On average, physicians reported in the Medscape Physician Compensation Report 2023 that they worked 50 hours per week. Five specialties, including critical care, cardiology, and general surgery reported working 55 or more hours weekly.

But there’s a small segment of physicians that has bucked the norm. They’ve scaled back their hours to part time, clocking in only 25-30 hours a week.

In 2011, The New England Journal of Medicine reported that part-time physician careers were rising. At the time, part-time doctors made up 21% of the physician workforce, up from 13% in 2005.

In a more recent survey from the California Health Care Foundation, only 12% of California physicians said they devoted 20-29 hours a week to patient care. 

Amy Knoup, a senior recruitment adviser with Provider Solutions & Development), has been helping doctors find jobs for over a decade, and she’s noticed a trend.

“Not only are more physicians seeking part-time roles than they were 10 years ago, but more large health care systems are also offering part time or per diem as well,” said Ms. Knoup.
 

Who’s working part time, and why?

Ten years ago, the fastest growing segment of part-timers were men nearing retirement and early- to mid-career women.

Pediatricians led the part-time pack in 2002, according to an American Academy of Pediatrics study. At the time, 15% of pediatricians reported their hours as part time. However, the numbers may have increased over the years. For example, a 2021 study by the department of pediatrics, Boston Medical Center, and Boston University found that almost 30% of graduating pediatricians sought part-time work at the end of their training. 

At PS&D, Ms. Knoup said she has noticed a trend toward part-timers among primary care, behavioral health, and outpatient specialties such as endocrinology. “We’re also seeing it with the inpatient side in roles that are more shift based like hospitalists, radiologists, and critical care and ER doctors.”

Another trend Ms. Knoup has noticed is with early-career doctors. “They have a different mindset,” she said. “Younger generations are acutely aware of burnout. They may have experienced it in residency or during the pandemic. They’ve had a taste of that and don’t want to go down that road again, so they’re seeking part-time roles. It’s an intentional choice.” 

Tracey O’Connell, MD, a radiologist, always knew that she wanted to work part time. “I had a baby as a resident, and I was pregnant with my second child as a fellow,” she said. “I was already feeling overwhelmed with medical training and having a family.”

Dr. O’Connell worked in private practice for 16 years on Mondays, Wednesdays, and Fridays, with no nights or weekends. 

“I still found it completely overwhelming,” she said. “Even though I had more days not working than working, I felt like the demands of medical life had advanced faster than human beings could adapt, and I still feel that way.”

Today she runs a part-time teleradiology practice from home but spends more time on her second career as a life coach. “Most of my clients are physicians looking for more fulfillment and sustainable ways of practicing medicine while maintaining their own identity as human beings, not just the all-consuming identity of ‘doctor,’ ” she said. 

On the other end of the career spectrum is Lois Goodman, MD, an ob.gyn. in her late 70s. After 42 years in a group practice, she started her solo practice at 72, seeing patients 3 days per week. “I’m just happy to be working. That’s a tremendous payoff for me. I need to keep working for my mental health.”
 

How does part-time work affect physician shortages and care delivery?

Reducing clinical effort is one of the strategies physicians use to scale down overload. Still, it’s not viable as a long-term solution, said Christine Sinsky, MD, AMA’s vice president of professional satisfaction and a nationally regarded researcher on physician burnout.

“If all the physicians in a community went from working 100% FTE clinical to 50% FTE clinical, then the people in that community would have half the access to care that they had,” said Dr. Sinsky. “There’s less capacity in the system to care for patients.”

Some could argue, then, that part-time physician work may contribute to physician shortage predictions. An Association of American Medical Colleges report estimates there will be a shortage of 37,800 to 124,000 physicians by 2034.

But physicians working part-time express a contrasting point of view. “I don’t believe that part-time workers are responsible for the health care shortage but rather, a great solution,” said Dr. O’Connell. “Because in order to continue working for a long time rather than quitting when the demands exceed human capacity, working part time is a great compromise to offer a life of more sustainable well-being and longevity as a physician, and still live a wholehearted life.”
 

Pros and cons of being a part-time physician

Pros

Less burnout: The American Medical Association has tracked burnout rates for 22 years. By the end of 2021, nearly 63% of physicians reported burnout symptoms, compared with 38% the year before. Going part time appears to reduce burnout, suggests a study published in Mayo Clinic Proceedings.

Better work-life balance: Rachel Miller, MD, an ob.gyn., worked 60-70 hours weekly for 9 years. In 2022, she went to work as an OB hospitalist for a health care system that welcomes part-time clinicians. Since then, she has achieved a better work-life balance, putting in 26-28 hours a week. Dr. Miller now spends more time with her kids and in her additional role as an executive coach to leaders in the medical field. 

More focus: “When I’m at work, I’m 100% mentally in and focused,” said Dr. Miller. “My interactions with patients are different because I’m not burned out. My demeanor and my willingness to connect are stronger.”

Better health: Mehmet Cilingiroglu, MD, with CardioSolution, traded full-time work for part time when health issues and a kidney transplant sidelined his 30-year career in 2018. “Despite my significant health issues, I’ve been able to continue working at a pace that suits me rather than having to retire,” he said. “Part-time physicians can still enjoy patient care, research, innovation, education, and training while balancing that with other areas of life.” 

Errin Weisman, a DO who gave up full-time work in 2016, said cutting back makes her feel healthier, happier, and more energized. “Part-time work helps me to bring my A game each day I work and deliver the best care.” She’s also a life coach encouraging other physicians to find balance in their professional and personal lives.
 

Cons

Cut in pay: Obviously, the No. 1 con is you’ll make less working part time, so adjusting to a salary decrease can be a huge issue, especially if you don’t have other sources of income. Physicians paying off student loans, those caring for children or elderly parents, or those in their prime earning years needing to save for retirement may not be able to go part time.

Diminished career: The chance for promotions or being well known in your field can be diminished, as well as a loss of proficiency if you’re only performing surgery or procedures part time. In some specialties, working part time and not keeping up with (or being able to practice) newer technology developments can harm your career or reputation in the long run.

Missing out: While working part time has many benefits, physicians also experience a wide range of drawbacks. Dr. Goodman, for example, said she misses delivering babies and doing surgeries. Dr. Miller said she gave up some aspects of her specialty, like performing hysterectomies, participating in complex cases, and no longer having an office like she did as a full-time ob.gyn.

Loss of fellowship: Dr. O’Connell said she missed the camaraderie and sense of belonging when she scaled back her hours. “I felt like a fish out of water, that my values didn’t align with the group’s values,” she said. This led to self-doubt, frustrated colleagues, and a reduction in benefits.

Lost esteem: Dr. O’Connell also felt she was expected to work overtime without additional pay and was no longer eligible for bonuses. “I was treated as a team player when I was needed, but not when it came to perks and benefits and insider privilege,” she said. There may be a loss of esteem among colleagues and supervisors.

Overcoming stigma: Because part-time physician work is still not prevalent among colleagues, some may resist the idea, have less respect for it, perceive it as not being serious about your career as a physician, or associate it with being lazy or entitled.

Summing it up

Every physician must weigh the value and drawbacks of part-time work, but the more physicians who go this route, the more part-time medicine gains traction and the more physicians can learn about its values versus its drawbacks.

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

On average, physicians reported in the Medscape Physician Compensation Report 2023 that they worked 50 hours per week. Five specialties, including critical care, cardiology, and general surgery reported working 55 or more hours weekly.

But there’s a small segment of physicians that has bucked the norm. They’ve scaled back their hours to part time, clocking in only 25-30 hours a week.

In 2011, The New England Journal of Medicine reported that part-time physician careers were rising. At the time, part-time doctors made up 21% of the physician workforce, up from 13% in 2005.

In a more recent survey from the California Health Care Foundation, only 12% of California physicians said they devoted 20-29 hours a week to patient care. 

Amy Knoup, a senior recruitment adviser with Provider Solutions & Development), has been helping doctors find jobs for over a decade, and she’s noticed a trend.

“Not only are more physicians seeking part-time roles than they were 10 years ago, but more large health care systems are also offering part time or per diem as well,” said Ms. Knoup.
 

Who’s working part time, and why?

Ten years ago, the fastest growing segment of part-timers were men nearing retirement and early- to mid-career women.

Pediatricians led the part-time pack in 2002, according to an American Academy of Pediatrics study. At the time, 15% of pediatricians reported their hours as part time. However, the numbers may have increased over the years. For example, a 2021 study by the department of pediatrics, Boston Medical Center, and Boston University found that almost 30% of graduating pediatricians sought part-time work at the end of their training. 

At PS&D, Ms. Knoup said she has noticed a trend toward part-timers among primary care, behavioral health, and outpatient specialties such as endocrinology. “We’re also seeing it with the inpatient side in roles that are more shift based like hospitalists, radiologists, and critical care and ER doctors.”

Another trend Ms. Knoup has noticed is with early-career doctors. “They have a different mindset,” she said. “Younger generations are acutely aware of burnout. They may have experienced it in residency or during the pandemic. They’ve had a taste of that and don’t want to go down that road again, so they’re seeking part-time roles. It’s an intentional choice.” 

Tracey O’Connell, MD, a radiologist, always knew that she wanted to work part time. “I had a baby as a resident, and I was pregnant with my second child as a fellow,” she said. “I was already feeling overwhelmed with medical training and having a family.”

Dr. O’Connell worked in private practice for 16 years on Mondays, Wednesdays, and Fridays, with no nights or weekends. 

“I still found it completely overwhelming,” she said. “Even though I had more days not working than working, I felt like the demands of medical life had advanced faster than human beings could adapt, and I still feel that way.”

Today she runs a part-time teleradiology practice from home but spends more time on her second career as a life coach. “Most of my clients are physicians looking for more fulfillment and sustainable ways of practicing medicine while maintaining their own identity as human beings, not just the all-consuming identity of ‘doctor,’ ” she said. 

On the other end of the career spectrum is Lois Goodman, MD, an ob.gyn. in her late 70s. After 42 years in a group practice, she started her solo practice at 72, seeing patients 3 days per week. “I’m just happy to be working. That’s a tremendous payoff for me. I need to keep working for my mental health.”
 

How does part-time work affect physician shortages and care delivery?

Reducing clinical effort is one of the strategies physicians use to scale down overload. Still, it’s not viable as a long-term solution, said Christine Sinsky, MD, AMA’s vice president of professional satisfaction and a nationally regarded researcher on physician burnout.

“If all the physicians in a community went from working 100% FTE clinical to 50% FTE clinical, then the people in that community would have half the access to care that they had,” said Dr. Sinsky. “There’s less capacity in the system to care for patients.”

Some could argue, then, that part-time physician work may contribute to physician shortage predictions. An Association of American Medical Colleges report estimates there will be a shortage of 37,800 to 124,000 physicians by 2034.

But physicians working part-time express a contrasting point of view. “I don’t believe that part-time workers are responsible for the health care shortage but rather, a great solution,” said Dr. O’Connell. “Because in order to continue working for a long time rather than quitting when the demands exceed human capacity, working part time is a great compromise to offer a life of more sustainable well-being and longevity as a physician, and still live a wholehearted life.”
 

Pros and cons of being a part-time physician

Pros

Less burnout: The American Medical Association has tracked burnout rates for 22 years. By the end of 2021, nearly 63% of physicians reported burnout symptoms, compared with 38% the year before. Going part time appears to reduce burnout, suggests a study published in Mayo Clinic Proceedings.

Better work-life balance: Rachel Miller, MD, an ob.gyn., worked 60-70 hours weekly for 9 years. In 2022, she went to work as an OB hospitalist for a health care system that welcomes part-time clinicians. Since then, she has achieved a better work-life balance, putting in 26-28 hours a week. Dr. Miller now spends more time with her kids and in her additional role as an executive coach to leaders in the medical field. 

More focus: “When I’m at work, I’m 100% mentally in and focused,” said Dr. Miller. “My interactions with patients are different because I’m not burned out. My demeanor and my willingness to connect are stronger.”

Better health: Mehmet Cilingiroglu, MD, with CardioSolution, traded full-time work for part time when health issues and a kidney transplant sidelined his 30-year career in 2018. “Despite my significant health issues, I’ve been able to continue working at a pace that suits me rather than having to retire,” he said. “Part-time physicians can still enjoy patient care, research, innovation, education, and training while balancing that with other areas of life.” 

Errin Weisman, a DO who gave up full-time work in 2016, said cutting back makes her feel healthier, happier, and more energized. “Part-time work helps me to bring my A game each day I work and deliver the best care.” She’s also a life coach encouraging other physicians to find balance in their professional and personal lives.
 

Cons

Cut in pay: Obviously, the No. 1 con is you’ll make less working part time, so adjusting to a salary decrease can be a huge issue, especially if you don’t have other sources of income. Physicians paying off student loans, those caring for children or elderly parents, or those in their prime earning years needing to save for retirement may not be able to go part time.

Diminished career: The chance for promotions or being well known in your field can be diminished, as well as a loss of proficiency if you’re only performing surgery or procedures part time. In some specialties, working part time and not keeping up with (or being able to practice) newer technology developments can harm your career or reputation in the long run.

Missing out: While working part time has many benefits, physicians also experience a wide range of drawbacks. Dr. Goodman, for example, said she misses delivering babies and doing surgeries. Dr. Miller said she gave up some aspects of her specialty, like performing hysterectomies, participating in complex cases, and no longer having an office like she did as a full-time ob.gyn.

Loss of fellowship: Dr. O’Connell said she missed the camaraderie and sense of belonging when she scaled back her hours. “I felt like a fish out of water, that my values didn’t align with the group’s values,” she said. This led to self-doubt, frustrated colleagues, and a reduction in benefits.

Lost esteem: Dr. O’Connell also felt she was expected to work overtime without additional pay and was no longer eligible for bonuses. “I was treated as a team player when I was needed, but not when it came to perks and benefits and insider privilege,” she said. There may be a loss of esteem among colleagues and supervisors.

Overcoming stigma: Because part-time physician work is still not prevalent among colleagues, some may resist the idea, have less respect for it, perceive it as not being serious about your career as a physician, or associate it with being lazy or entitled.

Summing it up

Every physician must weigh the value and drawbacks of part-time work, but the more physicians who go this route, the more part-time medicine gains traction and the more physicians can learn about its values versus its drawbacks.

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

On average, physicians reported in the Medscape Physician Compensation Report 2023 that they worked 50 hours per week. Five specialties, including critical care, cardiology, and general surgery reported working 55 or more hours weekly.

But there’s a small segment of physicians that has bucked the norm. They’ve scaled back their hours to part time, clocking in only 25-30 hours a week.

In 2011, The New England Journal of Medicine reported that part-time physician careers were rising. At the time, part-time doctors made up 21% of the physician workforce, up from 13% in 2005.

In a more recent survey from the California Health Care Foundation, only 12% of California physicians said they devoted 20-29 hours a week to patient care. 

Amy Knoup, a senior recruitment adviser with Provider Solutions & Development), has been helping doctors find jobs for over a decade, and she’s noticed a trend.

“Not only are more physicians seeking part-time roles than they were 10 years ago, but more large health care systems are also offering part time or per diem as well,” said Ms. Knoup.
 

Who’s working part time, and why?

Ten years ago, the fastest growing segment of part-timers were men nearing retirement and early- to mid-career women.

Pediatricians led the part-time pack in 2002, according to an American Academy of Pediatrics study. At the time, 15% of pediatricians reported their hours as part time. However, the numbers may have increased over the years. For example, a 2021 study by the department of pediatrics, Boston Medical Center, and Boston University found that almost 30% of graduating pediatricians sought part-time work at the end of their training. 

At PS&D, Ms. Knoup said she has noticed a trend toward part-timers among primary care, behavioral health, and outpatient specialties such as endocrinology. “We’re also seeing it with the inpatient side in roles that are more shift based like hospitalists, radiologists, and critical care and ER doctors.”

Another trend Ms. Knoup has noticed is with early-career doctors. “They have a different mindset,” she said. “Younger generations are acutely aware of burnout. They may have experienced it in residency or during the pandemic. They’ve had a taste of that and don’t want to go down that road again, so they’re seeking part-time roles. It’s an intentional choice.” 

Tracey O’Connell, MD, a radiologist, always knew that she wanted to work part time. “I had a baby as a resident, and I was pregnant with my second child as a fellow,” she said. “I was already feeling overwhelmed with medical training and having a family.”

Dr. O’Connell worked in private practice for 16 years on Mondays, Wednesdays, and Fridays, with no nights or weekends. 

“I still found it completely overwhelming,” she said. “Even though I had more days not working than working, I felt like the demands of medical life had advanced faster than human beings could adapt, and I still feel that way.”

Today she runs a part-time teleradiology practice from home but spends more time on her second career as a life coach. “Most of my clients are physicians looking for more fulfillment and sustainable ways of practicing medicine while maintaining their own identity as human beings, not just the all-consuming identity of ‘doctor,’ ” she said. 

On the other end of the career spectrum is Lois Goodman, MD, an ob.gyn. in her late 70s. After 42 years in a group practice, she started her solo practice at 72, seeing patients 3 days per week. “I’m just happy to be working. That’s a tremendous payoff for me. I need to keep working for my mental health.”
 

How does part-time work affect physician shortages and care delivery?

Reducing clinical effort is one of the strategies physicians use to scale down overload. Still, it’s not viable as a long-term solution, said Christine Sinsky, MD, AMA’s vice president of professional satisfaction and a nationally regarded researcher on physician burnout.

“If all the physicians in a community went from working 100% FTE clinical to 50% FTE clinical, then the people in that community would have half the access to care that they had,” said Dr. Sinsky. “There’s less capacity in the system to care for patients.”

Some could argue, then, that part-time physician work may contribute to physician shortage predictions. An Association of American Medical Colleges report estimates there will be a shortage of 37,800 to 124,000 physicians by 2034.

But physicians working part-time express a contrasting point of view. “I don’t believe that part-time workers are responsible for the health care shortage but rather, a great solution,” said Dr. O’Connell. “Because in order to continue working for a long time rather than quitting when the demands exceed human capacity, working part time is a great compromise to offer a life of more sustainable well-being and longevity as a physician, and still live a wholehearted life.”
 

Pros and cons of being a part-time physician

Pros

Less burnout: The American Medical Association has tracked burnout rates for 22 years. By the end of 2021, nearly 63% of physicians reported burnout symptoms, compared with 38% the year before. Going part time appears to reduce burnout, suggests a study published in Mayo Clinic Proceedings.

Better work-life balance: Rachel Miller, MD, an ob.gyn., worked 60-70 hours weekly for 9 years. In 2022, she went to work as an OB hospitalist for a health care system that welcomes part-time clinicians. Since then, she has achieved a better work-life balance, putting in 26-28 hours a week. Dr. Miller now spends more time with her kids and in her additional role as an executive coach to leaders in the medical field. 

More focus: “When I’m at work, I’m 100% mentally in and focused,” said Dr. Miller. “My interactions with patients are different because I’m not burned out. My demeanor and my willingness to connect are stronger.”

Better health: Mehmet Cilingiroglu, MD, with CardioSolution, traded full-time work for part time when health issues and a kidney transplant sidelined his 30-year career in 2018. “Despite my significant health issues, I’ve been able to continue working at a pace that suits me rather than having to retire,” he said. “Part-time physicians can still enjoy patient care, research, innovation, education, and training while balancing that with other areas of life.” 

Errin Weisman, a DO who gave up full-time work in 2016, said cutting back makes her feel healthier, happier, and more energized. “Part-time work helps me to bring my A game each day I work and deliver the best care.” She’s also a life coach encouraging other physicians to find balance in their professional and personal lives.
 

Cons

Cut in pay: Obviously, the No. 1 con is you’ll make less working part time, so adjusting to a salary decrease can be a huge issue, especially if you don’t have other sources of income. Physicians paying off student loans, those caring for children or elderly parents, or those in their prime earning years needing to save for retirement may not be able to go part time.

Diminished career: The chance for promotions or being well known in your field can be diminished, as well as a loss of proficiency if you’re only performing surgery or procedures part time. In some specialties, working part time and not keeping up with (or being able to practice) newer technology developments can harm your career or reputation in the long run.

Missing out: While working part time has many benefits, physicians also experience a wide range of drawbacks. Dr. Goodman, for example, said she misses delivering babies and doing surgeries. Dr. Miller said she gave up some aspects of her specialty, like performing hysterectomies, participating in complex cases, and no longer having an office like she did as a full-time ob.gyn.

Loss of fellowship: Dr. O’Connell said she missed the camaraderie and sense of belonging when she scaled back her hours. “I felt like a fish out of water, that my values didn’t align with the group’s values,” she said. This led to self-doubt, frustrated colleagues, and a reduction in benefits.

Lost esteem: Dr. O’Connell also felt she was expected to work overtime without additional pay and was no longer eligible for bonuses. “I was treated as a team player when I was needed, but not when it came to perks and benefits and insider privilege,” she said. There may be a loss of esteem among colleagues and supervisors.

Overcoming stigma: Because part-time physician work is still not prevalent among colleagues, some may resist the idea, have less respect for it, perceive it as not being serious about your career as a physician, or associate it with being lazy or entitled.

Summing it up

Every physician must weigh the value and drawbacks of part-time work, but the more physicians who go this route, the more part-time medicine gains traction and the more physicians can learn about its values versus its drawbacks.

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

SEATTLE – The use of Mohs surgery may improve survival for patients with early-stage Merkel cell carcinoma (MCC), results from a large, retrospective study show.

Compared with conventional wide local excision, survival was significantly improved among patients treated with Mohs, and a subgroup analysis showed that the survival benefit remained for patients with risk factors.

“At 10 years, overall survival was about 21% higher for those treated with Mohs surgery versus those treated with conventional surgery,” said lead author Shayan Cheraghlou, MD, a dermatology resident at the New York University School of Medicine. “On multivariable analysis, which controlled for tumor and patient factors, Mohs was associated with an over 40% reduction in the hazard for death.”

The findings were presented at the annual meeting of the American College of Mohs Surgery.

MCC is a rare, aggressive, neuroendocrine cutaneous malignancy that carries a high mortality rate. The estimated 5-year survival for patients with localized disease is about 50%, Dr. Cheraghlou noted. “That extrapolates to about 55% for T1 tumors and down to about 30% for T4 tumors.”

Although it’s considered to be a rare cancer, the incidence of MCC has been rapidly rising, and in fact it doubled during the period from the 1990s to the 2010s.

Most commonly treated with wide local excision with or without adjuvant radiation therapy, Mohs as monotherapy may offer an alternative treatment option for patients with MCC. It is generally accepted that the optimal treatment for tumors without regional lymph node involvement is surgical, but the data regarding the optimal surgical approach are mixed. Current National Comprehensive Cancer Network guidelines state that either Mohs surgery or wide local excision can be used.

“However, these guidelines do not indicate a preference for one modality over the other,” said Dr. Cheraghlou, “and present them as interchangeable treatment options.”

A growing body of literature supports Mohs surgery for many types of rare tumors, including MCC. For example, as previously reported at the 2021 ACMS meeting, one study found that Mohs surgery compared favorably with the standard treatment approach when it came to recurrence rates for patients with MCC. The 5-year disease-specific survival rate was 91.2% for patients with stage I disease and 68.6% for patients with stage IIa. These rates were comparable with rates for historical control patients who were treated with wide local excision, with or without radiation (81%-87% for stage I disease, and 63%-67% for stage II).

Study details

In the current study, Dr. Cheraghlou and colleagues sought to evaluate the association of the type of surgical approach with patient survival after excision of early-stage MCC. They conducted a retrospective cohort study using the National Cancer Database to identify cases of MCC with T1/T2 tumors. A total of 2,313 patients who were diagnosed from 2004 to 2018 with pathologically confirmed negative lymph node involvement and who were treated with Mohs surgery or wide lesion excision were included in the analysis.

“About 90% were T1 tumors, about 40% were located on the head and neck, and the vast majority – about 60% – were treated with wide local excision,” he explained. “Only about 5% received Mohs surgery for treatment of the primary tumor.”

But when the researchers assessed survival outcomes, they found that treatment with Mohs surgery was associated with significantly improved overall survival.

The unadjusted 3-, 5-, and 10-year survival rates for patients treated with Mohs was 87.4% (SE: 3.4%), 84.5% (SE: 3.9%), and 81.8% (SE: 4.6%), respectively, while for wide lesion excision, the rates were 86.1% (SE: 0.9%), 76.9% (SE: 1.2%), and 60.9% (SE: 2.0%), respectively.

