary endpoint – may seem modest, “in the world of hypertension it’s a meaningful reduction” that, if sustained over the long term, would be expected to produce meaningful cuts in adverse cardiovascular events such as heart failure, stroke, and MI.

“The question is whether the effects are durable,” highlighted Dr. Bhatt, who helped lead the first sham-controlled trial of renal denervation, SYMPLICITY HTN-3, which failed to show a significant blood pressure reduction, compared with controls using radiofrequency energy to ablate renal nerves. A more recent study that used a different radiofrequency catheter and sham controls showed a significant effect on reducing systolic blood pressure in the SPYRAL HTN-OFF MED Pivotal trial, which by design did not maintain patients on any antihypertensive medications following their renal denervation procedure.

Dr. Kirtane noted that, although the median systolic blood pressure reduction, compared with controls treated by a sham procedure, was 4.5 mm Hg, the total median systolic pressure reduction after 2 months in the actively treated patients was 8.0 mm Hg when compared with their baseline blood pressure.

Concurrently with his report the results also appeared in an article posted online (Lancet. 2021 May 16;doi: 10.1016/S0140-6736(21)00788-1).

Denervation coupled with a single, daily three-drug pill

The RADIANCE-HTN TRIO study ran at 53 centers in the United States and Europe, and randomized 136 adults with an office-measured blood pressure of at least 140/90 mm Hg despite being on a stable regimen of at least three antihypertensive drugs including a diuretic. The enrolled cohort averaged 52 years of age and had an average office-measured pressure of about 162/104 mm Hg despite being on an average of four agents, although only about a third of enrolled patients were on treatment with a mineralocorticoid-receptor antagonist (MRA) such as spironolactone.

At the time of enrollment and 4 weeks before their denervation procedure, all patients switched to a uniform drug regimen of a single, daily, oral pill containing the calcium channel blocker amlodipine, the angiotensin receptor blocker valsartan or olmesartan, and the diuretic hydrochlorothiazide with no other drug treatment allowed except for unusual, prespecified clinical circumstances. All patients remained on this drug regimen for the initial 2-month follow-up period unless their blood pressure exceeded 180/110 mm Hg during in-office measurement.

The denervation treatment was well tolerated, although patients reported brief, transient, and “minor” pain associated with the procedure that did not affect treatment blinding or have any lingering consequences, said Dr. Kirtane, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons in New York.

A reason to use energy delivery by ultrasound rather than by radiofrequency to ablate nerves in the renal arteries is that the ultrasound approach exerts a more uniform effect, allowing effective treatment delivery without need for catheter repositioning into more distal branches of the renal arteries, said Dr. Kirtane, who is also an interventional cardiologist at NewYork-Presbyterian/Columbia University Irving Medical Center.

But each method has its advantages, he added.

He also conceded that additional questions need to be addressed regarding which patients are most appropriate for renal denervation. “We need to figure out in which patients we can apply a device-based treatment,” Dr. Kirtane said during the press briefing. Patients with what appears to be drug-resistant hypertension often do not receive treatment with a MRA because of adverse effects, and many of these patients are not usually assessed for primary aldosteronism.

In SYMPLICITY HTN-3, “about half the patients who were seemingly eligible became ineligible” when they started treatment with a MRA, noted Dr. Bhatt. “A little spironolactone can go a long way” toward resolving treatment-resistant hypertension in many patients, he said.

RADIANCE-HTN TRIO was sponsored by ReCor Medical, the company developing the tested ultrasound catheter. Dr. Kirtane has received travel expenses and meals from ReCor Medical and several other companies, and Columbia has received research funding from ReCor Medical and several other companies related to research he has conducted. Dr. Bhatt has no relationship with ReCor Medical. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an advisor to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies.

[email protected]

Renal denervation’s comeback as a potential treatment for patients with drug-resistant hypertension rolls on.

Renal denervation with ultrasound energy produced a significant, median 4.5–mm Hg incremental drop in daytime, ambulatory, systolic blood pressure, compared with sham-treatment after 2 months follow-up in a randomized study of 136 patients with drug-resistant hypertension maintained on a standardized, single-pill, triple-drug regimen during the study.

Courtesy American College of Cardiology

The results “confirm that ultrasound renal denervation can lower blood pressure across a spectrum of hypertension,” concluded Ajay J. Kirtane, MD, at the annual scientific sessions of the American College of Cardiology. Renal denervation procedures involve percutaneously placing an endovascular catheter bilaterally inside a patient’s renal arteries and using brief pulses of energy to ablate neurons involved in blood pressure regulation.

A former ‘hot concept’

“Renal denervation was a hot concept a number of years ago, but had been tested only in studies without a sham control,” and initial testing using sham controls failed to show a significant benefit from the intervention, noted Deepak L. Bhatt, MD, an interventional cardiologist and professor of medicine at Harvard Medical School in Boston who was not involved with the study. The significant reductions in systolic blood pressure reported with renal denervation, compared with control patients in this study, “are believable” because of inclusion of a true control cohort, he added. “This really exciting finding puts renal denervation squarely back on the map,” commented Dr. Bhatt during a press briefing.

Dr. Bhatt added that, while the median 4.5–mm Hg incremental reduction in daytime, ambulatory, systolic blood pressure, compared with control patients – the study’s primary endpoint – may seem modest, “in the world of hypertension it’s a meaningful reduction” that, if sustained over the long term, would be expected to produce meaningful cuts in adverse cardiovascular events such as heart failure, stroke, and MI.

“The question is whether the effects are durable,” highlighted Dr. Bhatt, who helped lead the first sham-controlled trial of renal denervation, SYMPLICITY HTN-3, which failed to show a significant blood pressure reduction, compared with controls using radiofrequency energy to ablate renal nerves. A more recent study that used a different radiofrequency catheter and sham controls showed a significant effect on reducing systolic blood pressure in the SPYRAL HTN-OFF MED Pivotal trial, which by design did not maintain patients on any antihypertensive medications following their renal denervation procedure.

Dr. Kirtane noted that, although the median systolic blood pressure reduction, compared with controls treated by a sham procedure, was 4.5 mm Hg, the total median systolic pressure reduction after 2 months in the actively treated patients was 8.0 mm Hg when compared with their baseline blood pressure.

Concurrently with his report the results also appeared in an article posted online (Lancet. 2021 May 16;doi: 10.1016/S0140-6736(21)00788-1).

Denervation coupled with a single, daily three-drug pill

The RADIANCE-HTN TRIO study ran at 53 centers in the United States and Europe, and randomized 136 adults with an office-measured blood pressure of at least 140/90 mm Hg despite being on a stable regimen of at least three antihypertensive drugs including a diuretic. The enrolled cohort averaged 52 years of age and had an average office-measured pressure of about 162/104 mm Hg despite being on an average of four agents, although only about a third of enrolled patients were on treatment with a mineralocorticoid-receptor antagonist (MRA) such as spironolactone.

At the time of enrollment and 4 weeks before their denervation procedure, all patients switched to a uniform drug regimen of a single, daily, oral pill containing the calcium channel blocker amlodipine, the angiotensin receptor blocker valsartan or olmesartan, and the diuretic hydrochlorothiazide with no other drug treatment allowed except for unusual, prespecified clinical circumstances. All patients remained on this drug regimen for the initial 2-month follow-up period unless their blood pressure exceeded 180/110 mm Hg during in-office measurement.

The denervation treatment was well tolerated, although patients reported brief, transient, and “minor” pain associated with the procedure that did not affect treatment blinding or have any lingering consequences, said Dr. Kirtane, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons in New York.

A reason to use energy delivery by ultrasound rather than by radiofrequency to ablate nerves in the renal arteries is that the ultrasound approach exerts a more uniform effect, allowing effective treatment delivery without need for catheter repositioning into more distal branches of the renal arteries, said Dr. Kirtane, who is also an interventional cardiologist at NewYork-Presbyterian/Columbia University Irving Medical Center.

But each method has its advantages, he added.

He also conceded that additional questions need to be addressed regarding which patients are most appropriate for renal denervation. “We need to figure out in which patients we can apply a device-based treatment,” Dr. Kirtane said during the press briefing. Patients with what appears to be drug-resistant hypertension often do not receive treatment with a MRA because of adverse effects, and many of these patients are not usually assessed for primary aldosteronism.