For patients who underwent treatment with narrow margin excision, survival rates were similar as for those treated with wide lesion excision, with 3-, 5-, and 10-year survival rates of 84.8% (SE: 1.4%), 78.3% (SE: 1.7%), and 60.8% (SE: 3.6%), respectively.

On multivariable survival analysis, Mohs surgery was associated with significantly improved survival, compared with wide lesion excision (hazard ratio, 0.594; P = .038). This was also true after multivariable analysis for patients who had one or more NCCN risk factors, for whom improved survival was also seen with Mohs (HR, 0.530; P = .026).

The results did not differ after a sensitivity analysis that included T3 and T4 tumors.

Given that the use of Mohs was so infrequent, compared with standard surgery, the researchers investigated the factors that were associated with the use of Mohs. High-volume MCC centers were significantly more likely to utilize Mohs than wide lesion excision (odds ratio, 1.993; P < .001), compared with other facilities.

“This study has important implications going forward,” Dr. Cheraghlou concluded. “We think it’s important how few patients were treated with Mohs for Merkel cell, and it was slightly more likely to happen in a high-volume center.”

The reasoning for that may be that high-volume centers are more likely to have a surgeon trained to perform Mohs surgery for MCC. “Or perhaps they are more attuned to the benefits of this procedure,” he said. “We can’t tell that from our data, but its notable that it’s such a small proportion of patients – especially when we consider that it is associated with improved survival for the patients who receive it.”

He added that efforts to increase the utilization of Mohs may yield improved local control and overall survival for these patients. “And perhaps with more data, future versions of guidelines may indicate a preference for Mohs over conventional incisions.”
 

No changes to current practice

Asked to comment on the study, Anthony J. Olszanski, RPh, MD, associate professor, department of hematology/oncology, Fox Chase Cancer Center, Philadelphia, noted that while the results are intriguing, they must be interpreted with caution.

“This study was retrospective in nature, and unrecognized biases can influence results,” he said. “Additionally, given the relative rarity of Merkel cell carcinoma, the sample size is expectantly small.”

But importantly, Dr. Olszanski emphasized, Mohs may more often have been recommended for patients with lesions that appear less aggressive. “Many patients undergoing wide lesion excision may have been referred by Mohs surgeons secondary to features or characteristics of lesions which were worrisome,” he explained. “The results of this study do not opine on why Mohs would impact overall survival over wide lesion excision, a point worthy of consideration. Presently, both modalities can be considered for patients with T1/T2 MCC. The results of this study should not change current practice and would lend themselves to a more robust study.”

No external funding of the study was reported. Dr. Cheraghlou has disclosed no relevant financial relationships. Dr. Olszanski has received financial support from Merck and BMS for participated on advisory boards.

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

SEATTLE – The use of Mohs surgery may improve survival for patients with early-stage Merkel cell carcinoma (MCC), results from a large, retrospective study show.

Compared with conventional wide local excision, survival was significantly improved among patients treated with Mohs, and a subgroup analysis showed that the survival benefit remained for patients with risk factors.

“At 10 years, overall survival was about 21% higher for those treated with Mohs surgery versus those treated with conventional surgery,” said lead author Shayan Cheraghlou, MD, a dermatology resident at the New York University School of Medicine. “On multivariable analysis, which controlled for tumor and patient factors, Mohs was associated with an over 40% reduction in the hazard for death.”

The findings were presented at the annual meeting of the American College of Mohs Surgery.

MCC is a rare, aggressive, neuroendocrine cutaneous malignancy that carries a high mortality rate. The estimated 5-year survival for patients with localized disease is about 50%, Dr. Cheraghlou noted. “That extrapolates to about 55% for T1 tumors and down to about 30% for T4 tumors.”

Although it’s considered to be a rare cancer, the incidence of MCC has been rapidly rising, and in fact it doubled during the period from the 1990s to the 2010s.

Most commonly treated with wide local excision with or without adjuvant radiation therapy, Mohs as monotherapy may offer an alternative treatment option for patients with MCC. It is generally accepted that the optimal treatment for tumors without regional lymph node involvement is surgical, but the data regarding the optimal surgical approach are mixed. Current National Comprehensive Cancer Network guidelines state that either Mohs surgery or wide local excision can be used.

“However, these guidelines do not indicate a preference for one modality over the other,” said Dr. Cheraghlou, “and present them as interchangeable treatment options.”

A growing body of literature supports Mohs surgery for many types of rare tumors, including MCC. For example, as previously reported at the 2021 ACMS meeting, one study found that Mohs surgery compared favorably with the standard treatment approach when it came to recurrence rates for patients with MCC. The 5-year disease-specific survival rate was 91.2% for patients with stage I disease and 68.6% for patients with stage IIa. These rates were comparable with rates for historical control patients who were treated with wide local excision, with or without radiation (81%-87% for stage I disease, and 63%-67% for stage II).

Study details

In the current study, Dr. Cheraghlou and colleagues sought to evaluate the association of the type of surgical approach with patient survival after excision of early-stage MCC. They conducted a retrospective cohort study using the National Cancer Database to identify cases of MCC with T1/T2 tumors. A total of 2,313 patients who were diagnosed from 2004 to 2018 with pathologically confirmed negative lymph node involvement and who were treated with Mohs surgery or wide lesion excision were included in the analysis.

“About 90% were T1 tumors, about 40% were located on the head and neck, and the vast majority – about 60% – were treated with wide local excision,” he explained. “Only about 5% received Mohs surgery for treatment of the primary tumor.”

But when the researchers assessed survival outcomes, they found that treatment with Mohs surgery was associated with significantly improved overall survival.

The unadjusted 3-, 5-, and 10-year survival rates for patients treated with Mohs was 87.4% (SE: 3.4%), 84.5% (SE: 3.9%), and 81.8% (SE: 4.6%), respectively, while for wide lesion excision, the rates were 86.1% (SE: 0.9%), 76.9% (SE: 1.2%), and 60.9% (SE: 2.0%), respectively.

For patients who underwent treatment with narrow margin excision, survival rates were similar as for those treated with wide lesion excision, with 3-, 5-, and 10-year survival rates of 84.8% (SE: 1.4%), 78.3% (SE: 1.7%), and 60.8% (SE: 3.6%), respectively.

On multivariable survival analysis, Mohs surgery was associated with significantly improved survival, compared with wide lesion excision (hazard ratio, 0.594; P = .038). This was also true after multivariable analysis for patients who had one or more NCCN risk factors, for whom improved survival was also seen with Mohs (HR, 0.530; P = .026).

The results did not differ after a sensitivity analysis that included T3 and T4 tumors.

Given that the use of Mohs was so infrequent, compared with standard surgery, the researchers investigated the factors that were associated with the use of Mohs. High-volume MCC centers were significantly more likely to utilize Mohs than wide lesion excision (odds ratio, 1.993; P < .001), compared with other facilities.

“This study has important implications going forward,” Dr. Cheraghlou concluded. “We think it’s important how few patients were treated with Mohs for Merkel cell, and it was slightly more likely to happen in a high-volume center.”

The reasoning for that may be that high-volume centers are more likely to have a surgeon trained to perform Mohs surgery for MCC. “Or perhaps they are more attuned to the benefits of this procedure,” he said. “We can’t tell that from our data, but its notable that it’s such a small proportion of patients – especially when we consider that it is associated with improved survival for the patients who receive it.”

He added that efforts to increase the utilization of Mohs may yield improved local control and overall survival for these patients. “And perhaps with more data, future versions of guidelines may indicate a preference for Mohs over conventional incisions.”
 

No changes to current practice

Asked to comment on the study, Anthony J. Olszanski, RPh, MD, associate professor, department of hematology/oncology, Fox Chase Cancer Center, Philadelphia, noted that while the results are intriguing, they must be interpreted with caution.

“This study was retrospective in nature, and unrecognized biases can influence results,” he said. “Additionally, given the relative rarity of Merkel cell carcinoma, the sample size is expectantly small.”

But importantly, Dr. Olszanski emphasized, Mohs may more often have been recommended for patients with lesions that appear less aggressive. “Many patients undergoing wide lesion excision may have been referred by Mohs surgeons secondary to features or characteristics of lesions which were worrisome,” he explained. “The results of this study do not opine on why Mohs would impact overall survival over wide lesion excision, a point worthy of consideration. Presently, both modalities can be considered for patients with T1/T2 MCC. The results of this study should not change current practice and would lend themselves to a more robust study.”

No external funding of the study was reported. Dr. Cheraghlou has disclosed no relevant financial relationships. Dr. Olszanski has received financial support from Merck and BMS for participated on advisory boards.

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

SEATTLE – The use of Mohs surgery may improve survival for patients with early-stage Merkel cell carcinoma (MCC), results from a large, retrospective study show.

Compared with conventional wide local excision, survival was significantly improved among patients treated with Mohs, and a subgroup analysis showed that the survival benefit remained for patients with risk factors.

“At 10 years, overall survival was about 21% higher for those treated with Mohs surgery versus those treated with conventional surgery,” said lead author Shayan Cheraghlou, MD, a dermatology resident at the New York University School of Medicine. “On multivariable analysis, which controlled for tumor and patient factors, Mohs was associated with an over 40% reduction in the hazard for death.”

The findings were presented at the annual meeting of the American College of Mohs Surgery.

MCC is a rare, aggressive, neuroendocrine cutaneous malignancy that carries a high mortality rate. The estimated 5-year survival for patients with localized disease is about 50%, Dr. Cheraghlou noted. “That extrapolates to about 55% for T1 tumors and down to about 30% for T4 tumors.”

Although it’s considered to be a rare cancer, the incidence of MCC has been rapidly rising, and in fact it doubled during the period from the 1990s to the 2010s.

Most commonly treated with wide local excision with or without adjuvant radiation therapy, Mohs as monotherapy may offer an alternative treatment option for patients with MCC. It is generally accepted that the optimal treatment for tumors without regional lymph node involvement is surgical, but the data regarding the optimal surgical approach are mixed. Current National Comprehensive Cancer Network guidelines state that either Mohs surgery or wide local excision can be used.

“However, these guidelines do not indicate a preference for one modality over the other,” said Dr. Cheraghlou, “and present them as interchangeable treatment options.”

A growing body of literature supports Mohs surgery for many types of rare tumors, including MCC. For example, as previously reported at the 2021 ACMS meeting, one study found that Mohs surgery compared favorably with the standard treatment approach when it came to recurrence rates for patients with MCC. The 5-year disease-specific survival rate was 91.2% for patients with stage I disease and 68.6% for patients with stage IIa. These rates were comparable with rates for historical control patients who were treated with wide local excision, with or without radiation (81%-87% for stage I disease, and 63%-67% for stage II).

Study details

In the current study, Dr. Cheraghlou and colleagues sought to evaluate the association of the type of surgical approach with patient survival after excision of early-stage MCC. They conducted a retrospective cohort study using the National Cancer Database to identify cases of MCC with T1/T2 tumors. A total of 2,313 patients who were diagnosed from 2004 to 2018 with pathologically confirmed negative lymph node involvement and who were treated with Mohs surgery or wide lesion excision were included in the analysis.

“About 90% were T1 tumors, about 40% were located on the head and neck, and the vast majority – about 60% – were treated with wide local excision,” he explained. “Only about 5% received Mohs surgery for treatment of the primary tumor.”

But when the researchers assessed survival outcomes, they found that treatment with Mohs surgery was associated with significantly improved overall survival.

The unadjusted 3-, 5-, and 10-year survival rates for patients treated with Mohs was 87.4% (SE: 3.4%), 84.5% (SE: 3.9%), and 81.8% (SE: 4.6%), respectively, while for wide lesion excision, the rates were 86.1% (SE: 0.9%), 76.9% (SE: 1.2%), and 60.9% (SE: 2.0%), respectively.

For patients who underwent treatment with narrow margin excision, survival rates were similar as for those treated with wide lesion excision, with 3-, 5-, and 10-year survival rates of 84.8% (SE: 1.4%), 78.3% (SE: 1.7%), and 60.8% (SE: 3.6%), respectively.

On multivariable survival analysis, Mohs surgery was associated with significantly improved survival, compared with wide lesion excision (hazard ratio, 0.594; P = .038). This was also true after multivariable analysis for patients who had one or more NCCN risk factors, for whom improved survival was also seen with Mohs (HR, 0.530; P = .026).

The results did not differ after a sensitivity analysis that included T3 and T4 tumors.

Given that the use of Mohs was so infrequent, compared with standard surgery, the researchers investigated the factors that were associated with the use of Mohs. High-volume MCC centers were significantly more likely to utilize Mohs than wide lesion excision (odds ratio, 1.993; P < .001), compared with other facilities.

“This study has important implications going forward,” Dr. Cheraghlou concluded. “We think it’s important how few patients were treated with Mohs for Merkel cell, and it was slightly more likely to happen in a high-volume center.”

The reasoning for that may be that high-volume centers are more likely to have a surgeon trained to perform Mohs surgery for MCC. “Or perhaps they are more attuned to the benefits of this procedure,” he said. “We can’t tell that from our data, but its notable that it’s such a small proportion of patients – especially when we consider that it is associated with improved survival for the patients who receive it.”

He added that efforts to increase the utilization of Mohs may yield improved local control and overall survival for these patients. “And perhaps with more data, future versions of guidelines may indicate a preference for Mohs over conventional incisions.”
 

No changes to current practice

Asked to comment on the study, Anthony J. Olszanski, RPh, MD, associate professor, department of hematology/oncology, Fox Chase Cancer Center, Philadelphia, noted that while the results are intriguing, they must be interpreted with caution.

“This study was retrospective in nature, and unrecognized biases can influence results,” he said. “Additionally, given the relative rarity of Merkel cell carcinoma, the sample size is expectantly small.”

But importantly, Dr. Olszanski emphasized, Mohs may more often have been recommended for patients with lesions that appear less aggressive. “Many patients undergoing wide lesion excision may have been referred by Mohs surgeons secondary to features or characteristics of lesions which were worrisome,” he explained. “The results of this study do not opine on why Mohs would impact overall survival over wide lesion excision, a point worthy of consideration. Presently, both modalities can be considered for patients with T1/T2 MCC. The results of this study should not change current practice and would lend themselves to a more robust study.”

No external funding of the study was reported. Dr. Cheraghlou has disclosed no relevant financial relationships. Dr. Olszanski has received financial support from Merck and BMS for participated on advisory boards.

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

BARCELONA – Clinically important arrhythmias, especially nonsustained ventricular tachycardia (NSVT), may be more prevalent in patients with hypertrophic cardiomyopathy (HCM) than widely believed, suggests a study that questions current risk stratification practices in HCM.

In the registry study, such arrythmias were observed in about six times as many HCM patients during 30 days of ambulatory electrocardiographic monitoring as would have been identified based on the first 24 hours of the monitoring period: 65% vs. 11% of the cohort.

Also, about 62% of the patients showed NSVT at “extended” 30-day monitoring, compared with an 8% prevalence of the arrhythmia based on the more conventional ECG monitoring period of 24 hours.

Nonsustained ventricular tachycardia, an important arrhythmia used every day in clinical practice to make decisions, is “much, much more prevalent than we thought” in patients with HCM, Juan Caro Codón, MD, the study’s principal investigator, said in an interview. “We should invest in further research regarding extended ECG monitoring in these patients.”

Dr. Caro Codón, of La Paz University Hospital, Madrid, presented the findings from the TEMPO-HCM study at the European Heart Rhythm Association 2023 Congress, held in Barcelona and virtually.

Its results, he said, have implications for stratifying HCM patients according to their risk for sudden cardiac death in deciding who should be offered an implantable cardioverter-defibrillator (ICD).

The life-incidence of atrial fibrillation (AF) in patients like those in the current analysis has previously been found to be about 20%, and the life-prevalence of NSVT about 20%-30%, using traditional 24- or 48-hour Holter monitoring, Dr. Caro Codón said.

“These arrhythmias are clinically relevant events because they are linked to very meaningful clinical endpoints,” including stroke and thromboembolism, he said, “but also for sudden cardiac death.”

Extended ECG monitoring has been shown useful in the setting of cryptogenic stroke and after AF ablation, but similar findings have been scarce in HCM. Patients using personal wearable monitors such as smart watches, Dr. Caro Codón said, have come to his clinic with concerns that the devices may have signaled a problem. But the lack of relevant data leaves them without a sufficient answer.

In other findings, invited discussant Isabelle van Gelder, MD, PhD, observed after Dr. Caro Codón’s presentation that the number of patients with AF almost doubled based on extended monitoring, compared with the first 24 hours of monitoring.

Based on European Society of Cardiology guidelines from 2020, “Once clinical AF has been documented, there is a class IIA recommendation to start anticoagulation,” said Dr. van Gelder, University of Groningen, the Netherlands. “Therefore, your data really are a call for more data on screening for AF in hypertrophic cardiomyopathy patients.”
 

Prospective multicenter registry

The TEMPO-HCM registry includes patients with HCM and a clinical indication for standard Holter monitoring at five hospitals in Spain. It excludes patients with an HCM-like phenotype but who lack the telltale genotype, as well as those already implanted with an ICD.

Those in the current analysis underwent 30-day ECG monitoring with a small, wearable device that Dr. Caro Codón described as about 7 cm long, worn in what is essentially a T-shirt with a pocket. Patients could remove the shirt and device to bathe or go swimming, for example, and still be monitored for most of the day.

The analysis included the registry’s first 100 patients (mean age, 57 years; 78% male). Hypertension was present in 47%, 58% were on beta-blockers, 16% had prior AF or atrial flutter, and 19% were taking anticoagulants. Only 8% were on antiarrhythmic drugs, Dr. Caro Codón reported.

The patients had good functional status (68% and 29% were in NYHA class 1 and 2, respectively) and their left ventricular ejection fraction averaged 66%. Of the 71 patients who underwent MRI, 28.2% showed late gadolinium enhancement suggesting myocardial scarring.
 

More arrhythmias on 30-day monitoring

The primary endpoint of clinically relevant arrhythmia (AF, atrial flutter, or NSVT) was identified during the first 24 hours of monitoring in 11% of patients. The prevalence rose to 65% (P < .001) based on 30-day monitoring.

Similarly, prevalences of the composite primary endpoint components grew on extended monitoring, but the increases reached statistical significance only for NSVT; its prevalence went from 8% to 62% (P < .001). Prevalences rose nonsignificantly from 6% to 10% for AF and 0% to 1% for sustained ventricular tachycardia.

The incidence of NSVT during monitoring climbed fastest from day 0 through about day 19 and then rose more slowly through day 30, Dr. Caro Codón said. “It actually didn’t reach a plateau during this time period, so there is the possibility that if we had continued monitoring patients, the difference between both periods may have been even higher.”

Three variables predicted the incidence of nonsustained VT during monitoring, he said: age, atrial wall thickness, and whether there was late gadolinium enhancement at MRI.

An exploratory analysis looked at the 5-year risk of sudden cardiac death using the European Society of Cardiology HCM-SCD risk calculator recommended in guidelines. Risk assessment based on the 30-day extended monitoring period, compared with the first 24 hours of monitoring alone, predicted a significantly higher 5-year risk of sudden death, Dr. Caro Codón said.

“Even more importantly,” he added, “over 20%” of patients would have been reclassified into a higher-risk group and possibly considered for an ICD based on extended monitoring, compared to 24-hour monitoring.

However, given that more than 50% of patients were found to have NSVT during extended monitoring, Dr. Caro Codón proposed that decisions on whether to implant an ICD should not be so “binary” based on the presence or absence of symptoms, and proposed further investigations be conducted into the complete phenotype of these arrhythmias.

The study has limitations, he observed, including a relatively small size; but it was able to detect important differences between 24-hour and 30-day monitoring outcomes even with only 100 patients. It was also limited by a lack of clinical follow-up for information on endpoints like stroke, thromboembolism, and sudden cardiac death.

Extended monitoring detected more cases of NSVT in the study’s relatively low-risk HCM patients who would not generally have an indication for ICD implantation, observed Dr. van Gelder. Also, at present the prognostic value of NSVT for SCD “seems to be more important at younger age” – that is, younger than 30 years – in patients with HCM.

Dr. van Gelder echoed Dr. Caro Codón’s call for more data from prolonged monitoring to help stratify patients according to risk; she proposed NSVT frequency, duration, and rate as possible targets.

The study was supported by an unrestricted grant from Nuubo, which provided the ECG monitoring systems. Dr. Caro Codón and Dr. van Gelder reported no relevant financial relationships.

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

BARCELONA – Clinically important arrhythmias, especially nonsustained ventricular tachycardia (NSVT), may be more prevalent in patients with hypertrophic cardiomyopathy (HCM) than widely believed, suggests a study that questions current risk stratification practices in HCM.

In the registry study, such arrythmias were observed in about six times as many HCM patients during 30 days of ambulatory electrocardiographic monitoring as would have been identified based on the first 24 hours of the monitoring period: 65% vs. 11% of the cohort.

Also, about 62% of the patients showed NSVT at “extended” 30-day monitoring, compared with an 8% prevalence of the arrhythmia based on the more conventional ECG monitoring period of 24 hours.

Nonsustained ventricular tachycardia, an important arrhythmia used every day in clinical practice to make decisions, is “much, much more prevalent than we thought” in patients with HCM, Juan Caro Codón, MD, the study’s principal investigator, said in an interview. “We should invest in further research regarding extended ECG monitoring in these patients.”

Dr. Caro Codón, of La Paz University Hospital, Madrid, presented the findings from the TEMPO-HCM study at the European Heart Rhythm Association 2023 Congress, held in Barcelona and virtually.

Its results, he said, have implications for stratifying HCM patients according to their risk for sudden cardiac death in deciding who should be offered an implantable cardioverter-defibrillator (ICD).

The life-incidence of atrial fibrillation (AF) in patients like those in the current analysis has previously been found to be about 20%, and the life-prevalence of NSVT about 20%-30%, using traditional 24- or 48-hour Holter monitoring, Dr. Caro Codón said.

“These arrhythmias are clinically relevant events because they are linked to very meaningful clinical endpoints,” including stroke and thromboembolism, he said, “but also for sudden cardiac death.”

Extended ECG monitoring has been shown useful in the setting of cryptogenic stroke and after AF ablation, but similar findings have been scarce in HCM. Patients using personal wearable monitors such as smart watches, Dr. Caro Codón said, have come to his clinic with concerns that the devices may have signaled a problem. But the lack of relevant data leaves them without a sufficient answer.

In other findings, invited discussant Isabelle van Gelder, MD, PhD, observed after Dr. Caro Codón’s presentation that the number of patients with AF almost doubled based on extended monitoring, compared with the first 24 hours of monitoring.

Based on European Society of Cardiology guidelines from 2020, “Once clinical AF has been documented, there is a class IIA recommendation to start anticoagulation,” said Dr. van Gelder, University of Groningen, the Netherlands. “Therefore, your data really are a call for more data on screening for AF in hypertrophic cardiomyopathy patients.”
 

Prospective multicenter registry

The TEMPO-HCM registry includes patients with HCM and a clinical indication for standard Holter monitoring at five hospitals in Spain. It excludes patients with an HCM-like phenotype but who lack the telltale genotype, as well as those already implanted with an ICD.

Those in the current analysis underwent 30-day ECG monitoring with a small, wearable device that Dr. Caro Codón described as about 7 cm long, worn in what is essentially a T-shirt with a pocket. Patients could remove the shirt and device to bathe or go swimming, for example, and still be monitored for most of the day.

The analysis included the registry’s first 100 patients (mean age, 57 years; 78% male). Hypertension was present in 47%, 58% were on beta-blockers, 16% had prior AF or atrial flutter, and 19% were taking anticoagulants. Only 8% were on antiarrhythmic drugs, Dr. Caro Codón reported.

The patients had good functional status (68% and 29% were in NYHA class 1 and 2, respectively) and their left ventricular ejection fraction averaged 66%. Of the 71 patients who underwent MRI, 28.2% showed late gadolinium enhancement suggesting myocardial scarring.
 

More arrhythmias on 30-day monitoring

The primary endpoint of clinically relevant arrhythmia (AF, atrial flutter, or NSVT) was identified during the first 24 hours of monitoring in 11% of patients. The prevalence rose to 65% (P < .001) based on 30-day monitoring.

Similarly, prevalences of the composite primary endpoint components grew on extended monitoring, but the increases reached statistical significance only for NSVT; its prevalence went from 8% to 62% (P < .001). Prevalences rose nonsignificantly from 6% to 10% for AF and 0% to 1% for sustained ventricular tachycardia.

The incidence of NSVT during monitoring climbed fastest from day 0 through about day 19 and then rose more slowly through day 30, Dr. Caro Codón said. “It actually didn’t reach a plateau during this time period, so there is the possibility that if we had continued monitoring patients, the difference between both periods may have been even higher.”

Three variables predicted the incidence of nonsustained VT during monitoring, he said: age, atrial wall thickness, and whether there was late gadolinium enhancement at MRI.

An exploratory analysis looked at the 5-year risk of sudden cardiac death using the European Society of Cardiology HCM-SCD risk calculator recommended in guidelines. Risk assessment based on the 30-day extended monitoring period, compared with the first 24 hours of monitoring alone, predicted a significantly higher 5-year risk of sudden death, Dr. Caro Codón said.

“Even more importantly,” he added, “over 20%” of patients would have been reclassified into a higher-risk group and possibly considered for an ICD based on extended monitoring, compared to 24-hour monitoring.

However, given that more than 50% of patients were found to have NSVT during extended monitoring, Dr. Caro Codón proposed that decisions on whether to implant an ICD should not be so “binary” based on the presence or absence of symptoms, and proposed further investigations be conducted into the complete phenotype of these arrhythmias.

The study has limitations, he observed, including a relatively small size; but it was able to detect important differences between 24-hour and 30-day monitoring outcomes even with only 100 patients. It was also limited by a lack of clinical follow-up for information on endpoints like stroke, thromboembolism, and sudden cardiac death.

Extended monitoring detected more cases of NSVT in the study’s relatively low-risk HCM patients who would not generally have an indication for ICD implantation, observed Dr. van Gelder. Also, at present the prognostic value of NSVT for SCD “seems to be more important at younger age” – that is, younger than 30 years – in patients with HCM.

Dr. van Gelder echoed Dr. Caro Codón’s call for more data from prolonged monitoring to help stratify patients according to risk; she proposed NSVT frequency, duration, and rate as possible targets.

The study was supported by an unrestricted grant from Nuubo, which provided the ECG monitoring systems. Dr. Caro Codón and Dr. van Gelder reported no relevant financial relationships.

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

BARCELONA – Clinically important arrhythmias, especially nonsustained ventricular tachycardia (NSVT), may be more prevalent in patients with hypertrophic cardiomyopathy (HCM) than widely believed, suggests a study that questions current risk stratification practices in HCM.

In the registry study, such arrythmias were observed in about six times as many HCM patients during 30 days of ambulatory electrocardiographic monitoring as would have been identified based on the first 24 hours of the monitoring period: 65% vs. 11% of the cohort.

Also, about 62% of the patients showed NSVT at “extended” 30-day monitoring, compared with an 8% prevalence of the arrhythmia based on the more conventional ECG monitoring period of 24 hours.

Nonsustained ventricular tachycardia, an important arrhythmia used every day in clinical practice to make decisions, is “much, much more prevalent than we thought” in patients with HCM, Juan Caro Codón, MD, the study’s principal investigator, said in an interview. “We should invest in further research regarding extended ECG monitoring in these patients.”

Dr. Caro Codón, of La Paz University Hospital, Madrid, presented the findings from the TEMPO-HCM study at the European Heart Rhythm Association 2023 Congress, held in Barcelona and virtually.

Its results, he said, have implications for stratifying HCM patients according to their risk for sudden cardiac death in deciding who should be offered an implantable cardioverter-defibrillator (ICD).

The life-incidence of atrial fibrillation (AF) in patients like those in the current analysis has previously been found to be about 20%, and the life-prevalence of NSVT about 20%-30%, using traditional 24- or 48-hour Holter monitoring, Dr. Caro Codón said.

“These arrhythmias are clinically relevant events because they are linked to very meaningful clinical endpoints,” including stroke and thromboembolism, he said, “but also for sudden cardiac death.”

Extended ECG monitoring has been shown useful in the setting of cryptogenic stroke and after AF ablation, but similar findings have been scarce in HCM. Patients using personal wearable monitors such as smart watches, Dr. Caro Codón said, have come to his clinic with concerns that the devices may have signaled a problem. But the lack of relevant data leaves them without a sufficient answer.

In other findings, invited discussant Isabelle van Gelder, MD, PhD, observed after Dr. Caro Codón’s presentation that the number of patients with AF almost doubled based on extended monitoring, compared with the first 24 hours of monitoring.

Based on European Society of Cardiology guidelines from 2020, “Once clinical AF has been documented, there is a class IIA recommendation to start anticoagulation,” said Dr. van Gelder, University of Groningen, the Netherlands. “Therefore, your data really are a call for more data on screening for AF in hypertrophic cardiomyopathy patients.”
 

Prospective multicenter registry

The TEMPO-HCM registry includes patients with HCM and a clinical indication for standard Holter monitoring at five hospitals in Spain. It excludes patients with an HCM-like phenotype but who lack the telltale genotype, as well as those already implanted with an ICD.

Those in the current analysis underwent 30-day ECG monitoring with a small, wearable device that Dr. Caro Codón described as about 7 cm long, worn in what is essentially a T-shirt with a pocket. Patients could remove the shirt and device to bathe or go swimming, for example, and still be monitored for most of the day.

The analysis included the registry’s first 100 patients (mean age, 57 years; 78% male). Hypertension was present in 47%, 58% were on beta-blockers, 16% had prior AF or atrial flutter, and 19% were taking anticoagulants. Only 8% were on antiarrhythmic drugs, Dr. Caro Codón reported.

The patients had good functional status (68% and 29% were in NYHA class 1 and 2, respectively) and their left ventricular ejection fraction averaged 66%. Of the 71 patients who underwent MRI, 28.2% showed late gadolinium enhancement suggesting myocardial scarring.
 

More arrhythmias on 30-day monitoring

The primary endpoint of clinically relevant arrhythmia (AF, atrial flutter, or NSVT) was identified during the first 24 hours of monitoring in 11% of patients. The prevalence rose to 65% (P < .001) based on 30-day monitoring.

Similarly, prevalences of the composite primary endpoint components grew on extended monitoring, but the increases reached statistical significance only for NSVT; its prevalence went from 8% to 62% (P < .001). Prevalences rose nonsignificantly from 6% to 10% for AF and 0% to 1% for sustained ventricular tachycardia.

The incidence of NSVT during monitoring climbed fastest from day 0 through about day 19 and then rose more slowly through day 30, Dr. Caro Codón said. “It actually didn’t reach a plateau during this time period, so there is the possibility that if we had continued monitoring patients, the difference between both periods may have been even higher.”

Three variables predicted the incidence of nonsustained VT during monitoring, he said: age, atrial wall thickness, and whether there was late gadolinium enhancement at MRI.

An exploratory analysis looked at the 5-year risk of sudden cardiac death using the European Society of Cardiology HCM-SCD risk calculator recommended in guidelines. Risk assessment based on the 30-day extended monitoring period, compared with the first 24 hours of monitoring alone, predicted a significantly higher 5-year risk of sudden death, Dr. Caro Codón said.

“Even more importantly,” he added, “over 20%” of patients would have been reclassified into a higher-risk group and possibly considered for an ICD based on extended monitoring, compared to 24-hour monitoring.

However, given that more than 50% of patients were found to have NSVT during extended monitoring, Dr. Caro Codón proposed that decisions on whether to implant an ICD should not be so “binary” based on the presence or absence of symptoms, and proposed further investigations be conducted into the complete phenotype of these arrhythmias.

The study has limitations, he observed, including a relatively small size; but it was able to detect important differences between 24-hour and 30-day monitoring outcomes even with only 100 patients. It was also limited by a lack of clinical follow-up for information on endpoints like stroke, thromboembolism, and sudden cardiac death.

Extended monitoring detected more cases of NSVT in the study’s relatively low-risk HCM patients who would not generally have an indication for ICD implantation, observed Dr. van Gelder. Also, at present the prognostic value of NSVT for SCD “seems to be more important at younger age” – that is, younger than 30 years – in patients with HCM.

Dr. van Gelder echoed Dr. Caro Codón’s call for more data from prolonged monitoring to help stratify patients according to risk; she proposed NSVT frequency, duration, and rate as possible targets.

The study was supported by an unrestricted grant from Nuubo, which provided the ECG monitoring systems. Dr. Caro Codón and Dr. van Gelder reported no relevant financial relationships.

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

The Centers for Disease Control and Prevention and the U.S. Census Bureau estimate that 6.1% of the U.S. adult population is living with long COVID, with millions more debilitated worldwide. The demand for substantial treatment is enormous, but the urgency to fund and begin the necessary range of clinical trials has not met the severity of the problem.
 

While trials are slowly beginning to happen, the treatment choices and trial design require crucial nuances and understanding of viral-onset illnesses, and few research groups are creating strong trials that fully reflect the complexities of this landscape.

This article aims to share key considerations and best practices that are essential to the success of these trials. These recommendations recognize that roughly half of long COVID patients have new-onset myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia from COVID, which must be at the forefront of how trials are designed and conducted, and are additionally based on the current hypotheses about long COVID’s pathophysiologies. 
 

1: Drugs proposed by experts in postviral fields should be prioritized

Upward of 50 drugs for viral-onset conditions like ME/CFS, dysautonomia, AIDS, and others have been waiting for years to go to trial, but have not had the funding to do so. 

Treatments proposed by experts in viral-onset illnesses (such as ME/CFS and dysautonomia) should be prioritized (PM R. 2022 Oct;14[10]:1270-91), as outside researchers are not familiar with these fields and their potential treatment options.
 

2: Drugs targeting a wide range of mechanisms should be trialed

Treatments that should be trialed include anticoagulants/antiplatelets for clotting and vascular functioning, immunomodulators including JAK-STAT inhibitors, COVID-specific antivirals and antivirals against reactivated herpesviruses (Valcyte, Valacyclovir, EBV vaccine). 

Other options include prescription mast cell stabilizers (ketotifen, cromolyn sodium), drugs that regulate microglial activation (low-dose naltrexone, low-dose aripiprazole), anti-CGRP medications, beta-blockers, and intravenous immunoglobulin.

Others include medications that target mitochondrial dysfunction; ivabradine; pyridostigmine;, DRP1 inhibitors; supplements showing success in patient communities including lactoferrin, ubiquinone, and nattokinase; and therapies targeting glymphatic/lymphatic dysfunction, microbiome therapies, and therapeutic peptides. 
 

3: Use appropriate long COVID subtypes 

Long COVID is an umbrella term that encompasses multiple new-onset and worsened conditions and symptoms after COVID. Roughly half of long COVID patients likely meet the criteria for ME/CFS and/or dysautonomia. Others may have new-onset diabetes, major clotting events, lung damage, neurological disorders, loss of smell or taste, and other manifestations. 

Patients in different categories likely have different responses to treatments. It’s critical to identify appropriate subtypes for each trial, ideally performing detailed analyses to identify the treatments that work best, and don’t, for each subtype. 
 

4: Behavioral treatments, especially those that have harmed similar populations, should not be trialed

Behavioral treatments including exercise, graded exercise therapy (GET), and cognitive-behavioral therapy (CBT) should not be trialed, let alone prioritized, for long COVID. 

In patients with postexertional malaise (PEM), one of the most common long COVID symptoms, exercise is actively harmful and causes dysfunctional metabolic patterns, cardiac preload failure, impaired systemic oxygen extraction, and more. GET and CBT have failed similar populations , and exercise is explicitly contraindicated by the World Health Organization, the British National Institute for Health and Care Excellence, the CDC, and other organizations. 

Resources should instead be put toward the wide range of medications that have not yet adequately undergone clinical trials.  
 

5: PCR and antibody tests should not be used as inclusion criteria for trial participants

Only an estimated 1%-3% of cases in the first wave of COVID were documented, and the CDC estimates that only 25% of cases through September 2021 were documented. Similarly, antibody tests are unreliable to determine past infection, as roughly a third of patients don’t seroconvert, and a similar proportion serorevert within a few months. Using polymerase chain reaction (PCR) and antibody testing to determine who should be included in clinical trials limits who is eligible to participate in research, particularly those who have been ill for longer. Additionally, the majority of those who serorevert are women, so using antibody tests for inclusion introduces a selection bias and may miss mechanisms of immune system functioning that are part of long COVID.

PCR tests also have high false-negative rates and requiring them in research excludes people with lower viral loads with long COVID, which would confound findings. 

These issues with testing also lead to COVID-infected people accidentally being included in control groups, which ruins the credibility of the research findings completely.
 

6: Include comparator groups

There are several common diagnoses that occur in people with long COVID, including ME/CFS, postural orthostatic tachycardia syndrome, small-fiber neuropathy, mast cell activation syndrome, and Ehlers-Danlos syndrome.

Identifying people with these conditions within the trial cohort improves research across all fields, benefiting all groups, and helps clarify what types of patients benefit most from certain medications. 
 

7: Identify the right endpoints; avoid the wrong ones

Even though our understanding of the pathophysiology of long COVID is still evolving, it’s still possible to do clinical trials by identifying strong endpoints and outcome measures. 

Several tools have been designed for viral-onset conditions and should be used alongside other endpoints. Postexertional malaise and autonomic symptoms, which are some of the most common symptoms of long COVID, can be measured with the validated DSQ-PEM and COMPASS-31, respectively. Tools for cognitive dysfunction trials should capture specific and common types of impairment, like processing speed. 

Endpoints should be high-impact and aim for large improvements that have clinical significance over small improvements that do not have clinical significance. 

Objective tests should be incorporated where possible; some to consider include natural killer cell functioning, cerebral blood flow, T-cell functioning, levels of reactivated herpesviruses, blood lactate levels, and microclots, as testing becomes available. 

Mental health outcomes shouldn’t be primary endpoints, except where a trial is targeting a specific mental health condition because of COVID (for example, premenstrual dysphoric disorder). 

If mental health conditions are tracked secondarily, it’s vital not to use questionnaires that include physical symptoms like fatigue, difficulty concentrating, difficulty sleeping, or palpitations, as these artificially increase depression and anxiety scores in chronically ill respondents. Tools that include physical symptoms (Patient Health Questionnaire–9, Beck Anxiety Inventory, Beck Depression Inventory) can be replaced with scales like the PHQ-2, General Anxiety Disorder–7, Hospital Anxiety and Depression Scale, or PROMIS-29 subscales.

Because certain cytokines and other inflammatory markers may naturally decrease over time without corresponding improvement in the ME/CFS subtype, caution should be taken when using cytokines as endpoints.
 

8: Consider enrollment and objectives carefully

A proportion of people with long COVID will recover in the early months after infection. Ideally, clinical trials will primarily study treatments in patients who have been ill 6 months or longer, as some natural recovery will happen before that can bias studies.

But where resources are abundant, it is ideal for trials to additionally look at whether the treatments can help patients in the early months recover and prevent progression to the later stage.
 

9: Tracking illness duration is crucial

Research from ME/CFS shows that there may be an immune change in the first few years of the illness, where cytokines decrease without any corresponding change in symptom improvement. 

Because of this and the possibility that other markers follow the same pattern, disease duration should be a core feature of all analyses and trial designs. Trial outcomes should be designed to answer the question of whether the medication helps patients at different durations of illness. 
 

10: Prioritize patient populations less likely to recover without intervention

Some long COVID phenotypes seem less likely to recover without intervention. Trials should take care to focus on these patient populations, which include those with neurologic symptoms and those meeting ME/CFS criteria.

 

11: Account for the relapsing/remitting nature

Outcome measures need to be assessed in a way that can distinguish a temporary remission, which is part of the natural course of the disease, from a permanent cure. 

Factors that can contribute to the relapsing/remitting nature include physical and cognitive postexertional malaise, menstrual cycle changes, and seasonal changes.
 

12: Trial participants should reflect the diversity of the long COVID population

Certain demographics are more likely to be affected by acute and long COVID and need to be appropriately recruited and reflected in research, including in patient engagement. 

Trials must include high numbers of Hispanic/Latinx, Black, and indigenous communities, queer and transgender populations, and women. Trial materials and design need to incorporate linguistic diversity in addition to racial/ethnic diversity.

Upward of 75% of long COVID cases happen after mild acute cases; clinical researchers should ensure that nonhospitalized patients make up the bulk of trial participants. 
 

13: Utilize meaningful engagement of patients, especially in treatment selection and study design

Meaningful patient engagement means engaging multiple patients at every step of the trial process, from treatment selection to study design to analysis to communication of the results. 

Patient experiences are extremely valuable and contain information that researchers may not be familiar with, including the nature and patterns of the illness, insights into possible treatments, and barriers to documentation and care that may also impact research. Tapping into those patient experiences will make trials stronger.

Overall, the landscape of long COVID clinical trials is ripe for discovery, and researchers choosing to go down this path will be deeply appreciated by the patient community. 

Hannah Davis is a long COVID patient-researcher and cofounder of the Patient-Led Research Collaborative, an organization studying the long-term effects of COVID.

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

The Centers for Disease Control and Prevention and the U.S. Census Bureau estimate that 6.1% of the U.S. adult population is living with long COVID, with millions more debilitated worldwide. The demand for substantial treatment is enormous, but the urgency to fund and begin the necessary range of clinical trials has not met the severity of the problem.
 

While trials are slowly beginning to happen, the treatment choices and trial design require crucial nuances and understanding of viral-onset illnesses, and few research groups are creating strong trials that fully reflect the complexities of this landscape.

This article aims to share key considerations and best practices that are essential to the success of these trials. These recommendations recognize that roughly half of long COVID patients have new-onset myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia from COVID, which must be at the forefront of how trials are designed and conducted, and are additionally based on the current hypotheses about long COVID’s pathophysiologies. 
 

1: Drugs proposed by experts in postviral fields should be prioritized

Upward of 50 drugs for viral-onset conditions like ME/CFS, dysautonomia, AIDS, and others have been waiting for years to go to trial, but have not had the funding to do so. 

Treatments proposed by experts in viral-onset illnesses (such as ME/CFS and dysautonomia) should be prioritized (PM R. 2022 Oct;14[10]:1270-91), as outside researchers are not familiar with these fields and their potential treatment options.
 

2: Drugs targeting a wide range of mechanisms should be trialed

Treatments that should be trialed include anticoagulants/antiplatelets for clotting and vascular functioning, immunomodulators including JAK-STAT inhibitors, COVID-specific antivirals and antivirals against reactivated herpesviruses (Valcyte, Valacyclovir, EBV vaccine). 

Other options include prescription mast cell stabilizers (ketotifen, cromolyn sodium), drugs that regulate microglial activation (low-dose naltrexone, low-dose aripiprazole), anti-CGRP medications, beta-blockers, and intravenous immunoglobulin.

Others include medications that target mitochondrial dysfunction; ivabradine; pyridostigmine;, DRP1 inhibitors; supplements showing success in patient communities including lactoferrin, ubiquinone, and nattokinase; and therapies targeting glymphatic/lymphatic dysfunction, microbiome therapies, and therapeutic peptides. 
 

3: Use appropriate long COVID subtypes 

Long COVID is an umbrella term that encompasses multiple new-onset and worsened conditions and symptoms after COVID. Roughly half of long COVID patients likely meet the criteria for ME/CFS and/or dysautonomia. Others may have new-onset diabetes, major clotting events, lung damage, neurological disorders, loss of smell or taste, and other manifestations. 

Patients in different categories likely have different responses to treatments. It’s critical to identify appropriate subtypes for each trial, ideally performing detailed analyses to identify the treatments that work best, and don’t, for each subtype. 
 

4: Behavioral treatments, especially those that have harmed similar populations, should not be trialed

Behavioral treatments including exercise, graded exercise therapy (GET), and cognitive-behavioral therapy (CBT) should not be trialed, let alone prioritized, for long COVID. 

In patients with postexertional malaise (PEM), one of the most common long COVID symptoms, exercise is actively harmful and causes dysfunctional metabolic patterns, cardiac preload failure, impaired systemic oxygen extraction, and more. GET and CBT have failed similar populations , and exercise is explicitly contraindicated by the World Health Organization, the British National Institute for Health and Care Excellence, the CDC, and other organizations. 

Resources should instead be put toward the wide range of medications that have not yet adequately undergone clinical trials.  
 

5: PCR and antibody tests should not be used as inclusion criteria for trial participants

Only an estimated 1%-3% of cases in the first wave of COVID were documented, and the CDC estimates that only 25% of cases through September 2021 were documented. Similarly, antibody tests are unreliable to determine past infection, as roughly a third of patients don’t seroconvert, and a similar proportion serorevert within a few months. Using polymerase chain reaction (PCR) and antibody testing to determine who should be included in clinical trials limits who is eligible to participate in research, particularly those who have been ill for longer. Additionally, the majority of those who serorevert are women, so using antibody tests for inclusion introduces a selection bias and may miss mechanisms of immune system functioning that are part of long COVID.

PCR tests also have high false-negative rates and requiring them in research excludes people with lower viral loads with long COVID, which would confound findings. 

These issues with testing also lead to COVID-infected people accidentally being included in control groups, which ruins the credibility of the research findings completely.
 

6: Include comparator groups

There are several common diagnoses that occur in people with long COVID, including ME/CFS, postural orthostatic tachycardia syndrome, small-fiber neuropathy, mast cell activation syndrome, and Ehlers-Danlos syndrome.

Identifying people with these conditions within the trial cohort improves research across all fields, benefiting all groups, and helps clarify what types of patients benefit most from certain medications. 
 

7: Identify the right endpoints; avoid the wrong ones

Even though our understanding of the pathophysiology of long COVID is still evolving, it’s still possible to do clinical trials by identifying strong endpoints and outcome measures. 

Several tools have been designed for viral-onset conditions and should be used alongside other endpoints. Postexertional malaise and autonomic symptoms, which are some of the most common symptoms of long COVID, can be measured with the validated DSQ-PEM and COMPASS-31, respectively. Tools for cognitive dysfunction trials should capture specific and common types of impairment, like processing speed. 

Endpoints should be high-impact and aim for large improvements that have clinical significance over small improvements that do not have clinical significance. 

Objective tests should be incorporated where possible; some to consider include natural killer cell functioning, cerebral blood flow, T-cell functioning, levels of reactivated herpesviruses, blood lactate levels, and microclots, as testing becomes available. 

Mental health outcomes shouldn’t be primary endpoints, except where a trial is targeting a specific mental health condition because of COVID (for example, premenstrual dysphoric disorder). 

If mental health conditions are tracked secondarily, it’s vital not to use questionnaires that include physical symptoms like fatigue, difficulty concentrating, difficulty sleeping, or palpitations, as these artificially increase depression and anxiety scores in chronically ill respondents. Tools that include physical symptoms (Patient Health Questionnaire–9, Beck Anxiety Inventory, Beck Depression Inventory) can be replaced with scales like the PHQ-2, General Anxiety Disorder–7, Hospital Anxiety and Depression Scale, or PROMIS-29 subscales.

Because certain cytokines and other inflammatory markers may naturally decrease over time without corresponding improvement in the ME/CFS subtype, caution should be taken when using cytokines as endpoints.
 

8: Consider enrollment and objectives carefully

A proportion of people with long COVID will recover in the early months after infection. Ideally, clinical trials will primarily study treatments in patients who have been ill 6 months or longer, as some natural recovery will happen before that can bias studies.

But where resources are abundant, it is ideal for trials to additionally look at whether the treatments can help patients in the early months recover and prevent progression to the later stage.
 

9: Tracking illness duration is crucial

Research from ME/CFS shows that there may be an immune change in the first few years of the illness, where cytokines decrease without any corresponding change in symptom improvement. 

Because of this and the possibility that other markers follow the same pattern, disease duration should be a core feature of all analyses and trial designs. Trial outcomes should be designed to answer the question of whether the medication helps patients at different durations of illness. 
 

10: Prioritize patient populations less likely to recover without intervention

Some long COVID phenotypes seem less likely to recover without intervention. Trials should take care to focus on these patient populations, which include those with neurologic symptoms and those meeting ME/CFS criteria.

 

11: Account for the relapsing/remitting nature

Outcome measures need to be assessed in a way that can distinguish a temporary remission, which is part of the natural course of the disease, from a permanent cure. 

Factors that can contribute to the relapsing/remitting nature include physical and cognitive postexertional malaise, menstrual cycle changes, and seasonal changes.
 

12: Trial participants should reflect the diversity of the long COVID population

Certain demographics are more likely to be affected by acute and long COVID and need to be appropriately recruited and reflected in research, including in patient engagement. 

Trials must include high numbers of Hispanic/Latinx, Black, and indigenous communities, queer and transgender populations, and women. Trial materials and design need to incorporate linguistic diversity in addition to racial/ethnic diversity.