In SYMPLICITY HTN-3, “about half the patients who were seemingly eligible became ineligible” when they started treatment with a MRA, noted Dr. Bhatt. “A little spironolactone can go a long way” toward resolving treatment-resistant hypertension in many patients, he said.

RADIANCE-HTN TRIO was sponsored by ReCor Medical, the company developing the tested ultrasound catheter. Dr. Kirtane has received travel expenses and meals from ReCor Medical and several other companies, and Columbia has received research funding from ReCor Medical and several other companies related to research he has conducted. Dr. Bhatt has no relationship with ReCor Medical. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an advisor to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies.

[email protected]

For patients with ST-elevated myocardial infarction (STEMI) undergoing complete revascularization, percutaneous coronary interventions (PCI) guided by fractional flow reserve (FFR) relative to angiography-guided PCI do not result in significantly lower risk of death or events, according to data from the randomized FLOWER-MI trial.

Wolfgang Filser/EyeEm/Getty Images

Rather, the events at 1 year were numerically lower among those randomized to the angiography-guided approach, according to the principal investigator of the trial, Etienne Puymirat, MD, PhD.

Prior studies showing an advantage for FFR-guided PCI in patients with coronary syndromes provided the hypothesis that FFR-guided PCI would also be superior for guiding PCI in STEMI patients. In the multicenter FAME trial, for example, FFR-guided PCI for patients with multivessel disease was associated with fewer stent placements (P < .001) and a nearly 30% lower rate of events at 1 year (P = .02).

While the advantage of complete revascularization, meaning PCI treatment of nonculprit as well as culprit lesions, has already been shown to be a better strategy than treatment of culprit lesions alone, FLOWER-MI is the first large study to compare FFR to angiography for guiding this approach to STEMI patients with multivessel disease, said Dr. Puymirat of Hôpital Européen George Pompidou, Paris, at the annual scientific sessions of the American College of Cardiology.

In this trial, involving multiple centers in France, STEMI patients were eligible for randomization if they had successful PCI of a culprit lesion and 50% or greater stenosis in at least one additional nonculprit lesion. The complete revascularization, whether patients were randomized to PCI guided by angiography or FFR, was performed during the index hospital admission. Patient management and follow-up was otherwise the same.

After a small number of exclusions, the intention-to-treat populations were 577 patients in the angiography-guided group and 586 in the FFR-guided group. The characteristics of the groups were well matched with an average age of about 62 years and similar rates of risk factors, such as hypertension and diabetes.

Angiography guidance just as good

The primary outcome was a composite of all-cause mortality, nonfatal MI, and unplanned revascularization. By hazard ratio, the risk of having one of these events within 1 year of PCI was numerically greater, at 32 in the FFR-guided group and 24 in the angiography-guided group, but the difference was not statistically significant (1.32; P = .31).

However, the total rate of events was low (5.5% vs. 4.2% for the angiography-guided and FFR-guided groups, respectively) and the confidence intervals were wide (95% CI, 0.78-2.23). This was also true of the components of the primary outcome.

No signal for a difference between strategies could be derived from these components, which included a higher rate of MI in the FFR-guided group (3.1% vs. 1.7%) but a lower rate of death (1.5% vs. 1.7%).

Unplanned hospitalizations leading to revascularization rates were also low (1.9% and 2.6% for angiography-guided and FFR-guided PCI, respectively), although it was reported that the rate of revascularization for nonculprit lesions was about twice as high in the FFR group (53.3% vs. 27.3%).

At 1 year, there were also low rates and no significant differences in a list of secondary outcomes that included hospitalization for recurrent ischemia or heart failure, stent thrombosis, and revascularization. As within the primary composite outcome, no pattern could be seen in the secondary events, some of which were numerically more common in the FFR-guided group and some numerically lower.

In a cost-efficacy analysis, the median per-patient cost of the FFR-guided strategy was about 500 Euros ($607) greater (8,832 vs. 8,322; P < .01), leading Dr. Puymirat to conclude that “the use of FFR for nonculprit lesions appears to be less effective but more expensive,” at least by costs derived in France.

Lack of statistical power limits interpretation

The conclusion of FLOWER-MI is that FFR-guided PCI in complete revascularization of nonculprit lesions in STEMI patients is not superior to an angiography-guided approach, but Dr. Puymirat cautioned that the low number of events precludes a definitive message.

William Fearon, MD, professor of cardiovascular medicine at Stanford (Calif.) University Medical Center, agreed. Based on his calculations, the trial was substantially underpowered. Evaluating the details of treatment in the FFR group, Dr. Fearon pointed out that a nonculprit lesion with a FFR of 0.80 or less was identified in about 55% of patients. Ultimately, 66% in the FFR group received PCI, eliminating the key distinction between strategies for the majority of patients enrolled.

“Only about one-third of the FFR-guided patients, or about 200 patients, did not receive nonculprit PCI, and therefore only in this small group could we expect a difference in outcomes from the angio-guided group,” Dr. Fearon said.

Fewer stents were placed in the FFR-guided than angiography-guided group (1.01 vs. 1.5), but Dr. Fearon suggested that it would be very difficult to show a difference in risk of events in a study of this size when event rates at 1 year reached only about 5%.

In response, Dr. Puymirat acknowledged that the rate of events for this trial, which was designed in 2015, were lower than expected. In recalculating the power needed based on the rate of events observed in FLOWER-MI, he estimated that about 8,000 patients would have been needed to show a meaningful difference in these PCI strategies.

Dr. Puymirat reports financial relationships with more than a dozen pharmaceutical companies, including Abbott, which provided some of the funding for this trial. Dr. Fearon reports financial relationships with Abbott, CathWorks, HeartFlow, and Medtronic.

For patients with ST-elevated myocardial infarction (STEMI) undergoing complete revascularization, percutaneous coronary interventions (PCI) guided by fractional flow reserve (FFR) relative to angiography-guided PCI do not result in significantly lower risk of death or events, according to data from the randomized FLOWER-MI trial.

Wolfgang Filser/EyeEm/Getty Images

Rather, the events at 1 year were numerically lower among those randomized to the angiography-guided approach, according to the principal investigator of the trial, Etienne Puymirat, MD, PhD.

Prior studies showing an advantage for FFR-guided PCI in patients with coronary syndromes provided the hypothesis that FFR-guided PCI would also be superior for guiding PCI in STEMI patients. In the multicenter FAME trial, for example, FFR-guided PCI for patients with multivessel disease was associated with fewer stent placements (P < .001) and a nearly 30% lower rate of events at 1 year (P = .02).

While the advantage of complete revascularization, meaning PCI treatment of nonculprit as well as culprit lesions, has already been shown to be a better strategy than treatment of culprit lesions alone, FLOWER-MI is the first large study to compare FFR to angiography for guiding this approach to STEMI patients with multivessel disease, said Dr. Puymirat of Hôpital Européen George Pompidou, Paris, at the annual scientific sessions of the American College of Cardiology.

In this trial, involving multiple centers in France, STEMI patients were eligible for randomization if they had successful PCI of a culprit lesion and 50% or greater stenosis in at least one additional nonculprit lesion. The complete revascularization, whether patients were randomized to PCI guided by angiography or FFR, was performed during the index hospital admission. Patient management and follow-up was otherwise the same.

After a small number of exclusions, the intention-to-treat populations were 577 patients in the angiography-guided group and 586 in the FFR-guided group. The characteristics of the groups were well matched with an average age of about 62 years and similar rates of risk factors, such as hypertension and diabetes.

Angiography guidance just as good

The primary outcome was a composite of all-cause mortality, nonfatal MI, and unplanned revascularization. By hazard ratio, the risk of having one of these events within 1 year of PCI was numerically greater, at 32 in the FFR-guided group and 24 in the angiography-guided group, but the difference was not statistically significant (1.32; P = .31).

However, the total rate of events was low (5.5% vs. 4.2% for the angiography-guided and FFR-guided groups, respectively) and the confidence intervals were wide (95% CI, 0.78-2.23). This was also true of the components of the primary outcome.