Upward of 75% of long COVID cases happen after mild acute cases; clinical researchers should ensure that nonhospitalized patients make up the bulk of trial participants. 
 

13: Utilize meaningful engagement of patients, especially in treatment selection and study design

Meaningful patient engagement means engaging multiple patients at every step of the trial process, from treatment selection to study design to analysis to communication of the results. 

Patient experiences are extremely valuable and contain information that researchers may not be familiar with, including the nature and patterns of the illness, insights into possible treatments, and barriers to documentation and care that may also impact research. Tapping into those patient experiences will make trials stronger.

Overall, the landscape of long COVID clinical trials is ripe for discovery, and researchers choosing to go down this path will be deeply appreciated by the patient community. 

Hannah Davis is a long COVID patient-researcher and cofounder of the Patient-Led Research Collaborative, an organization studying the long-term effects of COVID.

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

The Centers for Disease Control and Prevention and the U.S. Census Bureau estimate that 6.1% of the U.S. adult population is living with long COVID, with millions more debilitated worldwide. The demand for substantial treatment is enormous, but the urgency to fund and begin the necessary range of clinical trials has not met the severity of the problem.
 

While trials are slowly beginning to happen, the treatment choices and trial design require crucial nuances and understanding of viral-onset illnesses, and few research groups are creating strong trials that fully reflect the complexities of this landscape.

This article aims to share key considerations and best practices that are essential to the success of these trials. These recommendations recognize that roughly half of long COVID patients have new-onset myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia from COVID, which must be at the forefront of how trials are designed and conducted, and are additionally based on the current hypotheses about long COVID’s pathophysiologies. 
 

1: Drugs proposed by experts in postviral fields should be prioritized

Upward of 50 drugs for viral-onset conditions like ME/CFS, dysautonomia, AIDS, and others have been waiting for years to go to trial, but have not had the funding to do so. 

Treatments proposed by experts in viral-onset illnesses (such as ME/CFS and dysautonomia) should be prioritized (PM R. 2022 Oct;14[10]:1270-91), as outside researchers are not familiar with these fields and their potential treatment options.
 

2: Drugs targeting a wide range of mechanisms should be trialed

Treatments that should be trialed include anticoagulants/antiplatelets for clotting and vascular functioning, immunomodulators including JAK-STAT inhibitors, COVID-specific antivirals and antivirals against reactivated herpesviruses (Valcyte, Valacyclovir, EBV vaccine). 

Other options include prescription mast cell stabilizers (ketotifen, cromolyn sodium), drugs that regulate microglial activation (low-dose naltrexone, low-dose aripiprazole), anti-CGRP medications, beta-blockers, and intravenous immunoglobulin.

Others include medications that target mitochondrial dysfunction; ivabradine; pyridostigmine;, DRP1 inhibitors; supplements showing success in patient communities including lactoferrin, ubiquinone, and nattokinase; and therapies targeting glymphatic/lymphatic dysfunction, microbiome therapies, and therapeutic peptides. 
 

3: Use appropriate long COVID subtypes 

Long COVID is an umbrella term that encompasses multiple new-onset and worsened conditions and symptoms after COVID. Roughly half of long COVID patients likely meet the criteria for ME/CFS and/or dysautonomia. Others may have new-onset diabetes, major clotting events, lung damage, neurological disorders, loss of smell or taste, and other manifestations. 

Patients in different categories likely have different responses to treatments. It’s critical to identify appropriate subtypes for each trial, ideally performing detailed analyses to identify the treatments that work best, and don’t, for each subtype. 
 

4: Behavioral treatments, especially those that have harmed similar populations, should not be trialed

Behavioral treatments including exercise, graded exercise therapy (GET), and cognitive-behavioral therapy (CBT) should not be trialed, let alone prioritized, for long COVID. 

In patients with postexertional malaise (PEM), one of the most common long COVID symptoms, exercise is actively harmful and causes dysfunctional metabolic patterns, cardiac preload failure, impaired systemic oxygen extraction, and more. GET and CBT have failed similar populations , and exercise is explicitly contraindicated by the World Health Organization, the British National Institute for Health and Care Excellence, the CDC, and other organizations. 

Resources should instead be put toward the wide range of medications that have not yet adequately undergone clinical trials.  
 

5: PCR and antibody tests should not be used as inclusion criteria for trial participants

Only an estimated 1%-3% of cases in the first wave of COVID were documented, and the CDC estimates that only 25% of cases through September 2021 were documented. Similarly, antibody tests are unreliable to determine past infection, as roughly a third of patients don’t seroconvert, and a similar proportion serorevert within a few months. Using polymerase chain reaction (PCR) and antibody testing to determine who should be included in clinical trials limits who is eligible to participate in research, particularly those who have been ill for longer. Additionally, the majority of those who serorevert are women, so using antibody tests for inclusion introduces a selection bias and may miss mechanisms of immune system functioning that are part of long COVID.

PCR tests also have high false-negative rates and requiring them in research excludes people with lower viral loads with long COVID, which would confound findings. 

These issues with testing also lead to COVID-infected people accidentally being included in control groups, which ruins the credibility of the research findings completely.
 

6: Include comparator groups

There are several common diagnoses that occur in people with long COVID, including ME/CFS, postural orthostatic tachycardia syndrome, small-fiber neuropathy, mast cell activation syndrome, and Ehlers-Danlos syndrome.

Identifying people with these conditions within the trial cohort improves research across all fields, benefiting all groups, and helps clarify what types of patients benefit most from certain medications. 
 

7: Identify the right endpoints; avoid the wrong ones

Even though our understanding of the pathophysiology of long COVID is still evolving, it’s still possible to do clinical trials by identifying strong endpoints and outcome measures. 

Several tools have been designed for viral-onset conditions and should be used alongside other endpoints. Postexertional malaise and autonomic symptoms, which are some of the most common symptoms of long COVID, can be measured with the validated DSQ-PEM and COMPASS-31, respectively. Tools for cognitive dysfunction trials should capture specific and common types of impairment, like processing speed. 

Endpoints should be high-impact and aim for large improvements that have clinical significance over small improvements that do not have clinical significance. 

Objective tests should be incorporated where possible; some to consider include natural killer cell functioning, cerebral blood flow, T-cell functioning, levels of reactivated herpesviruses, blood lactate levels, and microclots, as testing becomes available. 

Mental health outcomes shouldn’t be primary endpoints, except where a trial is targeting a specific mental health condition because of COVID (for example, premenstrual dysphoric disorder). 

If mental health conditions are tracked secondarily, it’s vital not to use questionnaires that include physical symptoms like fatigue, difficulty concentrating, difficulty sleeping, or palpitations, as these artificially increase depression and anxiety scores in chronically ill respondents. Tools that include physical symptoms (Patient Health Questionnaire–9, Beck Anxiety Inventory, Beck Depression Inventory) can be replaced with scales like the PHQ-2, General Anxiety Disorder–7, Hospital Anxiety and Depression Scale, or PROMIS-29 subscales.

Because certain cytokines and other inflammatory markers may naturally decrease over time without corresponding improvement in the ME/CFS subtype, caution should be taken when using cytokines as endpoints.
 

8: Consider enrollment and objectives carefully

A proportion of people with long COVID will recover in the early months after infection. Ideally, clinical trials will primarily study treatments in patients who have been ill 6 months or longer, as some natural recovery will happen before that can bias studies.

But where resources are abundant, it is ideal for trials to additionally look at whether the treatments can help patients in the early months recover and prevent progression to the later stage.
 

9: Tracking illness duration is crucial

Research from ME/CFS shows that there may be an immune change in the first few years of the illness, where cytokines decrease without any corresponding change in symptom improvement. 

Because of this and the possibility that other markers follow the same pattern, disease duration should be a core feature of all analyses and trial designs. Trial outcomes should be designed to answer the question of whether the medication helps patients at different durations of illness. 
 

10: Prioritize patient populations less likely to recover without intervention

Some long COVID phenotypes seem less likely to recover without intervention. Trials should take care to focus on these patient populations, which include those with neurologic symptoms and those meeting ME/CFS criteria.

 

11: Account for the relapsing/remitting nature

Outcome measures need to be assessed in a way that can distinguish a temporary remission, which is part of the natural course of the disease, from a permanent cure. 

Factors that can contribute to the relapsing/remitting nature include physical and cognitive postexertional malaise, menstrual cycle changes, and seasonal changes.
 

12: Trial participants should reflect the diversity of the long COVID population

Certain demographics are more likely to be affected by acute and long COVID and need to be appropriately recruited and reflected in research, including in patient engagement. 

Trials must include high numbers of Hispanic/Latinx, Black, and indigenous communities, queer and transgender populations, and women. Trial materials and design need to incorporate linguistic diversity in addition to racial/ethnic diversity.

Upward of 75% of long COVID cases happen after mild acute cases; clinical researchers should ensure that nonhospitalized patients make up the bulk of trial participants. 
 

13: Utilize meaningful engagement of patients, especially in treatment selection and study design

Meaningful patient engagement means engaging multiple patients at every step of the trial process, from treatment selection to study design to analysis to communication of the results. 

Patient experiences are extremely valuable and contain information that researchers may not be familiar with, including the nature and patterns of the illness, insights into possible treatments, and barriers to documentation and care that may also impact research. Tapping into those patient experiences will make trials stronger.

Overall, the landscape of long COVID clinical trials is ripe for discovery, and researchers choosing to go down this path will be deeply appreciated by the patient community. 

Hannah Davis is a long COVID patient-researcher and cofounder of the Patient-Led Research Collaborative, an organization studying the long-term effects of COVID.

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

A large price increase for colchicine in 2010 led to a significant falloff in its use for gout that persisted for the next decade while emergency and rheumatology visits for gout rose, suggesting poorer disease control, a retrospective cohort study reported.
 

The price of colchicine, commonly prescribed for acute gout attacks, climbed from $11.25 per prescription in 2009 to $190.49 in 2011, with the average out-of-pocket cost more than quadrupling, from $7.37 to $29.42, the study noted. Colchicine prescriptions for gout declined 27% over the next decade, according to adjusted analyses that the study authors performed.

Massachusetts General Hospital

“A roughly 16-fold increase in colchicine prices appeared to have lowered colchicine use over the next decade,” senior author Zirui Song, MD, PhD, an associate professor of health care policy and medicine at Harvard Medical School and an internist at Massachusetts General Hospital in Boston, told this news organization in written comments. “Over the same period, patients with gout used more of other medications that could treat gout. They also had more emergency department visits for gout and rheumatologist visits for gout, which potentially signals poorer disease control.”

The study, published online in JAMA Internal Medicine, examined MarketScan data from a longitudinal cohort of patients who had employer-sponsored health insurance and a diagnosis of gout from 2007 to 2019. MarketScan is an IBM database of medical and drug data from employers and health plans. The study examined more than 2.7 million patient-year observations over the 13-year period.
 

How the price increase happened

After 2011, a large percentage of patients shifted to less effective but more affordable drugs to treat gout. Prescriptions for allopurinol increased 32% (P < .001) and oral corticosteroids 8.3% over the decade. “These are imperfect substitutes,” Dr. Song said. “Allopurinol is used to prevent gout, while oral corticosteroids can be used to treat a gout flare.”

At the same time, visits for gout-related complaints to emergency departments and rheumatology offices increased through the ensuing years: 39.8% and 10.5% on an adjusted analysis, respectively (P < .001 for both).

Colchicine is actually a drug that predates the creation of the U.S. Food and Drug Administration in 1938 and had been grandfathered under its Unapproved Drug Initiative. Then in 2009, the FDA determined that colchicine was effective for treating arthritis-related gout flares after the manufacturer, URL Pharma, presented results of a randomized, controlled trial of 185 patients with gout.

The next year, the FDA granted URL Pharma 3 years of market exclusivity for the drug under the brand name Colcrys, now trademarked by Takeda Pharmaceuticals.

The latest study noted that longer-term analysis of the impact of the FDA’s decision had been lacking. The goal, said Dr. Song, was “to better understand the long-run implications of large drug price increases in the U.S. by studying the case of colchicine.”

He added, “For drugs that lack competition, large price increases can have large economic and clinical consequences over many years.”
 

Absorbing the cost

Lead author Dan P. Ly, MD, PhD, MPP, assistant professor at the University of California, Los Angeles, added, “Our study has large implications [for] when generic medications or other medications experience large price increases. Use of the medication in question drops or patients have to pay more out of pocket, and patient health can suffer as a result.”

The dropoff in colchicine use in this patient population could have been worse, Dr. Song said. “Despite colchicine use decreasing by 27% over nearly a decade, the fact that it did not decline more suggests that for patients with gout, the large price increase was mostly absorbed by their insurers, employers, or themselves – e.g., passed through to higher premiums, lower wages, or higher cost-sharing.”

Harvard Medical School

Aaron Kesselheim, MD, JD, MPH, a professor at Harvard Medical School, Boston, reported previously on the price consequences of colchicine early on after the FDA granted the manufacturer market exclusivity.

“In our past research, we looked at how the massive increase in the price of colchicine increased spending on the drug and reduced use in a relatively short time period after the price hike,” said Dr. Kesselheim, who was not involved in this current study by Dr. Ly, Dr. Song, and Mia Giuriato, BBA, MA, from Harvard Medical School. “This study evaluated the experiences of patients with gout over multiple years and showed that the reductions in use persisted and were associated with increases in ED and rheumatology visits, suggesting worsening control of gout due to the relative inaccessibility of the drug at the new high price.”

The latest findings have public policy implications, Dr. Kesselheim said. “In the case of colchicine, the FDA made a bad pitch, leading to a home run for the manufacturer and a shutout for patients.”

“The FDA needs to make sure to take into account the quite predictable patient effects that can result from disruptions to competition when it considers taking steps like it did in the colchicine case to disrupt the market and create an artificial monopoly, even if the FDA acted in the best of intentions in this case,” Dr. Kesselheim added.

Dr. Song received funding for the study from the National Institutes of Health and Arnold Ventures. He also disclosed receiving personal fees from the Research Triangle Institute, Google Ventures, VBID Health, and the International Foundation of Employee Benefit Plans. Dr. Ly, Ms. Giuriato, and Dr. Kesselheim report no relevant financial relationships.

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

A large price increase for colchicine in 2010 led to a significant falloff in its use for gout that persisted for the next decade while emergency and rheumatology visits for gout rose, suggesting poorer disease control, a retrospective cohort study reported.
 

The price of colchicine, commonly prescribed for acute gout attacks, climbed from $11.25 per prescription in 2009 to $190.49 in 2011, with the average out-of-pocket cost more than quadrupling, from $7.37 to $29.42, the study noted. Colchicine prescriptions for gout declined 27% over the next decade, according to adjusted analyses that the study authors performed.

Massachusetts General Hospital

“A roughly 16-fold increase in colchicine prices appeared to have lowered colchicine use over the next decade,” senior author Zirui Song, MD, PhD, an associate professor of health care policy and medicine at Harvard Medical School and an internist at Massachusetts General Hospital in Boston, told this news organization in written comments. “Over the same period, patients with gout used more of other medications that could treat gout. They also had more emergency department visits for gout and rheumatologist visits for gout, which potentially signals poorer disease control.”

The study, published online in JAMA Internal Medicine, examined MarketScan data from a longitudinal cohort of patients who had employer-sponsored health insurance and a diagnosis of gout from 2007 to 2019. MarketScan is an IBM database of medical and drug data from employers and health plans. The study examined more than 2.7 million patient-year observations over the 13-year period.
 

How the price increase happened

After 2011, a large percentage of patients shifted to less effective but more affordable drugs to treat gout. Prescriptions for allopurinol increased 32% (P < .001) and oral corticosteroids 8.3% over the decade. “These are imperfect substitutes,” Dr. Song said. “Allopurinol is used to prevent gout, while oral corticosteroids can be used to treat a gout flare.”

At the same time, visits for gout-related complaints to emergency departments and rheumatology offices increased through the ensuing years: 39.8% and 10.5% on an adjusted analysis, respectively (P < .001 for both).

Colchicine is actually a drug that predates the creation of the U.S. Food and Drug Administration in 1938 and had been grandfathered under its Unapproved Drug Initiative. Then in 2009, the FDA determined that colchicine was effective for treating arthritis-related gout flares after the manufacturer, URL Pharma, presented results of a randomized, controlled trial of 185 patients with gout.

The next year, the FDA granted URL Pharma 3 years of market exclusivity for the drug under the brand name Colcrys, now trademarked by Takeda Pharmaceuticals.

The latest study noted that longer-term analysis of the impact of the FDA’s decision had been lacking. The goal, said Dr. Song, was “to better understand the long-run implications of large drug price increases in the U.S. by studying the case of colchicine.”

He added, “For drugs that lack competition, large price increases can have large economic and clinical consequences over many years.”
 

Absorbing the cost

Lead author Dan P. Ly, MD, PhD, MPP, assistant professor at the University of California, Los Angeles, added, “Our study has large implications [for] when generic medications or other medications experience large price increases. Use of the medication in question drops or patients have to pay more out of pocket, and patient health can suffer as a result.”

The dropoff in colchicine use in this patient population could have been worse, Dr. Song said. “Despite colchicine use decreasing by 27% over nearly a decade, the fact that it did not decline more suggests that for patients with gout, the large price increase was mostly absorbed by their insurers, employers, or themselves – e.g., passed through to higher premiums, lower wages, or higher cost-sharing.”

Harvard Medical School

Aaron Kesselheim, MD, JD, MPH, a professor at Harvard Medical School, Boston, reported previously on the price consequences of colchicine early on after the FDA granted the manufacturer market exclusivity.

“In our past research, we looked at how the massive increase in the price of colchicine increased spending on the drug and reduced use in a relatively short time period after the price hike,” said Dr. Kesselheim, who was not involved in this current study by Dr. Ly, Dr. Song, and Mia Giuriato, BBA, MA, from Harvard Medical School. “This study evaluated the experiences of patients with gout over multiple years and showed that the reductions in use persisted and were associated with increases in ED and rheumatology visits, suggesting worsening control of gout due to the relative inaccessibility of the drug at the new high price.”

The latest findings have public policy implications, Dr. Kesselheim said. “In the case of colchicine, the FDA made a bad pitch, leading to a home run for the manufacturer and a shutout for patients.”

“The FDA needs to make sure to take into account the quite predictable patient effects that can result from disruptions to competition when it considers taking steps like it did in the colchicine case to disrupt the market and create an artificial monopoly, even if the FDA acted in the best of intentions in this case,” Dr. Kesselheim added.

Dr. Song received funding for the study from the National Institutes of Health and Arnold Ventures. He also disclosed receiving personal fees from the Research Triangle Institute, Google Ventures, VBID Health, and the International Foundation of Employee Benefit Plans. Dr. Ly, Ms. Giuriato, and Dr. Kesselheim report no relevant financial relationships.

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

A large price increase for colchicine in 2010 led to a significant falloff in its use for gout that persisted for the next decade while emergency and rheumatology visits for gout rose, suggesting poorer disease control, a retrospective cohort study reported.
 

The price of colchicine, commonly prescribed for acute gout attacks, climbed from $11.25 per prescription in 2009 to $190.49 in 2011, with the average out-of-pocket cost more than quadrupling, from $7.37 to $29.42, the study noted. Colchicine prescriptions for gout declined 27% over the next decade, according to adjusted analyses that the study authors performed.

Massachusetts General Hospital

“A roughly 16-fold increase in colchicine prices appeared to have lowered colchicine use over the next decade,” senior author Zirui Song, MD, PhD, an associate professor of health care policy and medicine at Harvard Medical School and an internist at Massachusetts General Hospital in Boston, told this news organization in written comments. “Over the same period, patients with gout used more of other medications that could treat gout. They also had more emergency department visits for gout and rheumatologist visits for gout, which potentially signals poorer disease control.”

The study, published online in JAMA Internal Medicine, examined MarketScan data from a longitudinal cohort of patients who had employer-sponsored health insurance and a diagnosis of gout from 2007 to 2019. MarketScan is an IBM database of medical and drug data from employers and health plans. The study examined more than 2.7 million patient-year observations over the 13-year period.
 

How the price increase happened

After 2011, a large percentage of patients shifted to less effective but more affordable drugs to treat gout. Prescriptions for allopurinol increased 32% (P < .001) and oral corticosteroids 8.3% over the decade. “These are imperfect substitutes,” Dr. Song said. “Allopurinol is used to prevent gout, while oral corticosteroids can be used to treat a gout flare.”

At the same time, visits for gout-related complaints to emergency departments and rheumatology offices increased through the ensuing years: 39.8% and 10.5% on an adjusted analysis, respectively (P < .001 for both).

Colchicine is actually a drug that predates the creation of the U.S. Food and Drug Administration in 1938 and had been grandfathered under its Unapproved Drug Initiative. Then in 2009, the FDA determined that colchicine was effective for treating arthritis-related gout flares after the manufacturer, URL Pharma, presented results of a randomized, controlled trial of 185 patients with gout.

The next year, the FDA granted URL Pharma 3 years of market exclusivity for the drug under the brand name Colcrys, now trademarked by Takeda Pharmaceuticals.

The latest study noted that longer-term analysis of the impact of the FDA’s decision had been lacking. The goal, said Dr. Song, was “to better understand the long-run implications of large drug price increases in the U.S. by studying the case of colchicine.”

He added, “For drugs that lack competition, large price increases can have large economic and clinical consequences over many years.”
 

Absorbing the cost

Lead author Dan P. Ly, MD, PhD, MPP, assistant professor at the University of California, Los Angeles, added, “Our study has large implications [for] when generic medications or other medications experience large price increases. Use of the medication in question drops or patients have to pay more out of pocket, and patient health can suffer as a result.”

The dropoff in colchicine use in this patient population could have been worse, Dr. Song said. “Despite colchicine use decreasing by 27% over nearly a decade, the fact that it did not decline more suggests that for patients with gout, the large price increase was mostly absorbed by their insurers, employers, or themselves – e.g., passed through to higher premiums, lower wages, or higher cost-sharing.”

Harvard Medical School

Aaron Kesselheim, MD, JD, MPH, a professor at Harvard Medical School, Boston, reported previously on the price consequences of colchicine early on after the FDA granted the manufacturer market exclusivity.

“In our past research, we looked at how the massive increase in the price of colchicine increased spending on the drug and reduced use in a relatively short time period after the price hike,” said Dr. Kesselheim, who was not involved in this current study by Dr. Ly, Dr. Song, and Mia Giuriato, BBA, MA, from Harvard Medical School. “This study evaluated the experiences of patients with gout over multiple years and showed that the reductions in use persisted and were associated with increases in ED and rheumatology visits, suggesting worsening control of gout due to the relative inaccessibility of the drug at the new high price.”

The latest findings have public policy implications, Dr. Kesselheim said. “In the case of colchicine, the FDA made a bad pitch, leading to a home run for the manufacturer and a shutout for patients.”

“The FDA needs to make sure to take into account the quite predictable patient effects that can result from disruptions to competition when it considers taking steps like it did in the colchicine case to disrupt the market and create an artificial monopoly, even if the FDA acted in the best of intentions in this case,” Dr. Kesselheim added.

Dr. Song received funding for the study from the National Institutes of Health and Arnold Ventures. He also disclosed receiving personal fees from the Research Triangle Institute, Google Ventures, VBID Health, and the International Foundation of Employee Benefit Plans. Dr. Ly, Ms. Giuriato, and Dr. Kesselheim report no relevant financial relationships.

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

Sleep apnea is a heterogeneous group of conditions that may be attributable to a wide array of underlying conditions, with varying contributions of obstructive or central sleep-disordered breathing. The spectrum from obstructive sleep apnea (OSA) to central sleep apnea (CSA) includes mixed sleep apnea, treatment-emergent CSA (TECSA), and Cheyne-Stokes respiration (CSR).¹ The pathophysiologic causes of CSA can be attributed to delayed cardiopulmonary circulation in heart failure, decreased brainstem ventilatory response due to stroke, blunting of central chemoreceptors in chronic opioid use, and/or stimulation of the Hering-Breuer reflex from activation of pulmonary stretch receptors after initiating positive airway pressure (PAP) for treatment of OSA.^2,3 Medications are commonly implicated in many forms of sleep-disordered breathing; importantly, opioids and benzodiazepines may blunt the respiratory drive, leading to CSA, and/or impair upper airway patency, resulting in or worsening OSA.