No signal for a difference between strategies could be derived from these components, which included a higher rate of MI in the FFR-guided group (3.1% vs. 1.7%) but a lower rate of death (1.5% vs. 1.7%).

Unplanned hospitalizations leading to revascularization rates were also low (1.9% and 2.6% for angiography-guided and FFR-guided PCI, respectively), although it was reported that the rate of revascularization for nonculprit lesions was about twice as high in the FFR group (53.3% vs. 27.3%).

At 1 year, there were also low rates and no significant differences in a list of secondary outcomes that included hospitalization for recurrent ischemia or heart failure, stent thrombosis, and revascularization. As within the primary composite outcome, no pattern could be seen in the secondary events, some of which were numerically more common in the FFR-guided group and some numerically lower.

In a cost-efficacy analysis, the median per-patient cost of the FFR-guided strategy was about 500 Euros ($607) greater (8,832 vs. 8,322; P < .01), leading Dr. Puymirat to conclude that “the use of FFR for nonculprit lesions appears to be less effective but more expensive,” at least by costs derived in France.

Lack of statistical power limits interpretation

The conclusion of FLOWER-MI is that FFR-guided PCI in complete revascularization of nonculprit lesions in STEMI patients is not superior to an angiography-guided approach, but Dr. Puymirat cautioned that the low number of events precludes a definitive message.

William Fearon, MD, professor of cardiovascular medicine at Stanford (Calif.) University Medical Center, agreed. Based on his calculations, the trial was substantially underpowered. Evaluating the details of treatment in the FFR group, Dr. Fearon pointed out that a nonculprit lesion with a FFR of 0.80 or less was identified in about 55% of patients. Ultimately, 66% in the FFR group received PCI, eliminating the key distinction between strategies for the majority of patients enrolled.

“Only about one-third of the FFR-guided patients, or about 200 patients, did not receive nonculprit PCI, and therefore only in this small group could we expect a difference in outcomes from the angio-guided group,” Dr. Fearon said.

Fewer stents were placed in the FFR-guided than angiography-guided group (1.01 vs. 1.5), but Dr. Fearon suggested that it would be very difficult to show a difference in risk of events in a study of this size when event rates at 1 year reached only about 5%.

In response, Dr. Puymirat acknowledged that the rate of events for this trial, which was designed in 2015, were lower than expected. In recalculating the power needed based on the rate of events observed in FLOWER-MI, he estimated that about 8,000 patients would have been needed to show a meaningful difference in these PCI strategies.

Dr. Puymirat reports financial relationships with more than a dozen pharmaceutical companies, including Abbott, which provided some of the funding for this trial. Dr. Fearon reports financial relationships with Abbott, CathWorks, HeartFlow, and Medtronic.

For patients with ST-elevated myocardial infarction (STEMI) undergoing complete revascularization, percutaneous coronary interventions (PCI) guided by fractional flow reserve (FFR) relative to angiography-guided PCI do not result in significantly lower risk of death or events, according to data from the randomized FLOWER-MI trial.

Wolfgang Filser/EyeEm/Getty Images

Rather, the events at 1 year were numerically lower among those randomized to the angiography-guided approach, according to the principal investigator of the trial, Etienne Puymirat, MD, PhD.

Prior studies showing an advantage for FFR-guided PCI in patients with coronary syndromes provided the hypothesis that FFR-guided PCI would also be superior for guiding PCI in STEMI patients. In the multicenter FAME trial, for example, FFR-guided PCI for patients with multivessel disease was associated with fewer stent placements (P < .001) and a nearly 30% lower rate of events at 1 year (P = .02).

While the advantage of complete revascularization, meaning PCI treatment of nonculprit as well as culprit lesions, has already been shown to be a better strategy than treatment of culprit lesions alone, FLOWER-MI is the first large study to compare FFR to angiography for guiding this approach to STEMI patients with multivessel disease, said Dr. Puymirat of Hôpital Européen George Pompidou, Paris, at the annual scientific sessions of the American College of Cardiology.

In this trial, involving multiple centers in France, STEMI patients were eligible for randomization if they had successful PCI of a culprit lesion and 50% or greater stenosis in at least one additional nonculprit lesion. The complete revascularization, whether patients were randomized to PCI guided by angiography or FFR, was performed during the index hospital admission. Patient management and follow-up was otherwise the same.

After a small number of exclusions, the intention-to-treat populations were 577 patients in the angiography-guided group and 586 in the FFR-guided group. The characteristics of the groups were well matched with an average age of about 62 years and similar rates of risk factors, such as hypertension and diabetes.

Angiography guidance just as good

The primary outcome was a composite of all-cause mortality, nonfatal MI, and unplanned revascularization. By hazard ratio, the risk of having one of these events within 1 year of PCI was numerically greater, at 32 in the FFR-guided group and 24 in the angiography-guided group, but the difference was not statistically significant (1.32; P = .31).

However, the total rate of events was low (5.5% vs. 4.2% for the angiography-guided and FFR-guided groups, respectively) and the confidence intervals were wide (95% CI, 0.78-2.23). This was also true of the components of the primary outcome.

No signal for a difference between strategies could be derived from these components, which included a higher rate of MI in the FFR-guided group (3.1% vs. 1.7%) but a lower rate of death (1.5% vs. 1.7%).

Unplanned hospitalizations leading to revascularization rates were also low (1.9% and 2.6% for angiography-guided and FFR-guided PCI, respectively), although it was reported that the rate of revascularization for nonculprit lesions was about twice as high in the FFR group (53.3% vs. 27.3%).

At 1 year, there were also low rates and no significant differences in a list of secondary outcomes that included hospitalization for recurrent ischemia or heart failure, stent thrombosis, and revascularization. As within the primary composite outcome, no pattern could be seen in the secondary events, some of which were numerically more common in the FFR-guided group and some numerically lower.

In a cost-efficacy analysis, the median per-patient cost of the FFR-guided strategy was about 500 Euros ($607) greater (8,832 vs. 8,322; P < .01), leading Dr. Puymirat to conclude that “the use of FFR for nonculprit lesions appears to be less effective but more expensive,” at least by costs derived in France.

Lack of statistical power limits interpretation

The conclusion of FLOWER-MI is that FFR-guided PCI in complete revascularization of nonculprit lesions in STEMI patients is not superior to an angiography-guided approach, but Dr. Puymirat cautioned that the low number of events precludes a definitive message.

William Fearon, MD, professor of cardiovascular medicine at Stanford (Calif.) University Medical Center, agreed. Based on his calculations, the trial was substantially underpowered. Evaluating the details of treatment in the FFR group, Dr. Fearon pointed out that a nonculprit lesion with a FFR of 0.80 or less was identified in about 55% of patients. Ultimately, 66% in the FFR group received PCI, eliminating the key distinction between strategies for the majority of patients enrolled.

“Only about one-third of the FFR-guided patients, or about 200 patients, did not receive nonculprit PCI, and therefore only in this small group could we expect a difference in outcomes from the angio-guided group,” Dr. Fearon said.

Fewer stents were placed in the FFR-guided than angiography-guided group (1.01 vs. 1.5), but Dr. Fearon suggested that it would be very difficult to show a difference in risk of events in a study of this size when event rates at 1 year reached only about 5%.

In response, Dr. Puymirat acknowledged that the rate of events for this trial, which was designed in 2015, were lower than expected. In recalculating the power needed based on the rate of events observed in FLOWER-MI, he estimated that about 8,000 patients would have been needed to show a meaningful difference in these PCI strategies.

Dr. Puymirat reports financial relationships with more than a dozen pharmaceutical companies, including Abbott, which provided some of the funding for this trial. Dr. Fearon reports financial relationships with Abbott, CathWorks, HeartFlow, and Medtronic.

Patients with chronic lymphocytic leukemia (CLL) have increased risk for severe COVID-19 disease as well as mortality.

South_agency/Getty Images

Such patients are likely to have compromised immune systems, making them respond poorly to vaccines, as has been seen in studies involving pneumococcal, hepatitis B, and influenza A and B vaccination. 

In order to determine if vaccination against COVID-19 disease will be effective among these patients, researchers performed a study to determine the efficacy of a single COVID-19 vaccine in patients with CLL. They found that the response rate of patients with CLL to vaccination was significantly lower than that of healthy controls, according to the study published in Blood Advances.

Study details

The study (NCT04746092) assessed the humoral immune responses to BNT162b2 mRNA COVID-19 (Pfizer) vaccination in adult patients with CLL and compared responses with those obtained in age-matched healthy controls. Patients received two vaccine doses, 21 days apart, and antibody titers were measured 2-3 weeks after administration of the second dose, according to Yair Herishanu, MD, of the Tel-Aviv Sourasky Medical Center, Tel Aviv University, and colleagues.

Troubling results

The researchers found an antibody-mediated response to the BNT162b2 mRNA COVID-19 vaccine in only 66 of 167 (39.5%) of all patients with CLL. The response rate of 52 of these responding patients with CLL to the vaccine was significantly lower than that occurring in 52 age- and sex-matched healthy controls (52% vs. 100%, respectively; adjusted odds ratio, 0.010; 95% confidence interval, 0.001-0.162; P < .001). 

Among the patients with CLL, the response rate was highest in those who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naive patients, and it was only 16% in patients under treatment at the time of vaccination. 

In patients treated with either BTK inhibitors or venetoclax with and without anti-CD20 antibody, response rates were low (16.0% and 13.6%, respectively). In particular, none of the patients exposed to anti-CD20 antibodies less than 12 months prior to vaccination responded, according to the researchers.

Multivariate analysis showed that the independent predictors of a vaccine response were age (65 years or younger; odds ratio, 3.17; P = .025), sex (women; OR, 3.66; P = .006), lack of active therapy (including treatment naive and previously treated patients; OR 6.59; P < .001), IgG levels 550 mg/dL or greater (OR, 3.70; P = .037), and IgM levels 40mg/dL or greater (OR, 2.92; P = .017). 

Within a median follow-up period of 75 days since the first vaccine dose, none of the CLL patients developed COVID-19 infection, the researchers reported.

“Vaccinated patients with CLL should continue to adhere to masking, social distancing, and vaccination of their close contacts should be strongly recommended. Serological tests after the second injection of the COVID-19 vaccine can provide valuable information to the individual patient and perhaps, may be integrated in future clinical decisions,” the researchers concluded.

The study was sponsored by the Tel-Aviv Sourasky Medical Center. The authors reported that they had no conflicts of interest. 

[email protected] 

Patients with chronic lymphocytic leukemia (CLL) have increased risk for severe COVID-19 disease as well as mortality.

South_agency/Getty Images

Such patients are likely to have compromised immune systems, making them respond poorly to vaccines, as has been seen in studies involving pneumococcal, hepatitis B, and influenza A and B vaccination. 

In order to determine if vaccination against COVID-19 disease will be effective among these patients, researchers performed a study to determine the efficacy of a single COVID-19 vaccine in patients with CLL. They found that the response rate of patients with CLL to vaccination was significantly lower than that of healthy controls, according to the study published in Blood Advances.

Study details

The study (NCT04746092) assessed the humoral immune responses to BNT162b2 mRNA COVID-19 (Pfizer) vaccination in adult patients with CLL and compared responses with those obtained in age-matched healthy controls. Patients received two vaccine doses, 21 days apart, and antibody titers were measured 2-3 weeks after administration of the second dose, according to Yair Herishanu, MD, of the Tel-Aviv Sourasky Medical Center, Tel Aviv University, and colleagues.

Troubling results

The researchers found an antibody-mediated response to the BNT162b2 mRNA COVID-19 vaccine in only 66 of 167 (39.5%) of all patients with CLL. The response rate of 52 of these responding patients with CLL to the vaccine was significantly lower than that occurring in 52 age- and sex-matched healthy controls (52% vs. 100%, respectively; adjusted odds ratio, 0.010; 95% confidence interval, 0.001-0.162; P < .001). 

Among the patients with CLL, the response rate was highest in those who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naive patients, and it was only 16% in patients under treatment at the time of vaccination. 

In patients treated with either BTK inhibitors or venetoclax with and without anti-CD20 antibody, response rates were low (16.0% and 13.6%, respectively). In particular, none of the patients exposed to anti-CD20 antibodies less than 12 months prior to vaccination responded, according to the researchers.

Multivariate analysis showed that the independent predictors of a vaccine response were age (65 years or younger; odds ratio, 3.17; P = .025), sex (women; OR, 3.66; P = .006), lack of active therapy (including treatment naive and previously treated patients; OR 6.59; P < .001), IgG levels 550 mg/dL or greater (OR, 3.70; P = .037), and IgM levels 40mg/dL or greater (OR, 2.92; P = .017). 

Within a median follow-up period of 75 days since the first vaccine dose, none of the CLL patients developed COVID-19 infection, the researchers reported.

“Vaccinated patients with CLL should continue to adhere to masking, social distancing, and vaccination of their close contacts should be strongly recommended. Serological tests after the second injection of the COVID-19 vaccine can provide valuable information to the individual patient and perhaps, may be integrated in future clinical decisions,” the researchers concluded.

The study was sponsored by the Tel-Aviv Sourasky Medical Center. The authors reported that they had no conflicts of interest. 

[email protected] 

Patients with chronic lymphocytic leukemia (CLL) have increased risk for severe COVID-19 disease as well as mortality.

South_agency/Getty Images

Such patients are likely to have compromised immune systems, making them respond poorly to vaccines, as has been seen in studies involving pneumococcal, hepatitis B, and influenza A and B vaccination. 

In order to determine if vaccination against COVID-19 disease will be effective among these patients, researchers performed a study to determine the efficacy of a single COVID-19 vaccine in patients with CLL. They found that the response rate of patients with CLL to vaccination was significantly lower than that of healthy controls, according to the study published in Blood Advances.

Study details

The study (NCT04746092) assessed the humoral immune responses to BNT162b2 mRNA COVID-19 (Pfizer) vaccination in adult patients with CLL and compared responses with those obtained in age-matched healthy controls. Patients received two vaccine doses, 21 days apart, and antibody titers were measured 2-3 weeks after administration of the second dose, according to Yair Herishanu, MD, of the Tel-Aviv Sourasky Medical Center, Tel Aviv University, and colleagues.

Troubling results

The researchers found an antibody-mediated response to the BNT162b2 mRNA COVID-19 vaccine in only 66 of 167 (39.5%) of all patients with CLL. The response rate of 52 of these responding patients with CLL to the vaccine was significantly lower than that occurring in 52 age- and sex-matched healthy controls (52% vs. 100%, respectively; adjusted odds ratio, 0.010; 95% confidence interval, 0.001-0.162; P < .001). 

Among the patients with CLL, the response rate was highest in those who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naive patients, and it was only 16% in patients under treatment at the time of vaccination. 

In patients treated with either BTK inhibitors or venetoclax with and without anti-CD20 antibody, response rates were low (16.0% and 13.6%, respectively). In particular, none of the patients exposed to anti-CD20 antibodies less than 12 months prior to vaccination responded, according to the researchers.

Multivariate analysis showed that the independent predictors of a vaccine response were age (65 years or younger; odds ratio, 3.17; P = .025), sex (women; OR, 3.66; P = .006), lack of active therapy (including treatment naive and previously treated patients; OR 6.59; P < .001), IgG levels 550 mg/dL or greater (OR, 3.70; P = .037), and IgM levels 40mg/dL or greater (OR, 2.92; P = .017). 

Within a median follow-up period of 75 days since the first vaccine dose, none of the CLL patients developed COVID-19 infection, the researchers reported.

“Vaccinated patients with CLL should continue to adhere to masking, social distancing, and vaccination of their close contacts should be strongly recommended. Serological tests after the second injection of the COVID-19 vaccine can provide valuable information to the individual patient and perhaps, may be integrated in future clinical decisions,” the researchers concluded.

The study was sponsored by the Tel-Aviv Sourasky Medical Center. The authors reported that they had no conflicts of interest. 

[email protected] 

Significant improvement in the control of symptoms related to paroxysmal supraventricular tachycardia (PSVT) is resurrecting etripamil as a self-administered nasal spray a year after it failed to meet the primary endpoint in a phase 3 trial, according to a new analysis from this same study presented at the annual scientific sessions of the American College of Cardiology.