Continuous positive airway pressure (CPAP) therapy is largely ineffective in correcting CSA or improving outcomes and is often poorly tolerated in these patients.⁴ Adaptive servo-ventilation (ASV) is a form of bilevel PAP (BPAP) therapy that delivers variable adjusting pressure support, primarily to treat CSA. PAP also may relieve upper airway obstructions, thereby effectively treating any comorbid obstructive component. ASV has been well documented to improve sleep-related disorders and improve apnea-hypopnea index (AHI) in patients with CSA. However, longitudinal data have demonstrated increased mortality in patients with heart failure with reduced ejection fraction (HFrEF) who were treated with ASV.⁵ Since the SERVE-HF trial results came to light in 2015, there has been no consensus regarding the optimal use, if any, of ASV therapy.^6-8 This is partly related to the inability to fully explain the study’s major findings, which were unexpected at the time, and partly due to the absence of similar relevant mortality data in patients with CSA but without HFrEF.

TECSA may present in some patients with OSA who are new to PAP therapy. These events are frequently seen during PAP titration sleep studies, though patients can also experience significant TECSA shortly after initiating home PAP therapy. TECSA is felt to result from a combination of stimulating pulmonary stretch receptors and lowering arterial carbon dioxide below the apneic threshold. Chemoreceptors located in the medulla respond by attenuating the respiratory drive.⁹ Previous studies have shown most cases of mild TECSA resolve over time with CPAP treatment. However, in patients with persistent or worsening TECSA, ASV may be considered as an alternative to CPAP.

The prevalence of OSA in the veteran population is estimated to be as high as 60%, considerably higher than the general population estimation.¹⁰ Patients with more significant comorbidities may also experience a higher frequency of central events. Patients with CSA have also been shown to have a higher risk for cardiac-related hospital admissions, providing plausible justification for correcting CSA.¹⁰

In the current study, we aim to characterize the group of patients using ASV therapy in the modern era. We will assess the objective efficacy and adherence of ASV therapy in patients with primarily CSA compared with those having primarily OSA (ie, TECSA). Secondarily, we aim to identify baseline clinical and polysomnographic features that may be predictive of ASV adherence, as a surrogate for subjective benefit.¹¹ In the wake of the SERVE-HF study, the sleep medicine community has paused prescribing ASV therapy for CSA. We hope to provide more perspective on the treatment of veterans with CSA and identify the patient groups that would benefit most from ASV therapy.

Methods

This retrospective chart review examined patients prescribed ASV therapy at the Hampton Veterans Affairs Medical Center (HVAMC) in Virginia who had therapy data between January 1, 2015, and April 30, 2020. The start date was chosen to approximate the phase-in of wireless PAP devices at HVAMC and to correspond with the release of preliminary results from the SERVE-HF trial.

Patients were initially identified through a query into commercial wireless PAP management databases and cross-referenced with HVAMC patients. Adherence and efficacy data were obtained from the most recent clinical PAP data, which allowed for the evaluation of patients who discontinued therapy for reasons other than intolerance. Clinical, demographic, and polysomnography (PSG) data were obtained from the electronic health record. One patient, identified through the database query but not found in the electronic health record, was excluded. In cases of missing PSG data, especially AHI or similar values, all attempts were made to calculate the data with other provided values. This study was determined to be exempt by the HVAMC Institutional Review Board (protocol #20-01).

Statistics

Statistical analyses were designed to compare clinical characteristics and adherence to therapy of those with primarily CSA on PSG and those with primarily OSA. Because it was not currently known how many patients would fit into each of these categories, we also planned secondary comparisons of the clinical and PSG characteristics of those patients who were adherent with therapy and those who were not. Adherence with ASV therapy was defined as device use for ≥ 4 hours for ≥ 70% of nights.

Comparisons between the means of 2 normally distributed groups were performed with an unpaired t test. Comparisons between 2 nonnormally distributed groups and groups of dates were done with the Mann-Whitney U test. The normality of a group distribution was determined using D’Agostino-Pearson omnibus normality test. Two groups of dichotomous variables were compared with the Fisher exact test. P value < .05 was considered statistically significant.

Results

Thirty-one patients were prescribed ASV therapy and had follow-up at HVAMC since 2015. All patients were male. The mean (SD) age was 67.2 (11.4) years, mean body mass index (BMI) was 34.0 (5.9), and the mean (SD) Epworth Sleepiness Scale (ESS) score was 10.9 (5.8). Patient comorbidities included 30 (97%) with hypertension, 17 (55%) with diabetes mellitus, 16 (52%) with coronary artery disease, and 11 (35%) with congestive heart failure. Three patients had no echocardiogram or other documentation of left ventricular ejection fraction (LVEF). One of these patients had voluntarily stopped using PAP therapy, another had been erroneously started on ASV (ordered for fixed BPAP), and the third had since been retitrated to CPAP. In the 28 patients with documented LVEF, the mean (SD) LVEF was 61.8% (6.9). Ten patients (32%) had opioids documented on their medication lists and 6 (19%) had benzodiazepines.

The median date of diagnostic sleep testing was January 9, 2015, and testing was completed after the release of the initial field safety notice regarding the SERVE-HF trial preliminary findings May 13, 2015, for 14 patients (45%).¹² On diagnostic sleep testing, the mean (SD) AHI was 47.3 (25.6) events/h and the median (IQR) oxygen saturation (SpO₂) nadir was 82% (78-84). Three patients (10%) were initially diagnosed with CSA, 19 (61%) with OSA, and 9 (29%) with both. Sixteen patients (52%) had ASV with fixed expiratory PAP (EPAP), and 15 (48%) had variable adjusting EPAP. Mean (SD) usage of ASV was 6.5 (2.6) hours and 66.0% (34.2) of nights for ≥ 4 hours. Mean (SD) titrated EPAP (set or 90th/95th percentile autotitrated) was 10.1 (3.4) cm H₂O and inspiratory PAP (IPAP) (90th/95th percentile) was 17.1 (3.3) cm H₂O. The median (IQR) residual AHI on ASV was 2.7 events/h (1.1-5.1), apnea index (AI) was 0.4 (0.1-1.0), and hypopnea index (HI) was 1.4 (1.0-3.2); the residual central and obstructive events were not available in most cases.

Adherence

There were no significant differences between the proportions of patients on ASV with set EPAP or the titrated EPAP and IPAP. The median (IQR) residual AHI was lower in the adherent group compared with the nonadherent group, both in absolute values (1.7 [0.9-3.2] events/h vs 4.7 [2.4-10.3] events/h, respectively [P = .004]), and as a percentage of the pretreatment AHI (3.1% [2.5-6.0] vs 10.2% [5.3-34.4], respectively; P = .002) (Figure 2).

Primarily Obstructive Sleep Apnea

Sleep apnea was a mixed picture of obstructive and central events in many patients. Only 3 patients had “pure” CSA. Thus, we were unable to define discrete comparison groups based on the sleep-disordered breathing phenotype. We identified 19 patients with primarily OSA (ie, initially diagnosed with OSA, OSA with TECSA, or complex sleep apnea). The mean (SD) age was 66.1 (12.8) years, BMI was 36.2 (4.7), and ESS was 11.4 (5.6). The mean (SD) baseline AHI was 46.9 (29.5), obstructive AHI was 40.5 (30.4), and central AHI was 0.4 (1.2); the median (IQR) SpO₂ nadir was 81% (78%-84%). The mean (SD) titrated EPAP was 10.2 (3.5) cm H₂O, and the 90th/95th percentile IPAP was 17.9 (3.5) cm H₂O. The mean (SD) usage of ASV was 7.9 (5.3) hours with 11 patients (58%) meeting the minimum standard for adherence to ASV therapy.

No significant differences were seen between the adherent and nonadherent groups in clinical or demographic characteristics or date of diagnostic sleep testing (eAppendix, available online at doi:10.12788/fp.0374). In baseline sleep studies the mean (SD) HI was 32.3 (15.8) in the adherent group compared with 14.7 (8.8) in the nonadherent group (P = .049). In contrast, obstructive AHI was not significantly lower in the adherent group: 51.9 (30.9) in the adherent group compared with 22.2 (20.6) in the nonadherent group (P = .09). The median (IQR) residual AHI on ASV as a percentage of the pretreatment AHI was 3.0% (2.4%-6.5%) in the adherent group compared with 11.3% (5.4%-89.1%) in the nonadherent group, a statistically significant difference (P = .01). No other significant differences were seen between the groups.

Discussion

This study describes a real-world cohort of patients using ASV therapy and the characteristics associated with benefit from therapy. The patients that were prescribed and started ASV therapy most often had a significant degree of obstructive component to sleep-disordered breathing, whether primary OSA with TECSA or comorbid OSA and CSA. Moreover, we found that a higher obstructive AHI on the baseline PSG was associated with adherence to ASV therapy. Another important finding was that a lower residual AHI on ASV as a proportion of the baseline was associated with PAP adherence. Adherent patients had similar clinical characteristics as the nonadherent patients, including comorbidities, severity of sleep-disordered breathing, and obesity.

Though the results of the SERVE-HF trial have dampened the enthusiasm somewhat, ASV therapy has long been considered an effective and well-tolerated treatment for many types of CSA.¹³ In fact, treatments that can eliminate the central AHI are fairly limited.^4,14 Our data suggest that ASV is also effective and tolerated in OSA with TECSA and/or comorbid CSA. Recent studies suggest that CSA resolves spontaneously in a majority of TECSA patients within 2 to 3 months of regular CPAP use.¹⁵ Other estimates suggest that persistent TESCA may be present in 2% of patients with OSA on treatment.¹⁶

Given the high and rising prevalence of OSA, many people are at risk for clinically significant TESCA. Another retrospective case series found that 72% of patients that failed treatment with CPAP or BPAP during PSG, met diagnostic criteria (at the time) for CSA; ASV was objectively beneficial in these patients.¹⁷ ASV can be an especially useful modality to treat OSA in patients with CSA that either prevents tolerance of standard therapies or causes clinical consequences, presuming the patient does not also have HFrEF.¹⁸ The long-term outcomes of treatment with ASV therapy remain a matter of debate.

The SERVE-HF trial remains among the only studies that have assessed the mortality effects of CSA treatments, with unfavorable findings. Treatment of OSA has been associated with favorable chronic health benefits, though recent studies have questioned the degree of benefit attributable to OSA treatment.^19-24 Similar studies have not been done for comorbidities represented by our study cohort (ie, OSA with TECSA and/or comorbid CSA).

The lack of CSA diagnosis alone in our cohort may be partially attributable to changing practice patterns following the SERVE-HF trial, though it is not clear from these data why a higher baseline obstructive AHI was associated with adherence to ASV therapy. Our data in this regard are somewhat at odds with the preliminary results of the ADVENT-HF trial. In that study, adherence to ASV therapy in patients with predominantly OSA declined significantly more than in patients with predominantly CSA.²⁵ Most of our patients were diagnosed with predominantly OSA, so a direct comparison with the CSA group is problematic; additionally, the primary brand and the pressure adjustments algorithm used in our study differed from the ADVENT-HF trial.

OSA and CSA may present with similar clinical symptoms, including sleep fragmentation, insomnia, and excessive daytime sleepiness; however, the degree of symptomatology, especially daytime sleepiness, and the response to treatment, may be less in CSA.^2,26 Both the subjective report of symptoms (ESS) and PSG measures of sleep fragmentation were similar in our patients, again likely explained by the predominance of obstructive events.

The pathophysiology of CSA is more varied than OSA, which is probably relevant in this case. ASV was originally designed for the management of CSA with CSR, accomplishing this goal by stabilizing the periods of central apnea and hyperpnea characteristic of CSR.²⁷ Although other forms of CSA demonstrate breathing patterns distinct from CSR, ASV has become an accepted treatment for most of these. It is plausible that the long-term subjective benefit and tolerance of ASV in CSA without CSR is less than for CSA with CSR or OSA. None of the patients in our study had CSA with CSR.

Ultimately, it may be the objective treatment effect that lends to adherence, as has been shown previously in OSA patients; our group of adherent patients showed a greater improvement in AHI, relative to baseline, than the nonadherent patients did.²⁸ The technology behind ASV therapy can greatly reduce the frequencies of central apneas, yet this same treatment effectively splints the upper airway and even more effectively eliminates obstructive apneas and hypopneas. Variable adjusting EPAP devices would plausibly provide even more benefit in these patients, as has been shown in prior studies.²⁹ To the contrary, our small sample of patients with TESCA showed a nonsignificant trend toward adherence with fixed EPAP ASV.

Opioid use was substantial in our population, without significant differences between the groups. CPAP therapy is ineffective in improving opioid-associated CSA. In a recent study, 20 patients on opioid therapy with CSA were treated with CPAP therapy; after several weeks, the average therapeutic use was 4 to 5 hours per night and CPAP was abandoned in favor of ASV therapy due to persistent central apnea. ASV treatment was associated with a considerable reduction in central apnea index, AHI, arousal index, and oxygen desaturations in a remarkable improvement over CPAP.³⁰

Limitations and Future Directions

This retrospective, single-center study may have limited applicability to other populations. Adherence was used as a surrogate for subjective benefit from treatment, though benefit was not confirmed by the patients directly. Only patients seen in follow-up for documentation of the ASV download were identified for inclusion and data analysis. As a single center, we risk homogeneity in the treatment algorithms, though sleep medicine treatments are often decided at the time of the sleep studies. Studies and treatment recommendations were made at a variety of sites, including our sleep center, other US Department of Veterans Affairs hospitals, in the community network, and at US Department of Defense centers. Our population was homogenous in some ways; notably, 100% of our group was male, which is substantially higher than both the veteran population and the general population. Risk factors for OSA and CSA are more common in male patients, which may partially explain this anomaly. Lastly, with our small sample size, there is increased risk that the results seen occurred by chance.

There are several areas for further study. A larger multicenter study may permit these results to be generalized to the population and should include subjective measures of benefit. Patients with primarily CSA were largely absent in our group and may be the focus of future studies; data on predictors of treatment adherence in CSA are lacking. With the availability of consistent older adherence data, comparisons may be made between the efficacies of clinical practice habits, including treatment efficacy, before and after the results of the SERVE-HF trial became known.

Conclusions

In selected patients with preserved LVEF, ASV therapy appears especially effective in patients with OSA combined with CSA. Adherence to ASV treatment was associated with higher obstructive AHI during the baseline PSG and with a greater reduction in the AHI. This understanding may help guide sleep specialists in personalizing treatments for sleep-disordered breathing. Because objective efficacy appears to be important for therapy adherence, clinicians should be able to consistently determine the obstructive and central components of the residual AHI, thus taking all information into account when optimizing the treatment. Additionally, both OSA and CSA pressure requirements should be considered when developing ASV devices.

Acknowledgments

We thank Martha Harper, RRT, of Hampton Veterans Affairs Medical Center (HVAMC) for helping to identify our patients and assisting with data collection. This material is the result of work supported with resources and the use of HVAMC facilities.

Sleep apnea is a heterogeneous group of conditions that may be attributable to a wide array of underlying conditions, with varying contributions of obstructive or central sleep-disordered breathing. The spectrum from obstructive sleep apnea (OSA) to central sleep apnea (CSA) includes mixed sleep apnea, treatment-emergent CSA (TECSA), and Cheyne-Stokes respiration (CSR).¹ The pathophysiologic causes of CSA can be attributed to delayed cardiopulmonary circulation in heart failure, decreased brainstem ventilatory response due to stroke, blunting of central chemoreceptors in chronic opioid use, and/or stimulation of the Hering-Breuer reflex from activation of pulmonary stretch receptors after initiating positive airway pressure (PAP) for treatment of OSA.^2,3 Medications are commonly implicated in many forms of sleep-disordered breathing; importantly, opioids and benzodiazepines may blunt the respiratory drive, leading to CSA, and/or impair upper airway patency, resulting in or worsening OSA.

Continuous positive airway pressure (CPAP) therapy is largely ineffective in correcting CSA or improving outcomes and is often poorly tolerated in these patients.⁴ Adaptive servo-ventilation (ASV) is a form of bilevel PAP (BPAP) therapy that delivers variable adjusting pressure support, primarily to treat CSA. PAP also may relieve upper airway obstructions, thereby effectively treating any comorbid obstructive component. ASV has been well documented to improve sleep-related disorders and improve apnea-hypopnea index (AHI) in patients with CSA. However, longitudinal data have demonstrated increased mortality in patients with heart failure with reduced ejection fraction (HFrEF) who were treated with ASV.⁵ Since the SERVE-HF trial results came to light in 2015, there has been no consensus regarding the optimal use, if any, of ASV therapy.^6-8 This is partly related to the inability to fully explain the study’s major findings, which were unexpected at the time, and partly due to the absence of similar relevant mortality data in patients with CSA but without HFrEF.

TECSA may present in some patients with OSA who are new to PAP therapy. These events are frequently seen during PAP titration sleep studies, though patients can also experience significant TECSA shortly after initiating home PAP therapy. TECSA is felt to result from a combination of stimulating pulmonary stretch receptors and lowering arterial carbon dioxide below the apneic threshold. Chemoreceptors located in the medulla respond by attenuating the respiratory drive.⁹ Previous studies have shown most cases of mild TECSA resolve over time with CPAP treatment. However, in patients with persistent or worsening TECSA, ASV may be considered as an alternative to CPAP.

The prevalence of OSA in the veteran population is estimated to be as high as 60%, considerably higher than the general population estimation.¹⁰ Patients with more significant comorbidities may also experience a higher frequency of central events. Patients with CSA have also been shown to have a higher risk for cardiac-related hospital admissions, providing plausible justification for correcting CSA.¹⁰

In the current study, we aim to characterize the group of patients using ASV therapy in the modern era. We will assess the objective efficacy and adherence of ASV therapy in patients with primarily CSA compared with those having primarily OSA (ie, TECSA). Secondarily, we aim to identify baseline clinical and polysomnographic features that may be predictive of ASV adherence, as a surrogate for subjective benefit.¹¹ In the wake of the SERVE-HF study, the sleep medicine community has paused prescribing ASV therapy for CSA. We hope to provide more perspective on the treatment of veterans with CSA and identify the patient groups that would benefit most from ASV therapy.

Methods

This retrospective chart review examined patients prescribed ASV therapy at the Hampton Veterans Affairs Medical Center (HVAMC) in Virginia who had therapy data between January 1, 2015, and April 30, 2020. The start date was chosen to approximate the phase-in of wireless PAP devices at HVAMC and to correspond with the release of preliminary results from the SERVE-HF trial.

Patients were initially identified through a query into commercial wireless PAP management databases and cross-referenced with HVAMC patients. Adherence and efficacy data were obtained from the most recent clinical PAP data, which allowed for the evaluation of patients who discontinued therapy for reasons other than intolerance. Clinical, demographic, and polysomnography (PSG) data were obtained from the electronic health record. One patient, identified through the database query but not found in the electronic health record, was excluded. In cases of missing PSG data, especially AHI or similar values, all attempts were made to calculate the data with other provided values. This study was determined to be exempt by the HVAMC Institutional Review Board (protocol #20-01).

Statistics

Statistical analyses were designed to compare clinical characteristics and adherence to therapy of those with primarily CSA on PSG and those with primarily OSA. Because it was not currently known how many patients would fit into each of these categories, we also planned secondary comparisons of the clinical and PSG characteristics of those patients who were adherent with therapy and those who were not. Adherence with ASV therapy was defined as device use for ≥ 4 hours for ≥ 70% of nights.

Comparisons between the means of 2 normally distributed groups were performed with an unpaired t test. Comparisons between 2 nonnormally distributed groups and groups of dates were done with the Mann-Whitney U test. The normality of a group distribution was determined using D’Agostino-Pearson omnibus normality test. Two groups of dichotomous variables were compared with the Fisher exact test. P value < .05 was considered statistically significant.

Results

Thirty-one patients were prescribed ASV therapy and had follow-up at HVAMC since 2015. All patients were male. The mean (SD) age was 67.2 (11.4) years, mean body mass index (BMI) was 34.0 (5.9), and the mean (SD) Epworth Sleepiness Scale (ESS) score was 10.9 (5.8). Patient comorbidities included 30 (97%) with hypertension, 17 (55%) with diabetes mellitus, 16 (52%) with coronary artery disease, and 11 (35%) with congestive heart failure. Three patients had no echocardiogram or other documentation of left ventricular ejection fraction (LVEF). One of these patients had voluntarily stopped using PAP therapy, another had been erroneously started on ASV (ordered for fixed BPAP), and the third had since been retitrated to CPAP. In the 28 patients with documented LVEF, the mean (SD) LVEF was 61.8% (6.9). Ten patients (32%) had opioids documented on their medication lists and 6 (19%) had benzodiazepines.

The median date of diagnostic sleep testing was January 9, 2015, and testing was completed after the release of the initial field safety notice regarding the SERVE-HF trial preliminary findings May 13, 2015, for 14 patients (45%).¹² On diagnostic sleep testing, the mean (SD) AHI was 47.3 (25.6) events/h and the median (IQR) oxygen saturation (SpO₂) nadir was 82% (78-84). Three patients (10%) were initially diagnosed with CSA, 19 (61%) with OSA, and 9 (29%) with both. Sixteen patients (52%) had ASV with fixed expiratory PAP (EPAP), and 15 (48%) had variable adjusting EPAP. Mean (SD) usage of ASV was 6.5 (2.6) hours and 66.0% (34.2) of nights for ≥ 4 hours. Mean (SD) titrated EPAP (set or 90th/95th percentile autotitrated) was 10.1 (3.4) cm H₂O and inspiratory PAP (IPAP) (90th/95th percentile) was 17.1 (3.3) cm H₂O. The median (IQR) residual AHI on ASV was 2.7 events/h (1.1-5.1), apnea index (AI) was 0.4 (0.1-1.0), and hypopnea index (HI) was 1.4 (1.0-3.2); the residual central and obstructive events were not available in most cases.

Adherence

There were no significant differences between the proportions of patients on ASV with set EPAP or the titrated EPAP and IPAP. The median (IQR) residual AHI was lower in the adherent group compared with the nonadherent group, both in absolute values (1.7 [0.9-3.2] events/h vs 4.7 [2.4-10.3] events/h, respectively [P = .004]), and as a percentage of the pretreatment AHI (3.1% [2.5-6.0] vs 10.2% [5.3-34.4], respectively; P = .002) (Figure 2).

Primarily Obstructive Sleep Apnea

Sleep apnea was a mixed picture of obstructive and central events in many patients. Only 3 patients had “pure” CSA. Thus, we were unable to define discrete comparison groups based on the sleep-disordered breathing phenotype. We identified 19 patients with primarily OSA (ie, initially diagnosed with OSA, OSA with TECSA, or complex sleep apnea). The mean (SD) age was 66.1 (12.8) years, BMI was 36.2 (4.7), and ESS was 11.4 (5.6). The mean (SD) baseline AHI was 46.9 (29.5), obstructive AHI was 40.5 (30.4), and central AHI was 0.4 (1.2); the median (IQR) SpO₂ nadir was 81% (78%-84%). The mean (SD) titrated EPAP was 10.2 (3.5) cm H₂O, and the 90th/95th percentile IPAP was 17.9 (3.5) cm H₂O. The mean (SD) usage of ASV was 7.9 (5.3) hours with 11 patients (58%) meeting the minimum standard for adherence to ASV therapy.

No significant differences were seen between the adherent and nonadherent groups in clinical or demographic characteristics or date of diagnostic sleep testing (eAppendix, available online at doi:10.12788/fp.0374). In baseline sleep studies the mean (SD) HI was 32.3 (15.8) in the adherent group compared with 14.7 (8.8) in the nonadherent group (P = .049). In contrast, obstructive AHI was not significantly lower in the adherent group: 51.9 (30.9) in the adherent group compared with 22.2 (20.6) in the nonadherent group (P = .09). The median (IQR) residual AHI on ASV as a percentage of the pretreatment AHI was 3.0% (2.4%-6.5%) in the adherent group compared with 11.3% (5.4%-89.1%) in the nonadherent group, a statistically significant difference (P = .01). No other significant differences were seen between the groups.

Discussion

This study describes a real-world cohort of patients using ASV therapy and the characteristics associated with benefit from therapy. The patients that were prescribed and started ASV therapy most often had a significant degree of obstructive component to sleep-disordered breathing, whether primary OSA with TECSA or comorbid OSA and CSA. Moreover, we found that a higher obstructive AHI on the baseline PSG was associated with adherence to ASV therapy. Another important finding was that a lower residual AHI on ASV as a proportion of the baseline was associated with PAP adherence. Adherent patients had similar clinical characteristics as the nonadherent patients, including comorbidities, severity of sleep-disordered breathing, and obesity.