Thinkstock

In the phase 3 NODE-301 trial, presented at the 2020 Heart Rhythm Society annual meeting, etripamil did not show an advantage over placebo at 5 hours for achieving sinus rhythm. Nevertheless, a new presentation of the secondary outcomes suggests substantial clinical benefit.

These advantages include significant reductions in PSVT symptoms, a trend for fewer emergency room visits, and a degree of patient satisfaction that appears meaningful, according to Bruce S. Stambler, MD, an electrophysiologist affiliated with Piedmont Heart Institute, Atlanta.

The data, despite the phase 3 trial results, “support continued development of etripamil nasal spray acute treatment of PSVT,” Dr. Stambler said.
Etripamil is an L-type calcium channel blocker. When administered by nasal spray, it reaches peak effects within about 10 minutes. But the action is short, with a decline in antiarrhythmia effects beginning about 30 minutes after the peak effect. 

In the NODE-301 trial, which employed a 2:1 randomization ratio, 138 patients self-administered 70 mg of etripamil or placebo immediately upon experiencing a suspected episode of PSVT.

Up until 45 minutes, the proportion of episodes that converted to sinus rhythm was about 66% greater (hazard ratio, 1.66; P = .02) on etripamil than placebo, but the advantage was then lost. By predefined primary endpoint of 5 hours, when 100% of placebo patients but not all etripamil patients had converted, there was a slight but nonstatistical advantage for placebo (HR 1.08; P = .1212).

However, because of the rapid onset and then the rapid offset of this agent, the 5-hour time point for comparing effects might not have been the optimal duration to compare effects, according to Dr. Stambler.

On the basis of safety of etripamil, which was not associated with any significant adverse events in NODE-301, and the early clinical effect, the investigators have looked again at the data.

For relief of patient-reported symptoms and patient-reported satisfaction, which were secondary endpoints of the study, the data support a clinical role, according to this new analysis. 

Specifically, there were large differences on a 7-point scale for all of the measured symptoms of PSVT in favor of etripamil, including rapid pulse (P = .002), palpitations (P = .0001), dizziness (P = 0.01), shortness of breath (P = 0.008), and anxiety (P = 0.006). A numerical advantage for chest pain did not reach significance.

“In general, patients reported scores of 4 to 5 on this scale, which corresponds to ‘not satisfied’ to ‘satisfied,’ while the placebo-treated patients reported scores of 2 to 3, which corresponds to ‘dissatisfied’ or ‘very dissatisfied,’ ” Dr. Stambler reported.

The favorable patient experience is also reflected in the Treatment Satisfaction with Questionnaire for Medication (TSQM-9), which was another NODE-301 endpoint. Evaluated when patients were still blinded to their assigned therapy, the advantage of etripamil over placebo for both global satisfaction (P = .007) and treatment effectiveness (P = .002) were also highly statistically significant.

The subjective experience of patients appeared to be reflected in objective measures. When the two groups were compared for interventions in an emergency room, the need was reduced by about half (12.1% vs. 24.5%; P = .051) among those treated with etripamil. Although this just missed the conventional measure of statistical significance, it was close. Similarly, patients randomized to etripamil required numerically fewer rescue medications (14.0% vs. 26.5%; P = .059). 

Adenosine was the most common of the rescue medications, according to Dr. Stambler. He said there was no difference between the groups in use of rescue oral therapies.

When comparing etripamil and placebo in the subgroup that did visit an emergency room for PSVT, there was a delay in ER visits among those randomized to etripamil (116 vs. 79 minutes; P < 0.05), suggesting that this agent reduced the sense of urgency when PSVT symptoms develop, according to Dr. Stambler.

On average, the patients who enrolled in this trial had a PSVT history of about 1.5 years. In the year prior to enrollment, the mean number of ER visits was about nine. 

In the trial design, patients were required to take a test dose of etripamil under observation by a physician before being sent home with their assigned therapy, but Dr. Stambler does not believe that the requirement, if the drug is approved, will be in the label. 

Unexpectedly, many patients had symptom relief even without converting to sinus rhythm, Dr. Stambler acknowledged. He speculated that the reduction in heart rate associated with etripamil might have provided a relief of symptoms sufficient to relieve anxiety, producing the relative advantage for patient satisfaction.

Jodie L. Hurwitz, MD, director of the electrophysiology lab at Medical City Hospital, Dallas, indicated that there is a need for new options for PSVT. An expert panelist during the session where these data were presented, she was particularly interested in rapid symptom relief. 

“It would be great to have a therapy that could be self-administered at home. Patients would like it, too,” she said. 

Mary N. Walsh, MD, a heart failure specialist affiliated with Indiana University, Indianapolis, sees a potential role of a self-administered therapy like etripamil in conjunction with wearable devices. She noted that the proportion of patients using these devices to monitor arrhythmias is increasing, providing a role for an easily transportable therapy that could be used quickly when symptoms develop. 

However, after the negative phase 3 trial, more data must now be collected to satisfy the regulatory authorities that this agent is safe and effective. Dr. Stambler said that the developer is now committed to pursue these studies.

Dr. Stambler has a financial relationship with Milestone Pharmaceuticals, which is developing etripamil nasal spray and was the sponsor of this trial. Dr. Walsh and Dr. Hurwitz have no potential relevant conflicts of interest.
 

Significant improvement in the control of symptoms related to paroxysmal supraventricular tachycardia (PSVT) is resurrecting etripamil as a self-administered nasal spray a year after it failed to meet the primary endpoint in a phase 3 trial, according to a new analysis from this same study presented at the annual scientific sessions of the American College of Cardiology.

Thinkstock

In the phase 3 NODE-301 trial, presented at the 2020 Heart Rhythm Society annual meeting, etripamil did not show an advantage over placebo at 5 hours for achieving sinus rhythm. Nevertheless, a new presentation of the secondary outcomes suggests substantial clinical benefit.

These advantages include significant reductions in PSVT symptoms, a trend for fewer emergency room visits, and a degree of patient satisfaction that appears meaningful, according to Bruce S. Stambler, MD, an electrophysiologist affiliated with Piedmont Heart Institute, Atlanta.

The data, despite the phase 3 trial results, “support continued development of etripamil nasal spray acute treatment of PSVT,” Dr. Stambler said.
Etripamil is an L-type calcium channel blocker. When administered by nasal spray, it reaches peak effects within about 10 minutes. But the action is short, with a decline in antiarrhythmia effects beginning about 30 minutes after the peak effect. 

In the NODE-301 trial, which employed a 2:1 randomization ratio, 138 patients self-administered 70 mg of etripamil or placebo immediately upon experiencing a suspected episode of PSVT.

Up until 45 minutes, the proportion of episodes that converted to sinus rhythm was about 66% greater (hazard ratio, 1.66; P = .02) on etripamil than placebo, but the advantage was then lost. By predefined primary endpoint of 5 hours, when 100% of placebo patients but not all etripamil patients had converted, there was a slight but nonstatistical advantage for placebo (HR 1.08; P = .1212).

However, because of the rapid onset and then the rapid offset of this agent, the 5-hour time point for comparing effects might not have been the optimal duration to compare effects, according to Dr. Stambler.

On the basis of safety of etripamil, which was not associated with any significant adverse events in NODE-301, and the early clinical effect, the investigators have looked again at the data.

For relief of patient-reported symptoms and patient-reported satisfaction, which were secondary endpoints of the study, the data support a clinical role, according to this new analysis. 

Specifically, there were large differences on a 7-point scale for all of the measured symptoms of PSVT in favor of etripamil, including rapid pulse (P = .002), palpitations (P = .0001), dizziness (P = 0.01), shortness of breath (P = 0.008), and anxiety (P = 0.006). A numerical advantage for chest pain did not reach significance.

“In general, patients reported scores of 4 to 5 on this scale, which corresponds to ‘not satisfied’ to ‘satisfied,’ while the placebo-treated patients reported scores of 2 to 3, which corresponds to ‘dissatisfied’ or ‘very dissatisfied,’ ” Dr. Stambler reported.

The favorable patient experience is also reflected in the Treatment Satisfaction with Questionnaire for Medication (TSQM-9), which was another NODE-301 endpoint. Evaluated when patients were still blinded to their assigned therapy, the advantage of etripamil over placebo for both global satisfaction (P = .007) and treatment effectiveness (P = .002) were also highly statistically significant.

The subjective experience of patients appeared to be reflected in objective measures. When the two groups were compared for interventions in an emergency room, the need was reduced by about half (12.1% vs. 24.5%; P = .051) among those treated with etripamil. Although this just missed the conventional measure of statistical significance, it was close. Similarly, patients randomized to etripamil required numerically fewer rescue medications (14.0% vs. 26.5%; P = .059). 

Adenosine was the most common of the rescue medications, according to Dr. Stambler. He said there was no difference between the groups in use of rescue oral therapies.

When comparing etripamil and placebo in the subgroup that did visit an emergency room for PSVT, there was a delay in ER visits among those randomized to etripamil (116 vs. 79 minutes; P < 0.05), suggesting that this agent reduced the sense of urgency when PSVT symptoms develop, according to Dr. Stambler.

On average, the patients who enrolled in this trial had a PSVT history of about 1.5 years. In the year prior to enrollment, the mean number of ER visits was about nine. 

In the trial design, patients were required to take a test dose of etripamil under observation by a physician before being sent home with their assigned therapy, but Dr. Stambler does not believe that the requirement, if the drug is approved, will be in the label. 

Unexpectedly, many patients had symptom relief even without converting to sinus rhythm, Dr. Stambler acknowledged. He speculated that the reduction in heart rate associated with etripamil might have provided a relief of symptoms sufficient to relieve anxiety, producing the relative advantage for patient satisfaction.

Jodie L. Hurwitz, MD, director of the electrophysiology lab at Medical City Hospital, Dallas, indicated that there is a need for new options for PSVT. An expert panelist during the session where these data were presented, she was particularly interested in rapid symptom relief. 

“It would be great to have a therapy that could be self-administered at home. Patients would like it, too,” she said. 

Mary N. Walsh, MD, a heart failure specialist affiliated with Indiana University, Indianapolis, sees a potential role of a self-administered therapy like etripamil in conjunction with wearable devices. She noted that the proportion of patients using these devices to monitor arrhythmias is increasing, providing a role for an easily transportable therapy that could be used quickly when symptoms develop. 

However, after the negative phase 3 trial, more data must now be collected to satisfy the regulatory authorities that this agent is safe and effective. Dr. Stambler said that the developer is now committed to pursue these studies.

Dr. Stambler has a financial relationship with Milestone Pharmaceuticals, which is developing etripamil nasal spray and was the sponsor of this trial. Dr. Walsh and Dr. Hurwitz have no potential relevant conflicts of interest.
 

Significant improvement in the control of symptoms related to paroxysmal supraventricular tachycardia (PSVT) is resurrecting etripamil as a self-administered nasal spray a year after it failed to meet the primary endpoint in a phase 3 trial, according to a new analysis from this same study presented at the annual scientific sessions of the American College of Cardiology.

Thinkstock

In the phase 3 NODE-301 trial, presented at the 2020 Heart Rhythm Society annual meeting, etripamil did not show an advantage over placebo at 5 hours for achieving sinus rhythm. Nevertheless, a new presentation of the secondary outcomes suggests substantial clinical benefit.

These advantages include significant reductions in PSVT symptoms, a trend for fewer emergency room visits, and a degree of patient satisfaction that appears meaningful, according to Bruce S. Stambler, MD, an electrophysiologist affiliated with Piedmont Heart Institute, Atlanta.

The data, despite the phase 3 trial results, “support continued development of etripamil nasal spray acute treatment of PSVT,” Dr. Stambler said.
Etripamil is an L-type calcium channel blocker. When administered by nasal spray, it reaches peak effects within about 10 minutes. But the action is short, with a decline in antiarrhythmia effects beginning about 30 minutes after the peak effect. 

In the NODE-301 trial, which employed a 2:1 randomization ratio, 138 patients self-administered 70 mg of etripamil or placebo immediately upon experiencing a suspected episode of PSVT.

Up until 45 minutes, the proportion of episodes that converted to sinus rhythm was about 66% greater (hazard ratio, 1.66; P = .02) on etripamil than placebo, but the advantage was then lost. By predefined primary endpoint of 5 hours, when 100% of placebo patients but not all etripamil patients had converted, there was a slight but nonstatistical advantage for placebo (HR 1.08; P = .1212).

However, because of the rapid onset and then the rapid offset of this agent, the 5-hour time point for comparing effects might not have been the optimal duration to compare effects, according to Dr. Stambler.

On the basis of safety of etripamil, which was not associated with any significant adverse events in NODE-301, and the early clinical effect, the investigators have looked again at the data.

For relief of patient-reported symptoms and patient-reported satisfaction, which were secondary endpoints of the study, the data support a clinical role, according to this new analysis. 

Specifically, there were large differences on a 7-point scale for all of the measured symptoms of PSVT in favor of etripamil, including rapid pulse (P = .002), palpitations (P = .0001), dizziness (P = 0.01), shortness of breath (P = 0.008), and anxiety (P = 0.006). A numerical advantage for chest pain did not reach significance.

“In general, patients reported scores of 4 to 5 on this scale, which corresponds to ‘not satisfied’ to ‘satisfied,’ while the placebo-treated patients reported scores of 2 to 3, which corresponds to ‘dissatisfied’ or ‘very dissatisfied,’ ” Dr. Stambler reported.

The favorable patient experience is also reflected in the Treatment Satisfaction with Questionnaire for Medication (TSQM-9), which was another NODE-301 endpoint. Evaluated when patients were still blinded to their assigned therapy, the advantage of etripamil over placebo for both global satisfaction (P = .007) and treatment effectiveness (P = .002) were also highly statistically significant.

The subjective experience of patients appeared to be reflected in objective measures. When the two groups were compared for interventions in an emergency room, the need was reduced by about half (12.1% vs. 24.5%; P = .051) among those treated with etripamil. Although this just missed the conventional measure of statistical significance, it was close. Similarly, patients randomized to etripamil required numerically fewer rescue medications (14.0% vs. 26.5%; P = .059). 

Adenosine was the most common of the rescue medications, according to Dr. Stambler. He said there was no difference between the groups in use of rescue oral therapies.

When comparing etripamil and placebo in the subgroup that did visit an emergency room for PSVT, there was a delay in ER visits among those randomized to etripamil (116 vs. 79 minutes; P < 0.05), suggesting that this agent reduced the sense of urgency when PSVT symptoms develop, according to Dr. Stambler.

On average, the patients who enrolled in this trial had a PSVT history of about 1.5 years. In the year prior to enrollment, the mean number of ER visits was about nine. 

In the trial design, patients were required to take a test dose of etripamil under observation by a physician before being sent home with their assigned therapy, but Dr. Stambler does not believe that the requirement, if the drug is approved, will be in the label. 

Unexpectedly, many patients had symptom relief even without converting to sinus rhythm, Dr. Stambler acknowledged. He speculated that the reduction in heart rate associated with etripamil might have provided a relief of symptoms sufficient to relieve anxiety, producing the relative advantage for patient satisfaction.

Jodie L. Hurwitz, MD, director of the electrophysiology lab at Medical City Hospital, Dallas, indicated that there is a need for new options for PSVT. An expert panelist during the session where these data were presented, she was particularly interested in rapid symptom relief. 

“It would be great to have a therapy that could be self-administered at home. Patients would like it, too,” she said. 

Mary N. Walsh, MD, a heart failure specialist affiliated with Indiana University, Indianapolis, sees a potential role of a self-administered therapy like etripamil in conjunction with wearable devices. She noted that the proportion of patients using these devices to monitor arrhythmias is increasing, providing a role for an easily transportable therapy that could be used quickly when symptoms develop. 

However, after the negative phase 3 trial, more data must now be collected to satisfy the regulatory authorities that this agent is safe and effective. Dr. Stambler said that the developer is now committed to pursue these studies.

Dr. Stambler has a financial relationship with Milestone Pharmaceuticals, which is developing etripamil nasal spray and was the sponsor of this trial. Dr. Walsh and Dr. Hurwitz have no potential relevant conflicts of interest.
 