Though the results of the SERVE-HF trial have dampened the enthusiasm somewhat, ASV therapy has long been considered an effective and well-tolerated treatment for many types of CSA.¹³ In fact, treatments that can eliminate the central AHI are fairly limited.^4,14 Our data suggest that ASV is also effective and tolerated in OSA with TECSA and/or comorbid CSA. Recent studies suggest that CSA resolves spontaneously in a majority of TECSA patients within 2 to 3 months of regular CPAP use.¹⁵ Other estimates suggest that persistent TESCA may be present in 2% of patients with OSA on treatment.¹⁶

Given the high and rising prevalence of OSA, many people are at risk for clinically significant TESCA. Another retrospective case series found that 72% of patients that failed treatment with CPAP or BPAP during PSG, met diagnostic criteria (at the time) for CSA; ASV was objectively beneficial in these patients.¹⁷ ASV can be an especially useful modality to treat OSA in patients with CSA that either prevents tolerance of standard therapies or causes clinical consequences, presuming the patient does not also have HFrEF.¹⁸ The long-term outcomes of treatment with ASV therapy remain a matter of debate.

The SERVE-HF trial remains among the only studies that have assessed the mortality effects of CSA treatments, with unfavorable findings. Treatment of OSA has been associated with favorable chronic health benefits, though recent studies have questioned the degree of benefit attributable to OSA treatment.^19-24 Similar studies have not been done for comorbidities represented by our study cohort (ie, OSA with TECSA and/or comorbid CSA).

The lack of CSA diagnosis alone in our cohort may be partially attributable to changing practice patterns following the SERVE-HF trial, though it is not clear from these data why a higher baseline obstructive AHI was associated with adherence to ASV therapy. Our data in this regard are somewhat at odds with the preliminary results of the ADVENT-HF trial. In that study, adherence to ASV therapy in patients with predominantly OSA declined significantly more than in patients with predominantly CSA.²⁵ Most of our patients were diagnosed with predominantly OSA, so a direct comparison with the CSA group is problematic; additionally, the primary brand and the pressure adjustments algorithm used in our study differed from the ADVENT-HF trial.

OSA and CSA may present with similar clinical symptoms, including sleep fragmentation, insomnia, and excessive daytime sleepiness; however, the degree of symptomatology, especially daytime sleepiness, and the response to treatment, may be less in CSA.^2,26 Both the subjective report of symptoms (ESS) and PSG measures of sleep fragmentation were similar in our patients, again likely explained by the predominance of obstructive events.

The pathophysiology of CSA is more varied than OSA, which is probably relevant in this case. ASV was originally designed for the management of CSA with CSR, accomplishing this goal by stabilizing the periods of central apnea and hyperpnea characteristic of CSR.²⁷ Although other forms of CSA demonstrate breathing patterns distinct from CSR, ASV has become an accepted treatment for most of these. It is plausible that the long-term subjective benefit and tolerance of ASV in CSA without CSR is less than for CSA with CSR or OSA. None of the patients in our study had CSA with CSR.

Ultimately, it may be the objective treatment effect that lends to adherence, as has been shown previously in OSA patients; our group of adherent patients showed a greater improvement in AHI, relative to baseline, than the nonadherent patients did.²⁸ The technology behind ASV therapy can greatly reduce the frequencies of central apneas, yet this same treatment effectively splints the upper airway and even more effectively eliminates obstructive apneas and hypopneas. Variable adjusting EPAP devices would plausibly provide even more benefit in these patients, as has been shown in prior studies.²⁹ To the contrary, our small sample of patients with TESCA showed a nonsignificant trend toward adherence with fixed EPAP ASV.

Opioid use was substantial in our population, without significant differences between the groups. CPAP therapy is ineffective in improving opioid-associated CSA. In a recent study, 20 patients on opioid therapy with CSA were treated with CPAP therapy; after several weeks, the average therapeutic use was 4 to 5 hours per night and CPAP was abandoned in favor of ASV therapy due to persistent central apnea. ASV treatment was associated with a considerable reduction in central apnea index, AHI, arousal index, and oxygen desaturations in a remarkable improvement over CPAP.³⁰

Limitations and Future Directions

This retrospective, single-center study may have limited applicability to other populations. Adherence was used as a surrogate for subjective benefit from treatment, though benefit was not confirmed by the patients directly. Only patients seen in follow-up for documentation of the ASV download were identified for inclusion and data analysis. As a single center, we risk homogeneity in the treatment algorithms, though sleep medicine treatments are often decided at the time of the sleep studies. Studies and treatment recommendations were made at a variety of sites, including our sleep center, other US Department of Veterans Affairs hospitals, in the community network, and at US Department of Defense centers. Our population was homogenous in some ways; notably, 100% of our group was male, which is substantially higher than both the veteran population and the general population. Risk factors for OSA and CSA are more common in male patients, which may partially explain this anomaly. Lastly, with our small sample size, there is increased risk that the results seen occurred by chance.

There are several areas for further study. A larger multicenter study may permit these results to be generalized to the population and should include subjective measures of benefit. Patients with primarily CSA were largely absent in our group and may be the focus of future studies; data on predictors of treatment adherence in CSA are lacking. With the availability of consistent older adherence data, comparisons may be made between the efficacies of clinical practice habits, including treatment efficacy, before and after the results of the SERVE-HF trial became known.

Conclusions

In selected patients with preserved LVEF, ASV therapy appears especially effective in patients with OSA combined with CSA. Adherence to ASV treatment was associated with higher obstructive AHI during the baseline PSG and with a greater reduction in the AHI. This understanding may help guide sleep specialists in personalizing treatments for sleep-disordered breathing. Because objective efficacy appears to be important for therapy adherence, clinicians should be able to consistently determine the obstructive and central components of the residual AHI, thus taking all information into account when optimizing the treatment. Additionally, both OSA and CSA pressure requirements should be considered when developing ASV devices.

Acknowledgments

We thank Martha Harper, RRT, of Hampton Veterans Affairs Medical Center (HVAMC) for helping to identify our patients and assisting with data collection. This material is the result of work supported with resources and the use of HVAMC facilities.

Sleep apnea is a heterogeneous group of conditions that may be attributable to a wide array of underlying conditions, with varying contributions of obstructive or central sleep-disordered breathing. The spectrum from obstructive sleep apnea (OSA) to central sleep apnea (CSA) includes mixed sleep apnea, treatment-emergent CSA (TECSA), and Cheyne-Stokes respiration (CSR).¹ The pathophysiologic causes of CSA can be attributed to delayed cardiopulmonary circulation in heart failure, decreased brainstem ventilatory response due to stroke, blunting of central chemoreceptors in chronic opioid use, and/or stimulation of the Hering-Breuer reflex from activation of pulmonary stretch receptors after initiating positive airway pressure (PAP) for treatment of OSA.^2,3 Medications are commonly implicated in many forms of sleep-disordered breathing; importantly, opioids and benzodiazepines may blunt the respiratory drive, leading to CSA, and/or impair upper airway patency, resulting in or worsening OSA.

Continuous positive airway pressure (CPAP) therapy is largely ineffective in correcting CSA or improving outcomes and is often poorly tolerated in these patients.⁴ Adaptive servo-ventilation (ASV) is a form of bilevel PAP (BPAP) therapy that delivers variable adjusting pressure support, primarily to treat CSA. PAP also may relieve upper airway obstructions, thereby effectively treating any comorbid obstructive component. ASV has been well documented to improve sleep-related disorders and improve apnea-hypopnea index (AHI) in patients with CSA. However, longitudinal data have demonstrated increased mortality in patients with heart failure with reduced ejection fraction (HFrEF) who were treated with ASV.⁵ Since the SERVE-HF trial results came to light in 2015, there has been no consensus regarding the optimal use, if any, of ASV therapy.^6-8 This is partly related to the inability to fully explain the study’s major findings, which were unexpected at the time, and partly due to the absence of similar relevant mortality data in patients with CSA but without HFrEF.

TECSA may present in some patients with OSA who are new to PAP therapy. These events are frequently seen during PAP titration sleep studies, though patients can also experience significant TECSA shortly after initiating home PAP therapy. TECSA is felt to result from a combination of stimulating pulmonary stretch receptors and lowering arterial carbon dioxide below the apneic threshold. Chemoreceptors located in the medulla respond by attenuating the respiratory drive.⁹ Previous studies have shown most cases of mild TECSA resolve over time with CPAP treatment. However, in patients with persistent or worsening TECSA, ASV may be considered as an alternative to CPAP.

The prevalence of OSA in the veteran population is estimated to be as high as 60%, considerably higher than the general population estimation.¹⁰ Patients with more significant comorbidities may also experience a higher frequency of central events. Patients with CSA have also been shown to have a higher risk for cardiac-related hospital admissions, providing plausible justification for correcting CSA.¹⁰

In the current study, we aim to characterize the group of patients using ASV therapy in the modern era. We will assess the objective efficacy and adherence of ASV therapy in patients with primarily CSA compared with those having primarily OSA (ie, TECSA). Secondarily, we aim to identify baseline clinical and polysomnographic features that may be predictive of ASV adherence, as a surrogate for subjective benefit.¹¹ In the wake of the SERVE-HF study, the sleep medicine community has paused prescribing ASV therapy for CSA. We hope to provide more perspective on the treatment of veterans with CSA and identify the patient groups that would benefit most from ASV therapy.

Methods

This retrospective chart review examined patients prescribed ASV therapy at the Hampton Veterans Affairs Medical Center (HVAMC) in Virginia who had therapy data between January 1, 2015, and April 30, 2020. The start date was chosen to approximate the phase-in of wireless PAP devices at HVAMC and to correspond with the release of preliminary results from the SERVE-HF trial.

Patients were initially identified through a query into commercial wireless PAP management databases and cross-referenced with HVAMC patients. Adherence and efficacy data were obtained from the most recent clinical PAP data, which allowed for the evaluation of patients who discontinued therapy for reasons other than intolerance. Clinical, demographic, and polysomnography (PSG) data were obtained from the electronic health record. One patient, identified through the database query but not found in the electronic health record, was excluded. In cases of missing PSG data, especially AHI or similar values, all attempts were made to calculate the data with other provided values. This study was determined to be exempt by the HVAMC Institutional Review Board (protocol #20-01).

Statistics

Statistical analyses were designed to compare clinical characteristics and adherence to therapy of those with primarily CSA on PSG and those with primarily OSA. Because it was not currently known how many patients would fit into each of these categories, we also planned secondary comparisons of the clinical and PSG characteristics of those patients who were adherent with therapy and those who were not. Adherence with ASV therapy was defined as device use for ≥ 4 hours for ≥ 70% of nights.

Comparisons between the means of 2 normally distributed groups were performed with an unpaired t test. Comparisons between 2 nonnormally distributed groups and groups of dates were done with the Mann-Whitney U test. The normality of a group distribution was determined using D’Agostino-Pearson omnibus normality test. Two groups of dichotomous variables were compared with the Fisher exact test. P value < .05 was considered statistically significant.

Results

Thirty-one patients were prescribed ASV therapy and had follow-up at HVAMC since 2015. All patients were male. The mean (SD) age was 67.2 (11.4) years, mean body mass index (BMI) was 34.0 (5.9), and the mean (SD) Epworth Sleepiness Scale (ESS) score was 10.9 (5.8). Patient comorbidities included 30 (97%) with hypertension, 17 (55%) with diabetes mellitus, 16 (52%) with coronary artery disease, and 11 (35%) with congestive heart failure. Three patients had no echocardiogram or other documentation of left ventricular ejection fraction (LVEF). One of these patients had voluntarily stopped using PAP therapy, another had been erroneously started on ASV (ordered for fixed BPAP), and the third had since been retitrated to CPAP. In the 28 patients with documented LVEF, the mean (SD) LVEF was 61.8% (6.9). Ten patients (32%) had opioids documented on their medication lists and 6 (19%) had benzodiazepines.

The median date of diagnostic sleep testing was January 9, 2015, and testing was completed after the release of the initial field safety notice regarding the SERVE-HF trial preliminary findings May 13, 2015, for 14 patients (45%).¹² On diagnostic sleep testing, the mean (SD) AHI was 47.3 (25.6) events/h and the median (IQR) oxygen saturation (SpO₂) nadir was 82% (78-84). Three patients (10%) were initially diagnosed with CSA, 19 (61%) with OSA, and 9 (29%) with both. Sixteen patients (52%) had ASV with fixed expiratory PAP (EPAP), and 15 (48%) had variable adjusting EPAP. Mean (SD) usage of ASV was 6.5 (2.6) hours and 66.0% (34.2) of nights for ≥ 4 hours. Mean (SD) titrated EPAP (set or 90th/95th percentile autotitrated) was 10.1 (3.4) cm H₂O and inspiratory PAP (IPAP) (90th/95th percentile) was 17.1 (3.3) cm H₂O. The median (IQR) residual AHI on ASV was 2.7 events/h (1.1-5.1), apnea index (AI) was 0.4 (0.1-1.0), and hypopnea index (HI) was 1.4 (1.0-3.2); the residual central and obstructive events were not available in most cases.

Adherence

There were no significant differences between the proportions of patients on ASV with set EPAP or the titrated EPAP and IPAP. The median (IQR) residual AHI was lower in the adherent group compared with the nonadherent group, both in absolute values (1.7 [0.9-3.2] events/h vs 4.7 [2.4-10.3] events/h, respectively [P = .004]), and as a percentage of the pretreatment AHI (3.1% [2.5-6.0] vs 10.2% [5.3-34.4], respectively; P = .002) (Figure 2).

Primarily Obstructive Sleep Apnea

Sleep apnea was a mixed picture of obstructive and central events in many patients. Only 3 patients had “pure” CSA. Thus, we were unable to define discrete comparison groups based on the sleep-disordered breathing phenotype. We identified 19 patients with primarily OSA (ie, initially diagnosed with OSA, OSA with TECSA, or complex sleep apnea). The mean (SD) age was 66.1 (12.8) years, BMI was 36.2 (4.7), and ESS was 11.4 (5.6). The mean (SD) baseline AHI was 46.9 (29.5), obstructive AHI was 40.5 (30.4), and central AHI was 0.4 (1.2); the median (IQR) SpO₂ nadir was 81% (78%-84%). The mean (SD) titrated EPAP was 10.2 (3.5) cm H₂O, and the 90th/95th percentile IPAP was 17.9 (3.5) cm H₂O. The mean (SD) usage of ASV was 7.9 (5.3) hours with 11 patients (58%) meeting the minimum standard for adherence to ASV therapy.

No significant differences were seen between the adherent and nonadherent groups in clinical or demographic characteristics or date of diagnostic sleep testing (eAppendix, available online at doi:10.12788/fp.0374). In baseline sleep studies the mean (SD) HI was 32.3 (15.8) in the adherent group compared with 14.7 (8.8) in the nonadherent group (P = .049). In contrast, obstructive AHI was not significantly lower in the adherent group: 51.9 (30.9) in the adherent group compared with 22.2 (20.6) in the nonadherent group (P = .09). The median (IQR) residual AHI on ASV as a percentage of the pretreatment AHI was 3.0% (2.4%-6.5%) in the adherent group compared with 11.3% (5.4%-89.1%) in the nonadherent group, a statistically significant difference (P = .01). No other significant differences were seen between the groups.

Discussion

This study describes a real-world cohort of patients using ASV therapy and the characteristics associated with benefit from therapy. The patients that were prescribed and started ASV therapy most often had a significant degree of obstructive component to sleep-disordered breathing, whether primary OSA with TECSA or comorbid OSA and CSA. Moreover, we found that a higher obstructive AHI on the baseline PSG was associated with adherence to ASV therapy. Another important finding was that a lower residual AHI on ASV as a proportion of the baseline was associated with PAP adherence. Adherent patients had similar clinical characteristics as the nonadherent patients, including comorbidities, severity of sleep-disordered breathing, and obesity.

Though the results of the SERVE-HF trial have dampened the enthusiasm somewhat, ASV therapy has long been considered an effective and well-tolerated treatment for many types of CSA.¹³ In fact, treatments that can eliminate the central AHI are fairly limited.^4,14 Our data suggest that ASV is also effective and tolerated in OSA with TECSA and/or comorbid CSA. Recent studies suggest that CSA resolves spontaneously in a majority of TECSA patients within 2 to 3 months of regular CPAP use.¹⁵ Other estimates suggest that persistent TESCA may be present in 2% of patients with OSA on treatment.¹⁶

Given the high and rising prevalence of OSA, many people are at risk for clinically significant TESCA. Another retrospective case series found that 72% of patients that failed treatment with CPAP or BPAP during PSG, met diagnostic criteria (at the time) for CSA; ASV was objectively beneficial in these patients.¹⁷ ASV can be an especially useful modality to treat OSA in patients with CSA that either prevents tolerance of standard therapies or causes clinical consequences, presuming the patient does not also have HFrEF.¹⁸ The long-term outcomes of treatment with ASV therapy remain a matter of debate.

The SERVE-HF trial remains among the only studies that have assessed the mortality effects of CSA treatments, with unfavorable findings. Treatment of OSA has been associated with favorable chronic health benefits, though recent studies have questioned the degree of benefit attributable to OSA treatment.^19-24 Similar studies have not been done for comorbidities represented by our study cohort (ie, OSA with TECSA and/or comorbid CSA).

The lack of CSA diagnosis alone in our cohort may be partially attributable to changing practice patterns following the SERVE-HF trial, though it is not clear from these data why a higher baseline obstructive AHI was associated with adherence to ASV therapy. Our data in this regard are somewhat at odds with the preliminary results of the ADVENT-HF trial. In that study, adherence to ASV therapy in patients with predominantly OSA declined significantly more than in patients with predominantly CSA.²⁵ Most of our patients were diagnosed with predominantly OSA, so a direct comparison with the CSA group is problematic; additionally, the primary brand and the pressure adjustments algorithm used in our study differed from the ADVENT-HF trial.

OSA and CSA may present with similar clinical symptoms, including sleep fragmentation, insomnia, and excessive daytime sleepiness; however, the degree of symptomatology, especially daytime sleepiness, and the response to treatment, may be less in CSA.^2,26 Both the subjective report of symptoms (ESS) and PSG measures of sleep fragmentation were similar in our patients, again likely explained by the predominance of obstructive events.

The pathophysiology of CSA is more varied than OSA, which is probably relevant in this case. ASV was originally designed for the management of CSA with CSR, accomplishing this goal by stabilizing the periods of central apnea and hyperpnea characteristic of CSR.²⁷ Although other forms of CSA demonstrate breathing patterns distinct from CSR, ASV has become an accepted treatment for most of these. It is plausible that the long-term subjective benefit and tolerance of ASV in CSA without CSR is less than for CSA with CSR or OSA. None of the patients in our study had CSA with CSR.

Ultimately, it may be the objective treatment effect that lends to adherence, as has been shown previously in OSA patients; our group of adherent patients showed a greater improvement in AHI, relative to baseline, than the nonadherent patients did.²⁸ The technology behind ASV therapy can greatly reduce the frequencies of central apneas, yet this same treatment effectively splints the upper airway and even more effectively eliminates obstructive apneas and hypopneas. Variable adjusting EPAP devices would plausibly provide even more benefit in these patients, as has been shown in prior studies.²⁹ To the contrary, our small sample of patients with TESCA showed a nonsignificant trend toward adherence with fixed EPAP ASV.

Opioid use was substantial in our population, without significant differences between the groups. CPAP therapy is ineffective in improving opioid-associated CSA. In a recent study, 20 patients on opioid therapy with CSA were treated with CPAP therapy; after several weeks, the average therapeutic use was 4 to 5 hours per night and CPAP was abandoned in favor of ASV therapy due to persistent central apnea. ASV treatment was associated with a considerable reduction in central apnea index, AHI, arousal index, and oxygen desaturations in a remarkable improvement over CPAP.³⁰

Limitations and Future Directions

This retrospective, single-center study may have limited applicability to other populations. Adherence was used as a surrogate for subjective benefit from treatment, though benefit was not confirmed by the patients directly. Only patients seen in follow-up for documentation of the ASV download were identified for inclusion and data analysis. As a single center, we risk homogeneity in the treatment algorithms, though sleep medicine treatments are often decided at the time of the sleep studies. Studies and treatment recommendations were made at a variety of sites, including our sleep center, other US Department of Veterans Affairs hospitals, in the community network, and at US Department of Defense centers. Our population was homogenous in some ways; notably, 100% of our group was male, which is substantially higher than both the veteran population and the general population. Risk factors for OSA and CSA are more common in male patients, which may partially explain this anomaly. Lastly, with our small sample size, there is increased risk that the results seen occurred by chance.

There are several areas for further study. A larger multicenter study may permit these results to be generalized to the population and should include subjective measures of benefit. Patients with primarily CSA were largely absent in our group and may be the focus of future studies; data on predictors of treatment adherence in CSA are lacking. With the availability of consistent older adherence data, comparisons may be made between the efficacies of clinical practice habits, including treatment efficacy, before and after the results of the SERVE-HF trial became known.

Conclusions

In selected patients with preserved LVEF, ASV therapy appears especially effective in patients with OSA combined with CSA. Adherence to ASV treatment was associated with higher obstructive AHI during the baseline PSG and with a greater reduction in the AHI. This understanding may help guide sleep specialists in personalizing treatments for sleep-disordered breathing. Because objective efficacy appears to be important for therapy adherence, clinicians should be able to consistently determine the obstructive and central components of the residual AHI, thus taking all information into account when optimizing the treatment. Additionally, both OSA and CSA pressure requirements should be considered when developing ASV devices.

Acknowledgments

We thank Martha Harper, RRT, of Hampton Veterans Affairs Medical Center (HVAMC) for helping to identify our patients and assisting with data collection. This material is the result of work supported with resources and the use of HVAMC facilities.

The inappropriate use of antibiotics is associated with an increased risk of antibiotic resistance, health care costs, and risk of adverse drug reactions.¹ According to the Centers for Disease Control and Prevention (CDC), a 10% decrease in overall antibiotic use across different wards was associated with a 34% decrease in Clostridioides difficile (C difficile) infections.² In addition, antimicrobial resistance accounts for > 2.8 million infections and > 35,000 deaths each year.³ The estimated total economic costs of antibiotic resistance to the US economy have ranged as high as $20 billion in excess direct health care costs.⁴ A main goal of an antimicrobial stewardship program (ASP) is to optimize antibiotic use to prevent the adverse consequences of inappropriate antibiotic prescribing.

During the COVID-19 pandemic, increased use of empiric antibiotic therapy has been observed. According to the CDC, almost 80% of patients hospitalized with COVID-19 received an antibiotic from March 2020 to October 2020.⁵ Studies were conducted to investigate the prevalence of bacterial coinfection in patients with COVID-19 and whether antibiotics were indicated in this patient population. A United Kingdom multicenter, prospective cohort study showed a high proportion of patients hospitalized with COVID-19 received antimicrobials despite microbiologically confirmed bacterial infections being rare and more likely to be secondary infections.⁶

Many other studies have reported similar findings. Langord and colleagues found the prevalence of bacterial coinfection in patients with COVID-19 was 3.5% but that 71.9% received antibiotics.⁷ Coenen and colleagues identified 12.4% of the patients with possible and 1.1% of patients with probable bacterial coinfection, while 81% of the study population and 78% of patients were classified as unlikely bacterial coinfection received antibiotics.⁸

At Veterans Affairs Southern Nevada Healthcare System (VASNHS), an ASP team consisting of an infectious disease (ID) physician and 2 pharmacists provide daily prospective audits with intervention and feedback along with other interventions, such as providing restricted order menus, institutional treatment guidelines, and staff education to help improve antibiotic prescribing. The ASP pharmacists have a scope of practice to make changes to anti-infective therapies. The purpose of this study was to describe antibiotic prescribing in patients hospitalized with COVID-19 from November 1, 2020, to January 31, 2021, in an ASP setting led by pharmacists.

Methods

This retrospective descriptive study included patients who were hospitalized for the treatment of laboratory-confirmed COVID-19 infection. The Theradoc clinical surveillance system was used to retrieve a list of patients who were admitted to VASNHS from November 1, 2020, to January 31, 2021, and tested positive for COVID-19. Patients with incidental positive COVID-19 test results or those who received antibiotics for extrapulmonary indications on hospital admission were excluded.