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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

Left atrial appendage occlusion performed at the time of other heart surgery reduces the risk for stroke by about one-third in high-risk patients with atrial fibrillation (AFib), according to results of the Left Atrial Appendage Occlusion Study III (LAAOS III).

At 3.8 years’ follow-up, the primary endpoint of ischemic stroke or systemic embolism occurred in 4.8% of patients randomly assigned to left atrial appendage occlusion (LAAO) and 7.0% of those with no occlusion. This translated into a 33% relative risk reduction (hazard ratio, 0.67; 95% confidence interval, 0.53-0.85; P = .001).

In a landmark analysis, the effect was present early on but was more pronounced after the first 30 days, reducing the relative risk by 42% (HR, 0.58; 95% CI, 0.42-0.80), the researchers report.

The reduction in ongoing stroke risk was on top of oral anticoagulation (OAC) and consistent across all subgroups, Richard Whitlock, MD, PhD, professor of surgery, McMaster University, Hamilton, Ont., reported in a late-breaking trial session at the annual scientific sessions of the American College of Cardiology.

The procedure was safe and added, on average, just 6 minutes to cardiopulmonary bypass time, according to the results, simultaneously published in the New England Journal of Medicine.

“Any patient who comes to the operating room who fits the profile of a LAAOS III patient – so has atrial fibrillation and an elevated stroke risk based on their CHA₂DS₂-VASc score – the appendage should come off,” he said in an interview.

Commenting during the formal discussion, panelist Michael J. Mack, MD, of Baylor Health Care System in Houston, said, “This is potentially a game-changing, practice-changing study” but asked if there are any patients who shouldn’t undergo LAAO, such as those with heart failure (HF).

Dr. Whitlock said about 10%-15% of patients coming for heart surgery have a history of AFib and “as surgeons, you do need to individualize therapy. If you have a very frail patient, have concerns about tissue quality, you really need to think about how you would occlude the left atrial appendage or if you would occlude.”

Reassuringly, he noted, the data show no increase in HF hospitalizations and a beneficial effect on stroke among patients with HF and those with low ejection fractions, below 50%.

Observational data on surgical occlusion have been inconsistent, and current guidelines offer a weak recommendation in patients with AFib who have a contraindication to long-term anticoagulation. This is the first study to definitively prove that ischemic stroke is reduced by managing the left atrial appendage, he said in an interview.

“The previous percutaneous trials failed to demonstrate that; they demonstrated noninferiority but it was driven primarily by the avoidance of hemorrhagic events or strokes through taking patients off oral anticoagulation,” he said.

The results should translate into a class I guideline recommendation, he added. “This opens up a new paradigm of treatment for atrial fibrillation and stroke prevention in that it is really the first study that has looked at the additive effects of managing the left atrial appendage in addition to oral anticoagulation, and it’s protective on top of oral anticoagulation. That is a paradigm shift.”

In an accompanying editorial, Richard L. Page, MD, University of Vermont in Burlington, said the trial provides no insight on the possible benefit of surgical occlusion in patients unable to receive anticoagulation or with a lower CHA2DS2-VASc score, but he agreed a class I recommendation is likely for the population studied.

“I hope and anticipate that the results of this paper will strengthen the guideline indications for surgical left atrial appendage occlusion and will increase the number of cardiac surgeons who routinely perform this add-on procedure,” he said. “While many already perform this procedure, cardiac surgeons should now feel more comfortable that surgical left atrial appendage occlusion is indicated and supported by high-quality randomized data.”

Unfortunately, LAAOS III does not answer the question of whether patients can come off anticoagulation, but it does show surgical occlusion provides added protection from strokes, which can be huge with atrial fibrillation, Dr. Whitlock said.

“I spoke with a patient today who is an active 66-year-old individual on a [direct oral anticoagulant], and his stroke risk has been further reduced by 30%-40%, so he was ecstatic to hear the results,” Dr. Whitlock said. “I think it’s peace of mind.”

Global, nonindustry effort

LAAOS III investigators at 105 centers in 27 countries enrolled 4,811 patients undergoing cardiac surgery (mean age, 71 years; 68% male) who had a CHA₂DS₂-VASc score of at least 2.

In all, 4,770 were randomly assigned to no LAAO or occlusion via the preferred technique of amputation with suture closure of the stump as well as stapler occlusion, or epicardial device closure with the AtriClip (AtriCure) or TigerPaw (Maquet Medical). The treating team, researchers, and patients were blinded to assignment.

Patients were followed every 6 months with a validated stroke questionnaire. The trial was stopped early by the data safety monitoring board after the second interim analysis.

The mean CHA₂DS₂-VASc score was 4.2, one-third of patients had permanent AFib, 9% had a history of stroke, and more than two-thirds underwent a valve procedure, which makes LAAOS III unique, as many previous trials excluded valvular AFib, Dr. Whitlock pointed out.

Operative outcomes in the LAAO and no-LAAO groups were as follows:

• Bypass time: mean, 119 minutes vs. 113 minutes.  
• Cross-clamp time: mean, 86 minutes vs. 82 minutes.
• Chest tube output: median, 520 mL vs. 500 mL.
• Reoperation for bleeding: both, 4.0%.
• Prolonged hospitalization due to HF: 5 vs. 14 events.
• 30-day mortality: 3.7% vs 4.0%.

The primary safety outcome of HF hospitalization at 3.8 years occurred in 7.7% of patients with LAAO and 6.8% without occlusion (HR, 1.13; 95% CI, 0.92-1.40), despite concerns that taking off the appendage could worsen HF risk by impairing renal clearance of salt and water.

“There’s observational data on either side of the fence, so it was an important endpoint that people were concerned about,” Dr. Whitlock told this news organization. “We had a data collection firm dedicated to admission for heart failure to really tease that out and, in the end, we saw no adverse effect.”

Although rates of ischemic stroke at 3.8 years were lower with LAAO than without (4.2% vs. 6.6%; HR, 0.62; 95% CI, 0.48-0.80), there was no difference in systemic embolism (0.3% for both) or death (22.6% vs. 22.5%).

In LAAOS III, fewer than 2% of the deaths were attributed to stroke, which is consistent with large stroke registries, Dr. Whitlock said. “Stroke is not what causes people with atrial fibrillation to die; it’s actually the progression on to heart failure.”

The positive effect on stroke was consistent across all subgroups, including sex, age, rheumatic heart disease, type of OAC at baseline, CHA₂DS₂-VASc score (≤4 vs. >4), type of surgery, history of heart failure or hypertension, and prior stroke/transient ischemic attack/systemic embolism.

Panelist Anne B. Curtis, MD, State University of New York at Buffalo, expressed surprise that about half of patients at baseline were not receiving anticoagulation and questioned whether event rates varied among those who did and didn’t stay on OAC.

Dr. Whitlock noted that OAC is often underused in AFib and that analyses showed the effects were consistent whether patients were on or off anticoagulants.

The study was sponsored by the Population Health Research Institute, McMaster University. Dr. Whitlock reported no relevant disclosures. Dr. Curtis reported consultant fees/honoraria from Abbott, Janssen, Medtronic, Milestone Pharmaceuticals, and Sanofi Aventis, and data safety monitoring board participation for Medtronic.
 

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

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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

No significant difference in cardiovascular events or major bleeding was shown between patients with established coronary heart disease assigned to a daily aspirin dose of 81 mg and those receiving a dose of 325 mg in the 15,000-patient ADAPTABLE trial.

Although substantial dose switching occurred in the trial, particularly from the higher to the lower dose, lead investigator W. Schuyler Jones, MD, believes the results support the use of the 81-mg dose in most patients.  

“While we would have liked to see higher adherence to the assigned doses, we think the results of the trial are reliable,” Dr. Jones said in an interview.

The real-world, open-label, pragmatic trial also involved an innovative low-cost design allowing researchers to identify and communicate with eligible patients directly, opening up a new cost-effective method to conduct clinical research going forward.

Dr. Jones, a cardiologist and associate professor of medicine at Duke University Medical Center, Durham, N.C., presented the ADAPTABLE results at the annual scientific sessions of the American College of Cardiology. They were simultaneously published online in the New England Journal of Medicine.   

He noted there were mixed signals in the results. “For example, the main intent-to-treat analysis showed a trend to a lower rate of all-cause death in the 81-mg group, but the subgroup of patients who stayed on the 325-mg dose throughout the study had a lower event rate. But overall, there was no difference.”

Dr. Jones said the investigators had the following take-home messages to patients: “If a patient is already taking 81 mg, staying on this dose is probably right given the similar study results for the primary endpoint and that we didn’t find conclusive evidence that 325 mg is better. But for patients who have tolerated 325 mg long term, then they may want to stay on this dose as it may be associated with moderate benefit.”

Dr. Jones pointed out that, overall, patients who switched doses tended to do worse, but he suggested this may have been more to do with underlying reasons for switching rather than the different dose itself. “For example, switching often happens after bleeding or bruising, which can also often preempt an ischemic event, and other illnesses, such as cancer or atrial fibrillation, can also lead patients to change doses.”

“With the caveat that this trial did not include new patients (the vast majority of patients had been taking aspirin previously) the results support the approach of starting new patients on 81 mg, which is what we have been seeing in evolving clinical practice in recent years,” he added.  

Dr. Jones explained that the trial set out to answer the simple but important question about the best dose of aspirin in patients with heart disease.

“Aspirin has been established as an appropriate long-term medication for patients with ischemic heart disease since the 1980s, but we really don’t have any good information on the correct dose.

He noted that the U.S. guidelines suggest any dose in the range of 81 mg to 325 mg daily can be used, whereas the European guidelines recommend 81 mg daily, although this is mainly based on observational data and expert opinion; there is little hard, randomized-trial evidence.

The ADAPTABLE trial randomly assigned 15,076 patients with established heart disease to receive 81 mg or 325 mg of aspirin. Before randomization, 96% of those with available information were already taking aspirin, 85% of whom were taking 81 mg.

After a mean follow-up of 26 months, the primary efficacy endpoint – a composite of all-cause death, myocardial infarction, or stroke – had occurred in 7.28% of the 81-mg group and 7.51% of the 325-mg group (hazard ratio, 1.02; 95% confidence interval, 0.91-1.14).     

The main safety endpoint, hospitalization for major bleeding with an associated blood transfusion, occurred in 0.63% of the 81-mg group and 0.60% of the 325-mg group (HR, 1.18; 95% CI, 0.79-1.77).

“The bleeding safety endpoint looked similar, which may be counterintuitive to what may have been expected,” Dr. Jones commented. “However, the safety endpoint was very stringent. We still haven’t analyzed all the less serious ADR [adverse drug event]/bleeding data, but overall, it does appear to be balanced.”

He added: “Most cardiologists probably may not have expected to see much difference in efficacy between these two doses but would maybe have anticipated a lower bleeding rate with the low dose. I was a little surprised to see such a low bleeding rate in the 325-mg group.”

Patients assigned to 325 mg had a higher incidence of dose switching (41.6%) than those assigned to 81 mg (7.1%) and were more likely to discontinue treatment (11.1% vs. 7.0%). This resulted in fewer median days of exposure to the assigned dose in the 325-mg group (434 vs. 650 days).

“This was an open-label study, and such studies always suffer from a degree of infidelity to the assigned treatment group,” Dr. Jones said. “In ADAPTABLE, this was unbalanced in that a much greater number of patients switched from 325 mg to 81 mg than the other way round.”   

“But our results do reflect what happens in normal life,” he added. “People behaved in the study like they do in the real world. They sometimes changed their dose and sometimes stopped taking aspirin altogether. So, I think the results are an accurate representation of the real world.”

A sensitivity analysis based on which dose the patient actually reported taking showed a higher risk for death, MI, or stroke in patients who took 81 mg than those who took 325 mg (HR, 1.25; 95% CI, 1.10-1.43). But as with any postrandomization analysis, this approach has many inherent biases, Dr. Jones cautioned.
 

Innovative study design  

The ADAPTABLE study used an innovative low-cost design, which involved direct communication with the patients themselves.

Using the National Patient-Centered Clinical Research Network (PCORnet), a group of 40 U.S. centers committed to compiling data in a common format, invitations to enroll in the study were sent to eligible patients identified from medical records. Consent and randomization took place on the patient web portal. 

Participants then purchased aspirin at the assigned dose themselves, and all follow-up was done virtually or on the phone, with outcomes ascertained remotely (from patient reports, electronic medical records, and insurance claims) without adjudication.   

“This is a pretty neat way to do clinical research, enabling us to conduct a 15,000-patient trial on a very tight budget,” Dr. Jones commented. 

He estimated that the trial cost around $18 to $19 million. “No industry funder would have sponsored such a study of aspirin, and a typical trial with this many patients conducted in the traditional way would have cost at least 5 or 10 times more,” he said.

“This is the first time this type of study has been done in the U.S. on such a large scale, and it opens up this method for future research.”

He explained that this design, communicating directly with patients, somewhat limits the questions that can be addressed. “As aspirin is purchased over the counter by patients themselves, this is a question that lent itself to be answered in this way.” 

Another innovative design feature was the inclusion of “patient partners,” with one patient nominated by each center to be part of the organization of the trial. “This helped keep the research relevant to what patients care about.

They also helped with the recruitment strategy and communication with participants. I think this is something we need to continue and prioritize in clinical research going forward,” Dr. Jones noted.

‘Pioneering’ trial

Discussants of the study at the ACC presentation congratulated the investigators on conducting such an innovative trial.

Donald Lloyd-Jones, MD, chair of preventive medicine at Northwestern University, Chicago, said, “This is really a pioneering large pragmatic trial, and we’re going to need to see more of these over the next few years. The most important legacy from this trial for me is that you did it, and that you showed us many of the promises and some of the pitfalls of these large pragmatic designs.”

Akshay Desai, MD, associate professor of medicine, Harvard Medical School, Boston, added: “This was an innovative approach to answering an important question for daily clinical practice.”

On the results of the study, Dr. Lloyd-Jones said, “Maybe the outcomes were not too surprising, and I certainly endorse your cautious status quo statement about patients staying on the dose that they are on.”

But he suggested that the bleeding safety outcomes were perhaps a little unexpected, being a little lower in the lower-dose group, and he asked whether there was a sensitivity analysis looking at bleeding on a per protocol basis. Dr. Jones answered that this was planned.

Dr. Desai also raised questions about the “unusual bleeding endpoint,” noting that the rates of bleeding were far lower than would be expected, compared with other clinical trials.

Dr. Jones replied that the bleeding endpoint with blood product transfusion was chosen to allow the researchers to accurately identify these events in claims codes. He said the endpoint probably mirrored the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding classification.

In an editorial accompanying the publication of ADAPTABLE, Colin Baigent, FMedSci, says the study provides proof of principle that large pragmatic randomized trials can be conducted in the United States.

But Dr. Baigent, who is professor of epidemiology and director of the Medical Research Council Population Health Research Unit at the University of Oxford (England), says that the high degree of switching between dosages that occurred during the trial gives rise to some uncertainty about the results.  

“Because switching was not likely to have been at random, bias arising from this degree of crossover could have obscured a true difference in efficacy or safety (or both), and moreover it is also not possible to conclude that the lack of any significant difference between the two dose groups implies equivalence of the effects of the doses,” he writes.

He suggests that a pilot study may have identified a preference for the 81-mg dose and allowed methods to facilitate equipoise, such as a run-in period with both doses, and only patients adhering being considered for randomization.  

But Dr. Baigent concludes that the ADAPTABLE trial is a “major achievement” in that it paves the way for low-cost randomized trials in the United States, which should allow many more clinical questions to be answered.

The trial was supported by an award from the Patient-Centred Outcomes Research Institute.  Dr. Schuyler Jones reports consultant fees/honoraria from Bayer Healthcare and Janssen and research grants from Boehringer Ingelheim, Bristol Myers Squibb, and the Patient-Centered Outcomes Research Institute. Dr. Baigent reports grants from Boehringer Ingelheim, Medical Research Council, British Heart Foundation, and National Institute of Health Research, outside the submitted work.
 

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