Each patient chart was reviewed and data, including clinical presentations, procalcitonin (PCT), the requirement of supplemental oxygen, vital signs, imaging findings, antibiotic orders on admission, ASP interventions such as discontinuation or changes to antibiotic therapy during the first 72 hours of hospital admission, clinical outcomes, culture results, and readmission rate, defined as any hospital admission related to COVID-19 or respiratory tract infection within 30 days from the previous discharge, were collected.

The primary objective of the study was to describe antibiotic prescribing in patients hospitalized with COVID-19. The secondary outcomes included the prevalence of bacterial coinfection and nosocomial bacterial infection in patients hospitalized with COVID-19.

Results

A total of 199 patients were admitted to the hospital for laboratory-confirmed COVID-19 infection from November 1, 2020, to January 31, 2021. Sixty-one patients (31%) received at least 1 antibiotic on hospital admission. Among those patients who received empiric antibiotic treatment, 29 patients (48%) met the Systemic Inflammatory Response Syndrome (SIRS) criteria. Fifty-six patients (92%) had ≥ 1 PCT level obtained, and 26 of those (46%) presented with elevated PCT levels (PCT > 0.25). Fifty patients (82%) required oxygen supplement and 49 (80%) presented with remarkable imaging findings. Of 138 patients who did not receive empiric antibiotic therapy within 72 hours of hospital admission, 56 (41%) met the SIRS criteria, 31 (29%) had elevated PCT levels, 100 (72%) required oxygen supplement, and 79 (59%) presented with remarkable imaging findings.

Antibiotic Prescribing

Forty-six of 61 patients (75%) received antibiotic treatment for community-acquired pneumonia (CAP) that included ceftriaxone and azithromycin. Three patients (5%) received ≥ 1 broad-spectrum antibiotic (4th generation cephalosporin [cefepime] or piperacillin-tazobactam), 2 (3%) received vancomycin, and 1 (2%) received a fluoroquinolone (levofloxacin) on admission.

Among 61 patients who received empiric antibiotics, the readmission rate was 6%. The mortality rate was 20%, and the mean (SD) duration of hospital stay was 13.1 (12.5) days. There were 47 patients (77%) who had antibiotics discontinued by the ASP within 72 hours of admission. Among these patients, the readmission rate was 8% and the mortality rate was 15%. The mean (SD) duration of hospital stay was 12.7 (13.3) days. In the group of patients without empiric antibiotic therapy, the readmission rate was 6%, the mortality rate was 10%, and the mean (SD) duration of hospital stay was 10.1 (9.5) days.

Six of 199 patients (3%) had microbiologically confirmed bacterial coinfection on hospital admission: 3 were Pseudomonas aeruginosa (P aeruginosa) and 2 were Klebsiella oxytoca (Table 1).

Discussion

Prospective audit and feedback and preauthorization are recommended in guidelines as “core components of any stewardship program.”⁹ At VASNHS, the ASP performs daily prospective audits with intervention and feedback. Efforts have been made to maintain daily ASP activities during the pandemic. This study aimed to describe antibiotic prescribing for patients hospitalized with COVID-19 in a pharmacist-led ASP setting. It was found that up to 31% of the patients received ≥ 1 antibiotic on admission for empiric treatment of bacterial coinfection. About half of these patients met the SIRS criteria. Most of these patients received ceftriaxone and azithromycin for concern of CAP. ASP discontinued antibiotics within 72 hours in most of the patients. Chart review and discussion with ID physicians and/or hospitalists determined the probability of bacterial coinfection as well as any potential complication or patient-specific risk factor. It is important to note that most patients who received antibiotics on admission had ≥ 1 PCT level and up to 46% of them had a PCT level > 0.25. However, according to Relph and colleagues, PCT may not be a reliable indicator of bacterial infection in severe viral diseases with raised interleukin-6 levels.¹⁰ An elevated PCT level should not be the sole indicator for empiric antibiotic treatment.

Study findings confirmed the low prevalence of bacterial coinfection in patients hospitalized with COVID-19. The overuse of empiric antibiotics in a patient population unlikely to present with bacterial coinfection is concerning. It is essential to continue promoting antimicrobial stewardship during the COVID-19 pandemic to ensure appropriate and responsible antimicrobial prescribing. A thorough clinical assessment consisting of comorbidities, clinical symptoms, radiologic and microbiologic findings, as well as other relevant workup or biomarker results is crucial to determine whether the antibiotic is strongly indicated in patients hospitalized with COVID-19. Empiric antibiotic therapy should be considered only in patients with clinical findings suggestive of bacterial coinfection.

Limitations

Limitations of our study included the study design (single-center, retrospective review, lack of comparative group) and small sample size with a 3-month study period. In addition, respiratory cultures are not commonly obtained in patients who present with mild-to-moderate CAP. Using culture results solely to confirm bacterial coinfection in patients with COVID-19 could have underestimated the prevalence of bacterial infection. Developing diagnostic criteria that include clinical signs and symptoms, imaging findings, and laboratory results as well as culture results would help to better assess the presence of bacterial coinfection in this patient population.

Conclusions

The study findings showed that up to 30% of patients hospitalized for COVID-19 infection received empiric antibiotic treatment for concern of bacterial coinfection. A pharmacist-led ASP provided interventions, including early discontinuation of antibiotics in 77% of these patients.

A low prevalence of bacterial coinfection (3%) in patients hospitalized with COVID-19 also was reported. A thorough clinical workup to determine the risk of bacterial coinfection in patients with COVID-19 is important before starting empiric antibiotic therapy. Continuing to promote the ASP during the COVID-19 pandemic to ensure responsible antibiotic use and prevent antimicrobial resistance is essential.

The inappropriate use of antibiotics is associated with an increased risk of antibiotic resistance, health care costs, and risk of adverse drug reactions.¹ According to the Centers for Disease Control and Prevention (CDC), a 10% decrease in overall antibiotic use across different wards was associated with a 34% decrease in Clostridioides difficile (C difficile) infections.² In addition, antimicrobial resistance accounts for > 2.8 million infections and > 35,000 deaths each year.³ The estimated total economic costs of antibiotic resistance to the US economy have ranged as high as $20 billion in excess direct health care costs.⁴ A main goal of an antimicrobial stewardship program (ASP) is to optimize antibiotic use to prevent the adverse consequences of inappropriate antibiotic prescribing.

During the COVID-19 pandemic, increased use of empiric antibiotic therapy has been observed. According to the CDC, almost 80% of patients hospitalized with COVID-19 received an antibiotic from March 2020 to October 2020.⁵ Studies were conducted to investigate the prevalence of bacterial coinfection in patients with COVID-19 and whether antibiotics were indicated in this patient population. A United Kingdom multicenter, prospective cohort study showed a high proportion of patients hospitalized with COVID-19 received antimicrobials despite microbiologically confirmed bacterial infections being rare and more likely to be secondary infections.⁶

Many other studies have reported similar findings. Langord and colleagues found the prevalence of bacterial coinfection in patients with COVID-19 was 3.5% but that 71.9% received antibiotics.⁷ Coenen and colleagues identified 12.4% of the patients with possible and 1.1% of patients with probable bacterial coinfection, while 81% of the study population and 78% of patients were classified as unlikely bacterial coinfection received antibiotics.⁸

At Veterans Affairs Southern Nevada Healthcare System (VASNHS), an ASP team consisting of an infectious disease (ID) physician and 2 pharmacists provide daily prospective audits with intervention and feedback along with other interventions, such as providing restricted order menus, institutional treatment guidelines, and staff education to help improve antibiotic prescribing. The ASP pharmacists have a scope of practice to make changes to anti-infective therapies. The purpose of this study was to describe antibiotic prescribing in patients hospitalized with COVID-19 from November 1, 2020, to January 31, 2021, in an ASP setting led by pharmacists.

Methods

This retrospective descriptive study included patients who were hospitalized for the treatment of laboratory-confirmed COVID-19 infection. The Theradoc clinical surveillance system was used to retrieve a list of patients who were admitted to VASNHS from November 1, 2020, to January 31, 2021, and tested positive for COVID-19. Patients with incidental positive COVID-19 test results or those who received antibiotics for extrapulmonary indications on hospital admission were excluded.

Each patient chart was reviewed and data, including clinical presentations, procalcitonin (PCT), the requirement of supplemental oxygen, vital signs, imaging findings, antibiotic orders on admission, ASP interventions such as discontinuation or changes to antibiotic therapy during the first 72 hours of hospital admission, clinical outcomes, culture results, and readmission rate, defined as any hospital admission related to COVID-19 or respiratory tract infection within 30 days from the previous discharge, were collected.

The primary objective of the study was to describe antibiotic prescribing in patients hospitalized with COVID-19. The secondary outcomes included the prevalence of bacterial coinfection and nosocomial bacterial infection in patients hospitalized with COVID-19.

Results

A total of 199 patients were admitted to the hospital for laboratory-confirmed COVID-19 infection from November 1, 2020, to January 31, 2021. Sixty-one patients (31%) received at least 1 antibiotic on hospital admission. Among those patients who received empiric antibiotic treatment, 29 patients (48%) met the Systemic Inflammatory Response Syndrome (SIRS) criteria. Fifty-six patients (92%) had ≥ 1 PCT level obtained, and 26 of those (46%) presented with elevated PCT levels (PCT > 0.25). Fifty patients (82%) required oxygen supplement and 49 (80%) presented with remarkable imaging findings. Of 138 patients who did not receive empiric antibiotic therapy within 72 hours of hospital admission, 56 (41%) met the SIRS criteria, 31 (29%) had elevated PCT levels, 100 (72%) required oxygen supplement, and 79 (59%) presented with remarkable imaging findings.

Antibiotic Prescribing

Forty-six of 61 patients (75%) received antibiotic treatment for community-acquired pneumonia (CAP) that included ceftriaxone and azithromycin. Three patients (5%) received ≥ 1 broad-spectrum antibiotic (4th generation cephalosporin [cefepime] or piperacillin-tazobactam), 2 (3%) received vancomycin, and 1 (2%) received a fluoroquinolone (levofloxacin) on admission.

Among 61 patients who received empiric antibiotics, the readmission rate was 6%. The mortality rate was 20%, and the mean (SD) duration of hospital stay was 13.1 (12.5) days. There were 47 patients (77%) who had antibiotics discontinued by the ASP within 72 hours of admission. Among these patients, the readmission rate was 8% and the mortality rate was 15%. The mean (SD) duration of hospital stay was 12.7 (13.3) days. In the group of patients without empiric antibiotic therapy, the readmission rate was 6%, the mortality rate was 10%, and the mean (SD) duration of hospital stay was 10.1 (9.5) days.

Six of 199 patients (3%) had microbiologically confirmed bacterial coinfection on hospital admission: 3 were Pseudomonas aeruginosa (P aeruginosa) and 2 were Klebsiella oxytoca (Table 1).

Discussion

Prospective audit and feedback and preauthorization are recommended in guidelines as “core components of any stewardship program.”⁹ At VASNHS, the ASP performs daily prospective audits with intervention and feedback. Efforts have been made to maintain daily ASP activities during the pandemic. This study aimed to describe antibiotic prescribing for patients hospitalized with COVID-19 in a pharmacist-led ASP setting. It was found that up to 31% of the patients received ≥ 1 antibiotic on admission for empiric treatment of bacterial coinfection. About half of these patients met the SIRS criteria. Most of these patients received ceftriaxone and azithromycin for concern of CAP. ASP discontinued antibiotics within 72 hours in most of the patients. Chart review and discussion with ID physicians and/or hospitalists determined the probability of bacterial coinfection as well as any potential complication or patient-specific risk factor. It is important to note that most patients who received antibiotics on admission had ≥ 1 PCT level and up to 46% of them had a PCT level > 0.25. However, according to Relph and colleagues, PCT may not be a reliable indicator of bacterial infection in severe viral diseases with raised interleukin-6 levels.¹⁰ An elevated PCT level should not be the sole indicator for empiric antibiotic treatment.

Study findings confirmed the low prevalence of bacterial coinfection in patients hospitalized with COVID-19. The overuse of empiric antibiotics in a patient population unlikely to present with bacterial coinfection is concerning. It is essential to continue promoting antimicrobial stewardship during the COVID-19 pandemic to ensure appropriate and responsible antimicrobial prescribing. A thorough clinical assessment consisting of comorbidities, clinical symptoms, radiologic and microbiologic findings, as well as other relevant workup or biomarker results is crucial to determine whether the antibiotic is strongly indicated in patients hospitalized with COVID-19. Empiric antibiotic therapy should be considered only in patients with clinical findings suggestive of bacterial coinfection.

Limitations

Limitations of our study included the study design (single-center, retrospective review, lack of comparative group) and small sample size with a 3-month study period. In addition, respiratory cultures are not commonly obtained in patients who present with mild-to-moderate CAP. Using culture results solely to confirm bacterial coinfection in patients with COVID-19 could have underestimated the prevalence of bacterial infection. Developing diagnostic criteria that include clinical signs and symptoms, imaging findings, and laboratory results as well as culture results would help to better assess the presence of bacterial coinfection in this patient population.

Conclusions

The study findings showed that up to 30% of patients hospitalized for COVID-19 infection received empiric antibiotic treatment for concern of bacterial coinfection. A pharmacist-led ASP provided interventions, including early discontinuation of antibiotics in 77% of these patients.

A low prevalence of bacterial coinfection (3%) in patients hospitalized with COVID-19 also was reported. A thorough clinical workup to determine the risk of bacterial coinfection in patients with COVID-19 is important before starting empiric antibiotic therapy. Continuing to promote the ASP during the COVID-19 pandemic to ensure responsible antibiotic use and prevent antimicrobial resistance is essential.

The inappropriate use of antibiotics is associated with an increased risk of antibiotic resistance, health care costs, and risk of adverse drug reactions.¹ According to the Centers for Disease Control and Prevention (CDC), a 10% decrease in overall antibiotic use across different wards was associated with a 34% decrease in Clostridioides difficile (C difficile) infections.² In addition, antimicrobial resistance accounts for > 2.8 million infections and > 35,000 deaths each year.³ The estimated total economic costs of antibiotic resistance to the US economy have ranged as high as $20 billion in excess direct health care costs.⁴ A main goal of an antimicrobial stewardship program (ASP) is to optimize antibiotic use to prevent the adverse consequences of inappropriate antibiotic prescribing.

During the COVID-19 pandemic, increased use of empiric antibiotic therapy has been observed. According to the CDC, almost 80% of patients hospitalized with COVID-19 received an antibiotic from March 2020 to October 2020.⁵ Studies were conducted to investigate the prevalence of bacterial coinfection in patients with COVID-19 and whether antibiotics were indicated in this patient population. A United Kingdom multicenter, prospective cohort study showed a high proportion of patients hospitalized with COVID-19 received antimicrobials despite microbiologically confirmed bacterial infections being rare and more likely to be secondary infections.⁶

Many other studies have reported similar findings. Langord and colleagues found the prevalence of bacterial coinfection in patients with COVID-19 was 3.5% but that 71.9% received antibiotics.⁷ Coenen and colleagues identified 12.4% of the patients with possible and 1.1% of patients with probable bacterial coinfection, while 81% of the study population and 78% of patients were classified as unlikely bacterial coinfection received antibiotics.⁸

At Veterans Affairs Southern Nevada Healthcare System (VASNHS), an ASP team consisting of an infectious disease (ID) physician and 2 pharmacists provide daily prospective audits with intervention and feedback along with other interventions, such as providing restricted order menus, institutional treatment guidelines, and staff education to help improve antibiotic prescribing. The ASP pharmacists have a scope of practice to make changes to anti-infective therapies. The purpose of this study was to describe antibiotic prescribing in patients hospitalized with COVID-19 from November 1, 2020, to January 31, 2021, in an ASP setting led by pharmacists.

Methods

This retrospective descriptive study included patients who were hospitalized for the treatment of laboratory-confirmed COVID-19 infection. The Theradoc clinical surveillance system was used to retrieve a list of patients who were admitted to VASNHS from November 1, 2020, to January 31, 2021, and tested positive for COVID-19. Patients with incidental positive COVID-19 test results or those who received antibiotics for extrapulmonary indications on hospital admission were excluded.

Each patient chart was reviewed and data, including clinical presentations, procalcitonin (PCT), the requirement of supplemental oxygen, vital signs, imaging findings, antibiotic orders on admission, ASP interventions such as discontinuation or changes to antibiotic therapy during the first 72 hours of hospital admission, clinical outcomes, culture results, and readmission rate, defined as any hospital admission related to COVID-19 or respiratory tract infection within 30 days from the previous discharge, were collected.

The primary objective of the study was to describe antibiotic prescribing in patients hospitalized with COVID-19. The secondary outcomes included the prevalence of bacterial coinfection and nosocomial bacterial infection in patients hospitalized with COVID-19.

Results

A total of 199 patients were admitted to the hospital for laboratory-confirmed COVID-19 infection from November 1, 2020, to January 31, 2021. Sixty-one patients (31%) received at least 1 antibiotic on hospital admission. Among those patients who received empiric antibiotic treatment, 29 patients (48%) met the Systemic Inflammatory Response Syndrome (SIRS) criteria. Fifty-six patients (92%) had ≥ 1 PCT level obtained, and 26 of those (46%) presented with elevated PCT levels (PCT > 0.25). Fifty patients (82%) required oxygen supplement and 49 (80%) presented with remarkable imaging findings. Of 138 patients who did not receive empiric antibiotic therapy within 72 hours of hospital admission, 56 (41%) met the SIRS criteria, 31 (29%) had elevated PCT levels, 100 (72%) required oxygen supplement, and 79 (59%) presented with remarkable imaging findings.

Antibiotic Prescribing

Forty-six of 61 patients (75%) received antibiotic treatment for community-acquired pneumonia (CAP) that included ceftriaxone and azithromycin. Three patients (5%) received ≥ 1 broad-spectrum antibiotic (4th generation cephalosporin [cefepime] or piperacillin-tazobactam), 2 (3%) received vancomycin, and 1 (2%) received a fluoroquinolone (levofloxacin) on admission.

Among 61 patients who received empiric antibiotics, the readmission rate was 6%. The mortality rate was 20%, and the mean (SD) duration of hospital stay was 13.1 (12.5) days. There were 47 patients (77%) who had antibiotics discontinued by the ASP within 72 hours of admission. Among these patients, the readmission rate was 8% and the mortality rate was 15%. The mean (SD) duration of hospital stay was 12.7 (13.3) days. In the group of patients without empiric antibiotic therapy, the readmission rate was 6%, the mortality rate was 10%, and the mean (SD) duration of hospital stay was 10.1 (9.5) days.

Six of 199 patients (3%) had microbiologically confirmed bacterial coinfection on hospital admission: 3 were Pseudomonas aeruginosa (P aeruginosa) and 2 were Klebsiella oxytoca (Table 1).

Discussion

Prospective audit and feedback and preauthorization are recommended in guidelines as “core components of any stewardship program.”⁹ At VASNHS, the ASP performs daily prospective audits with intervention and feedback. Efforts have been made to maintain daily ASP activities during the pandemic. This study aimed to describe antibiotic prescribing for patients hospitalized with COVID-19 in a pharmacist-led ASP setting. It was found that up to 31% of the patients received ≥ 1 antibiotic on admission for empiric treatment of bacterial coinfection. About half of these patients met the SIRS criteria. Most of these patients received ceftriaxone and azithromycin for concern of CAP. ASP discontinued antibiotics within 72 hours in most of the patients. Chart review and discussion with ID physicians and/or hospitalists determined the probability of bacterial coinfection as well as any potential complication or patient-specific risk factor. It is important to note that most patients who received antibiotics on admission had ≥ 1 PCT level and up to 46% of them had a PCT level > 0.25. However, according to Relph and colleagues, PCT may not be a reliable indicator of bacterial infection in severe viral diseases with raised interleukin-6 levels.¹⁰ An elevated PCT level should not be the sole indicator for empiric antibiotic treatment.

Study findings confirmed the low prevalence of bacterial coinfection in patients hospitalized with COVID-19. The overuse of empiric antibiotics in a patient population unlikely to present with bacterial coinfection is concerning. It is essential to continue promoting antimicrobial stewardship during the COVID-19 pandemic to ensure appropriate and responsible antimicrobial prescribing. A thorough clinical assessment consisting of comorbidities, clinical symptoms, radiologic and microbiologic findings, as well as other relevant workup or biomarker results is crucial to determine whether the antibiotic is strongly indicated in patients hospitalized with COVID-19. Empiric antibiotic therapy should be considered only in patients with clinical findings suggestive of bacterial coinfection.

Limitations

Limitations of our study included the study design (single-center, retrospective review, lack of comparative group) and small sample size with a 3-month study period. In addition, respiratory cultures are not commonly obtained in patients who present with mild-to-moderate CAP. Using culture results solely to confirm bacterial coinfection in patients with COVID-19 could have underestimated the prevalence of bacterial infection. Developing diagnostic criteria that include clinical signs and symptoms, imaging findings, and laboratory results as well as culture results would help to better assess the presence of bacterial coinfection in this patient population.

Conclusions

The study findings showed that up to 30% of patients hospitalized for COVID-19 infection received empiric antibiotic treatment for concern of bacterial coinfection. A pharmacist-led ASP provided interventions, including early discontinuation of antibiotics in 77% of these patients.

A low prevalence of bacterial coinfection (3%) in patients hospitalized with COVID-19 also was reported. A thorough clinical workup to determine the risk of bacterial coinfection in patients with COVID-19 is important before starting empiric antibiotic therapy. Continuing to promote the ASP during the COVID-19 pandemic to ensure responsible antibiotic use and prevent antimicrobial resistance is essential.

Infectious diseases are the most common reason for rehospitalization among patients with spinal cord injuries (SCI), regardless of the number of years postinjury.¹ The appropriate use and selection of antibiotics for properly diagnosed infectious diseases is especially important for this population. This principle helps to avoid the development of drug-resistant organisms and reduces the risk of recurrent infections, aligning with antibiotic stewardship.

Antibiotics are the most common class of drug allergies in the general population, and penicillin is the most frequently reported allergen (up to 10%).² Prescription drug–induced anaphylaxis is severe and life threatening with a reported frequency of 1.1%. Penicillin and sulfonamide (46 and 15 per 10,000 patients, respectively) are the most common allergens.³ Although there is a significant difference between an adverse drug reaction (ADR) and true hypersensitivity, once documented in the electronic health record (EHR) as an allergy, this information deters use of the listed drugs.

Genitourinary, skin, and respiratory diseases are the leading causes for rehospitalization in patients with SCI.¹ A large proportion of these are infectious in etiology and require antibiotic treatment. In fact, persons with SCI are at high risk for antibiotic overuse and hospital-acquired infection due to chronic bacteriuria, frequent health care exposure, implanted medical devices, and other factors.⁴ Concurrently, there is a crisis of antibiotic-resistant bacteria proliferation, described asa threat to patient safety and public health.^5,6 Its severity is illustrated by the report that 38% of the cultures from patients with spinal cord injury are multidrug resistant gram-negative organisms.⁷

The SCI center at James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, serves a high concentration of active-duty military members and veterans with SCI. A study that reviews the exact frequency of antibiotic drug allergies listed on the EHR would be a key first step to identify the magnitude of this issue. The results could guide investigation into differentiating true allergies from ADRs, thereby widening the options for potentially life-saving antibiotic treatment.

Methods

We performed a retrospective chart review of patients included in the local SCI registry between October 1, 2015, and September 30, 2017. We collected data on patient demographics (age, sex, race and ethnicity) and a description of patients’ injuries (International Standards for Neurological Classification of Spinal Cord Injury [ISNCSCI] and etiology of injury [traumatic vs atraumatic]). The outcomes included antibiotic allergy and ADRs.

In the EHR, allergies can be listed toward an antibiotic class or a specific antibiotic. An allergy to each specific antibiotic would be recorded separately; however, overlap among antibiotic classes was not duplicated. For example, if a subject has a listed antibiotic allergy to ceftriaxone and cefepime with listed reactions, we would record allergies to each of these antibiotics but would only report a single allergy to the cephalosporin subclass.

Since we did not differentiate hypersensitivity reactions (HSRs) from other ADRs, the reported reactions were grouped by signs and symptoms. There is a variety of terms used to report similar reactions, and best efforts were made to record the data as accurately as possible. Patient-reported history for risk stratification is a tool we used to group these historical reactions into high- vs low-risk for severe reactions. High-risk signs are those listed as anaphylaxis; anaphylactic reactions; angioedema presenting as swelling of mouth, eyes, lips, or tongue; blisters or ulcers involving the lips, mouth, eyes, urethra, vagina, or peeling skin; respiratory changes; shortness of breath; dyspnea; hypotension; or organ involvement (kidneys, lungs, liver).⁶

Inclusion criteria were all veterans who were diagnosed with tetraplegia or paraplegia and received annual evaluation between October 1, 2015, and September 30, 2017. We chose this period because it was the beginning of a financial year at the JAHVH SCI department using the SCI registry. The SCI annual evaluation is a routine practitioner encounter with the veteran, along with appropriate laboratory testing and imaging to follow up potential chronic health issues specific to patients with SCI. Annual evaluations provide an opportunity to maintain routine health screening and preventive care. Patients who had significant portions of data missing or missing elements of primary outcomes were excluded from analysis. The study was reviewed and approved by the University of South Florida Institutional Review Board (VA IRBNet #1573370-4 on September 9, 2019).

Results

Of 1866 patients reviewed, 207 (11.1%) were excluded due to missing data, resulting in 1659 records that were analyzed. Mean age was 64 years, and male to female ratio was about 10 to 1. Most of the SCI or diseases were classified as incomplete (n = 1249) per ISNCSCI (absence of sensory and motor function in the lowest sacral segments) compared with 373 classified as complete.

Of the 1659 patients, 494 (29.8%) had a recorded allergy to antibiotics. The most frequently recorded were 217 penicillin (13.1%), 159 sulfa drugs (9.6%), 75 fluoroquinolone (4.5%), 66 cephalosporin (4.0%), and 44 vancomycin (2.7%) allergies.

Discussion

In this study, we evaluated the frequency and characteristics of antibiotic allergies at a single SCI center to better identify potential areas for quality improvement when recording drug allergies. A study in the general population used self-reported methods to collect such information found about a 15% prevalence of antibiotic allergy, which was lower than the 29.8% prevalence noted in our study.⁸

Regarding the most common antibiotic allergies, one study reported allergy to penicillin in the EHR in 12.8% of patients at a major US regional health care system, while 13.1% of patients with SCI had documented allergy to penicillin in our study.⁹ Regarding the other antibiotic classes, the percentage of allergies were higher than those reported in the general population: sulfonamide (9.6% vs 7.4%), fluoroquinolones (4.5% vs 1.3%), and cephalosporins (4.0% vs 1.7%).¹⁰ The EHR appears to capture a much higher rate of antibiotic allergies than that in self-reported studies, such as a study of self-reported allergy in the general adult population in Portugal, where only 4.5% of patients reported allergy to any β-lactam medications.¹⁰

The prevalence of an antibiotic allergy could be affected by the health care setting and sex distribution. For example, the Zhou and colleagues’ study conducted in the Greater Boston area showed higher reported antibiotic rates than those in a study from a Southern California medical group. The higher proportion of tertiary referral patients in that specific network was suggested to be the cause of the difference.^8,9 Our results in the SCI population are more comparable to that in a tertiary setting. This is consistent with the fact that persons with SCI generally have more exposure to antibiotics and consequently a higher reported rate of allergic reactions to antibiotics.

Similarly, the same study in Southern California noted that female patients use more antibiotics than do male patients, thus potentially contributing to higher rates of reported allergy toward all classes of antibiotics.⁸ Our study did not investigate antibiotic allergy by sex; however, the significantly higher proportion of male sex among the veteran population would have impacted these results.

Limitations

Our study was limited as a single-center retrospective study. However, our center is one of the major SCI specialty hubs, and the results should be somewhat reflective of those in the veterans with SCI population. Veterans under the US Department of Veterans Affairs (VA) medical care have the option to seek care or procedures in non-VA facilities. If allergies to antibiotics occurred outside of the VA system, there is no mechanism to automatically merge with the VA EHR allergy list, unless they are later recorded and added to the VA EHR. Thus, there is potential for underreporting.

Drug anaphylaxis incidence was noted to change over time.^4,8,9 For example, a downtrend of reported antibiotic allergy was reported between 1990 and 2013.¹⁰ Our study only reflects an overall prevalence of a single cohort, without demonstration of relationship to time.

Lastly, this study did not aim to differentiate HSRs from other ADRs. This is exactly the point of the study, which investigated the frequency of EHR-recorded antibiotic allergies in our SCI population and reflects the issue with indiscriminate recording of ADRs and HSRs under the umbrella of allergy in the EHR. Further diagnosing true allergies should be considered in the SCI population after weighing the risks and benefits of assessment, aligning with the wishes of the veteran, obtaining informed consent, and addressing the cost-effectiveness of specific tests. We suggest that primary care practitioners work closely with allergy specialists to formulate a mechanism to diagnose various antibiotic allergic reactions, including serum tryptase, epicutaneous skin testing, intradermal skin testing, patch testing, delayed intradermal testing, and drug challenge as appropriate. It is also possible that in cases where very mild reactions/adverse effects of antibiotics were recorded in the EHR, the clinicians and veterans may discuss reintroducing the same antibiotics or proceeding with further testing if necessary. In contrast, the 12% of those with a high risk of severe allergic reactions to penicillin in our study would benefit from allergist evaluation and access to epinephrine auto-injectors at all times. Differentiating true allergy is the only clear way to deter unnecessary avoidance of first-line therapies for antibiotic treatment and avoid promotion of antibiotic resistance.

Future studies can analyze antibiotic allergy based on demographics, including sex and age difference, as well as exploring outpatient vs inpatient settings. Aside from prevalence, we hope to demonstrate antibiotic allergy over time, especially after integration of diagnostic allergy testing, to evaluate the impact to EHR-recorded allergies.

Conclusions

Almost 30% of patients with SCI had a recorded allergy to at least 1 antibiotic. The most common allergy was to penicillin, which is similar to what has previously been reported for the general adult US population. However, only 12% of those with a penicillin allergy were considered high risk of true allergic reactions. Consequently, there are opportunities to examine whether approaches to confirm true reactions (such as skin testing) would help to mitigate unnecessary avoidance of certain antibiotic classes due to mild ADRs, rather than a true allergy, in persons with SCI. This would be an important effort to combat both individual safety concerns and the public health crisis of antibiotic resistance. Given the available evidence, it is reasonable for SCI health care practitioners to discuss the potential risks and benefits of allergy testing with patients with SCI; this maintains a patient-centered approach that can ensure judicious use of antibiotics when necessary.

Acknowledgments

This material is based on work supported (or supported in part) with resources and the use of facilities at the James A. Haley Veterans’ Hospital

Infectious diseases are the most common reason for rehospitalization among patients with spinal cord injuries (SCI), regardless of the number of years postinjury.¹ The appropriate use and selection of antibiotics for properly diagnosed infectious diseases is especially important for this population. This principle helps to avoid the development of drug-resistant organisms and reduces the risk of recurrent infections, aligning with antibiotic stewardship.

Antibiotics are the most common class of drug allergies in the general population, and penicillin is the most frequently reported allergen (up to 10%).² Prescription drug–induced anaphylaxis is severe and life threatening with a reported frequency of 1.1%. Penicillin and sulfonamide (46 and 15 per 10,000 patients, respectively) are the most common allergens.³ Although there is a significant difference between an adverse drug reaction (ADR) and true hypersensitivity, once documented in the electronic health record (EHR) as an allergy, this information deters use of the listed drugs.

Genitourinary, skin, and respiratory diseases are the leading causes for rehospitalization in patients with SCI.¹ A large proportion of these are infectious in etiology and require antibiotic treatment. In fact, persons with SCI are at high risk for antibiotic overuse and hospital-acquired infection due to chronic bacteriuria, frequent health care exposure, implanted medical devices, and other factors.⁴ Concurrently, there is a crisis of antibiotic-resistant bacteria proliferation, described asa threat to patient safety and public health.^5,6 Its severity is illustrated by the report that 38% of the cultures from patients with spinal cord injury are multidrug resistant gram-negative organisms.⁷

The SCI center at James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, serves a high concentration of active-duty military members and veterans with SCI. A study that reviews the exact frequency of antibiotic drug allergies listed on the EHR would be a key first step to identify the magnitude of this issue. The results could guide investigation into differentiating true allergies from ADRs, thereby widening the options for potentially life-saving antibiotic treatment.

Methods

We performed a retrospective chart review of patients included in the local SCI registry between October 1, 2015, and September 30, 2017. We collected data on patient demographics (age, sex, race and ethnicity) and a description of patients’ injuries (International Standards for Neurological Classification of Spinal Cord Injury [ISNCSCI] and etiology of injury [traumatic vs atraumatic]). The outcomes included antibiotic allergy and ADRs.

In the EHR, allergies can be listed toward an antibiotic class or a specific antibiotic. An allergy to each specific antibiotic would be recorded separately; however, overlap among antibiotic classes was not duplicated. For example, if a subject has a listed antibiotic allergy to ceftriaxone and cefepime with listed reactions, we would record allergies to each of these antibiotics but would only report a single allergy to the cephalosporin subclass.

Since we did not differentiate hypersensitivity reactions (HSRs) from other ADRs, the reported reactions were grouped by signs and symptoms. There is a variety of terms used to report similar reactions, and best efforts were made to record the data as accurately as possible. Patient-reported history for risk stratification is a tool we used to group these historical reactions into high- vs low-risk for severe reactions. High-risk signs are those listed as anaphylaxis; anaphylactic reactions; angioedema presenting as swelling of mouth, eyes, lips, or tongue; blisters or ulcers involving the lips, mouth, eyes, urethra, vagina, or peeling skin; respiratory changes; shortness of breath; dyspnea; hypotension; or organ involvement (kidneys, lungs, liver).⁶

Inclusion criteria were all veterans who were diagnosed with tetraplegia or paraplegia and received annual evaluation between October 1, 2015, and September 30, 2017. We chose this period because it was the beginning of a financial year at the JAHVH SCI department using the SCI registry. The SCI annual evaluation is a routine practitioner encounter with the veteran, along with appropriate laboratory testing and imaging to follow up potential chronic health issues specific to patients with SCI. Annual evaluations provide an opportunity to maintain routine health screening and preventive care. Patients who had significant portions of data missing or missing elements of primary outcomes were excluded from analysis. The study was reviewed and approved by the University of South Florida Institutional Review Board (VA IRBNet #1573370-4 on September 9, 2019).

Results

Of 1866 patients reviewed, 207 (11.1%) were excluded due to missing data, resulting in 1659 records that were analyzed. Mean age was 64 years, and male to female ratio was about 10 to 1. Most of the SCI or diseases were classified as incomplete (n = 1249) per ISNCSCI (absence of sensory and motor function in the lowest sacral segments) compared with 373 classified as complete.

Of the 1659 patients, 494 (29.8%) had a recorded allergy to antibiotics. The most frequently recorded were 217 penicillin (13.1%), 159 sulfa drugs (9.6%), 75 fluoroquinolone (4.5%), 66 cephalosporin (4.0%), and 44 vancomycin (2.7%) allergies.

Discussion

In this study, we evaluated the frequency and characteristics of antibiotic allergies at a single SCI center to better identify potential areas for quality improvement when recording drug allergies. A study in the general population used self-reported methods to collect such information found about a 15% prevalence of antibiotic allergy, which was lower than the 29.8% prevalence noted in our study.⁸

Regarding the most common antibiotic allergies, one study reported allergy to penicillin in the EHR in 12.8% of patients at a major US regional health care system, while 13.1% of patients with SCI had documented allergy to penicillin in our study.⁹ Regarding the other antibiotic classes, the percentage of allergies were higher than those reported in the general population: sulfonamide (9.6% vs 7.4%), fluoroquinolones (4.5% vs 1.3%), and cephalosporins (4.0% vs 1.7%).¹⁰ The EHR appears to capture a much higher rate of antibiotic allergies than that in self-reported studies, such as a study of self-reported allergy in the general adult population in Portugal, where only 4.5% of patients reported allergy to any β-lactam medications.¹⁰

The prevalence of an antibiotic allergy could be affected by the health care setting and sex distribution. For example, the Zhou and colleagues’ study conducted in the Greater Boston area showed higher reported antibiotic rates than those in a study from a Southern California medical group. The higher proportion of tertiary referral patients in that specific network was suggested to be the cause of the difference.^8,9 Our results in the SCI population are more comparable to that in a tertiary setting. This is consistent with the fact that persons with SCI generally have more exposure to antibiotics and consequently a higher reported rate of allergic reactions to antibiotics.

Similarly, the same study in Southern California noted that female patients use more antibiotics than do male patients, thus potentially contributing to higher rates of reported allergy toward all classes of antibiotics.⁸ Our study did not investigate antibiotic allergy by sex; however, the significantly higher proportion of male sex among the veteran population would have impacted these results.

Limitations

Our study was limited as a single-center retrospective study. However, our center is one of the major SCI specialty hubs, and the results should be somewhat reflective of those in the veterans with SCI population. Veterans under the US Department of Veterans Affairs (VA) medical care have the option to seek care or procedures in non-VA facilities. If allergies to antibiotics occurred outside of the VA system, there is no mechanism to automatically merge with the VA EHR allergy list, unless they are later recorded and added to the VA EHR. Thus, there is potential for underreporting.

Drug anaphylaxis incidence was noted to change over time.^4,8,9 For example, a downtrend of reported antibiotic allergy was reported between 1990 and 2013.¹⁰ Our study only reflects an overall prevalence of a single cohort, without demonstration of relationship to time.

Lastly, this study did not aim to differentiate HSRs from other ADRs. This is exactly the point of the study, which investigated the frequency of EHR-recorded antibiotic allergies in our SCI population and reflects the issue with indiscriminate recording of ADRs and HSRs under the umbrella of allergy in the EHR. Further diagnosing true allergies should be considered in the SCI population after weighing the risks and benefits of assessment, aligning with the wishes of the veteran, obtaining informed consent, and addressing the cost-effectiveness of specific tests. We suggest that primary care practitioners work closely with allergy specialists to formulate a mechanism to diagnose various antibiotic allergic reactions, including serum tryptase, epicutaneous skin testing, intradermal skin testing, patch testing, delayed intradermal testing, and drug challenge as appropriate. It is also possible that in cases where very mild reactions/adverse effects of antibiotics were recorded in the EHR, the clinicians and veterans may discuss reintroducing the same antibiotics or proceeding with further testing if necessary. In contrast, the 12% of those with a high risk of severe allergic reactions to penicillin in our study would benefit from allergist evaluation and access to epinephrine auto-injectors at all times. Differentiating true allergy is the only clear way to deter unnecessary avoidance of first-line therapies for antibiotic treatment and avoid promotion of antibiotic resistance.

Future studies can analyze antibiotic allergy based on demographics, including sex and age difference, as well as exploring outpatient vs inpatient settings. Aside from prevalence, we hope to demonstrate antibiotic allergy over time, especially after integration of diagnostic allergy testing, to evaluate the impact to EHR-recorded allergies.

Conclusions

Almost 30% of patients with SCI had a recorded allergy to at least 1 antibiotic. The most common allergy was to penicillin, which is similar to what has previously been reported for the general adult US population. However, only 12% of those with a penicillin allergy were considered high risk of true allergic reactions. Consequently, there are opportunities to examine whether approaches to confirm true reactions (such as skin testing) would help to mitigate unnecessary avoidance of certain antibiotic classes due to mild ADRs, rather than a true allergy, in persons with SCI. This would be an important effort to combat both individual safety concerns and the public health crisis of antibiotic resistance. Given the available evidence, it is reasonable for SCI health care practitioners to discuss the potential risks and benefits of allergy testing with patients with SCI; this maintains a patient-centered approach that can ensure judicious use of antibiotics when necessary.

Acknowledgments

This material is based on work supported (or supported in part) with resources and the use of facilities at the James A. Haley Veterans’ Hospital

Infectious diseases are the most common reason for rehospitalization among patients with spinal cord injuries (SCI), regardless of the number of years postinjury.¹ The appropriate use and selection of antibiotics for properly diagnosed infectious diseases is especially important for this population. This principle helps to avoid the development of drug-resistant organisms and reduces the risk of recurrent infections, aligning with antibiotic stewardship.

Antibiotics are the most common class of drug allergies in the general population, and penicillin is the most frequently reported allergen (up to 10%).² Prescription drug–induced anaphylaxis is severe and life threatening with a reported frequency of 1.1%. Penicillin and sulfonamide (46 and 15 per 10,000 patients, respectively) are the most common allergens.³ Although there is a significant difference between an adverse drug reaction (ADR) and true hypersensitivity, once documented in the electronic health record (EHR) as an allergy, this information deters use of the listed drugs.

Genitourinary, skin, and respiratory diseases are the leading causes for rehospitalization in patients with SCI.¹ A large proportion of these are infectious in etiology and require antibiotic treatment. In fact, persons with SCI are at high risk for antibiotic overuse and hospital-acquired infection due to chronic bacteriuria, frequent health care exposure, implanted medical devices, and other factors.⁴ Concurrently, there is a crisis of antibiotic-resistant bacteria proliferation, described asa threat to patient safety and public health.^5,6 Its severity is illustrated by the report that 38% of the cultures from patients with spinal cord injury are multidrug resistant gram-negative organisms.⁷

The SCI center at James A. Haley Veterans’ Hospital (JAHVH) in Tampa, Florida, serves a high concentration of active-duty military members and veterans with SCI. A study that reviews the exact frequency of antibiotic drug allergies listed on the EHR would be a key first step to identify the magnitude of this issue. The results could guide investigation into differentiating true allergies from ADRs, thereby widening the options for potentially life-saving antibiotic treatment.

Methods

We performed a retrospective chart review of patients included in the local SCI registry between October 1, 2015, and September 30, 2017. We collected data on patient demographics (age, sex, race and ethnicity) and a description of patients’ injuries (International Standards for Neurological Classification of Spinal Cord Injury [ISNCSCI] and etiology of injury [traumatic vs atraumatic]). The outcomes included antibiotic allergy and ADRs.

In the EHR, allergies can be listed toward an antibiotic class or a specific antibiotic. An allergy to each specific antibiotic would be recorded separately; however, overlap among antibiotic classes was not duplicated. For example, if a subject has a listed antibiotic allergy to ceftriaxone and cefepime with listed reactions, we would record allergies to each of these antibiotics but would only report a single allergy to the cephalosporin subclass.

Since we did not differentiate hypersensitivity reactions (HSRs) from other ADRs, the reported reactions were grouped by signs and symptoms. There is a variety of terms used to report similar reactions, and best efforts were made to record the data as accurately as possible. Patient-reported history for risk stratification is a tool we used to group these historical reactions into high- vs low-risk for severe reactions. High-risk signs are those listed as anaphylaxis; anaphylactic reactions; angioedema presenting as swelling of mouth, eyes, lips, or tongue; blisters or ulcers involving the lips, mouth, eyes, urethra, vagina, or peeling skin; respiratory changes; shortness of breath; dyspnea; hypotension; or organ involvement (kidneys, lungs, liver).⁶

Inclusion criteria were all veterans who were diagnosed with tetraplegia or paraplegia and received annual evaluation between October 1, 2015, and September 30, 2017. We chose this period because it was the beginning of a financial year at the JAHVH SCI department using the SCI registry. The SCI annual evaluation is a routine practitioner encounter with the veteran, along with appropriate laboratory testing and imaging to follow up potential chronic health issues specific to patients with SCI. Annual evaluations provide an opportunity to maintain routine health screening and preventive care. Patients who had significant portions of data missing or missing elements of primary outcomes were excluded from analysis. The study was reviewed and approved by the University of South Florida Institutional Review Board (VA IRBNet #1573370-4 on September 9, 2019).

Results

Of 1866 patients reviewed, 207 (11.1%) were excluded due to missing data, resulting in 1659 records that were analyzed. Mean age was 64 years, and male to female ratio was about 10 to 1. Most of the SCI or diseases were classified as incomplete (n = 1249) per ISNCSCI (absence of sensory and motor function in the lowest sacral segments) compared with 373 classified as complete.

Of the 1659 patients, 494 (29.8%) had a recorded allergy to antibiotics. The most frequently recorded were 217 penicillin (13.1%), 159 sulfa drugs (9.6%), 75 fluoroquinolone (4.5%), 66 cephalosporin (4.0%), and 44 vancomycin (2.7%) allergies.

Discussion

In this study, we evaluated the frequency and characteristics of antibiotic allergies at a single SCI center to better identify potential areas for quality improvement when recording drug allergies. A study in the general population used self-reported methods to collect such information found about a 15% prevalence of antibiotic allergy, which was lower than the 29.8% prevalence noted in our study.⁸

Regarding the most common antibiotic allergies, one study reported allergy to penicillin in the EHR in 12.8% of patients at a major US regional health care system, while 13.1% of patients with SCI had documented allergy to penicillin in our study.⁹ Regarding the other antibiotic classes, the percentage of allergies were higher than those reported in the general population: sulfonamide (9.6% vs 7.4%), fluoroquinolones (4.5% vs 1.3%), and cephalosporins (4.0% vs 1.7%).¹⁰ The EHR appears to capture a much higher rate of antibiotic allergies than that in self-reported studies, such as a study of self-reported allergy in the general adult population in Portugal, where only 4.5% of patients reported allergy to any β-lactam medications.¹⁰

The prevalence of an antibiotic allergy could be affected by the health care setting and sex distribution. For example, the Zhou and colleagues’ study conducted in the Greater Boston area showed higher reported antibiotic rates than those in a study from a Southern California medical group. The higher proportion of tertiary referral patients in that specific network was suggested to be the cause of the difference.^8,9 Our results in the SCI population are more comparable to that in a tertiary setting. This is consistent with the fact that persons with SCI generally have more exposure to antibiotics and consequently a higher reported rate of allergic reactions to antibiotics.

Similarly, the same study in Southern California noted that female patients use more antibiotics than do male patients, thus potentially contributing to higher rates of reported allergy toward all classes of antibiotics.⁸ Our study did not investigate antibiotic allergy by sex; however, the significantly higher proportion of male sex among the veteran population would have impacted these results.

Limitations

Our study was limited as a single-center retrospective study. However, our center is one of the major SCI specialty hubs, and the results should be somewhat reflective of those in the veterans with SCI population. Veterans under the US Department of Veterans Affairs (VA) medical care have the option to seek care or procedures in non-VA facilities. If allergies to antibiotics occurred outside of the VA system, there is no mechanism to automatically merge with the VA EHR allergy list, unless they are later recorded and added to the VA EHR. Thus, there is potential for underreporting.

Drug anaphylaxis incidence was noted to change over time.^4,8,9 For example, a downtrend of reported antibiotic allergy was reported between 1990 and 2013.¹⁰ Our study only reflects an overall prevalence of a single cohort, without demonstration of relationship to time.

Lastly, this study did not aim to differentiate HSRs from other ADRs. This is exactly the point of the study, which investigated the frequency of EHR-recorded antibiotic allergies in our SCI population and reflects the issue with indiscriminate recording of ADRs and HSRs under the umbrella of allergy in the EHR. Further diagnosing true allergies should be considered in the SCI population after weighing the risks and benefits of assessment, aligning with the wishes of the veteran, obtaining informed consent, and addressing the cost-effectiveness of specific tests. We suggest that primary care practitioners work closely with allergy specialists to formulate a mechanism to diagnose various antibiotic allergic reactions, including serum tryptase, epicutaneous skin testing, intradermal skin testing, patch testing, delayed intradermal testing, and drug challenge as appropriate. It is also possible that in cases where very mild reactions/adverse effects of antibiotics were recorded in the EHR, the clinicians and veterans may discuss reintroducing the same antibiotics or proceeding with further testing if necessary. In contrast, the 12% of those with a high risk of severe allergic reactions to penicillin in our study would benefit from allergist evaluation and access to epinephrine auto-injectors at all times. Differentiating true allergy is the only clear way to deter unnecessary avoidance of first-line therapies for antibiotic treatment and avoid promotion of antibiotic resistance.

Future studies can analyze antibiotic allergy based on demographics, including sex and age difference, as well as exploring outpatient vs inpatient settings. Aside from prevalence, we hope to demonstrate antibiotic allergy over time, especially after integration of diagnostic allergy testing, to evaluate the impact to EHR-recorded allergies.

Conclusions

Almost 30% of patients with SCI had a recorded allergy to at least 1 antibiotic. The most common allergy was to penicillin, which is similar to what has previously been reported for the general adult US population. However, only 12% of those with a penicillin allergy were considered high risk of true allergic reactions. Consequently, there are opportunities to examine whether approaches to confirm true reactions (such as skin testing) would help to mitigate unnecessary avoidance of certain antibiotic classes due to mild ADRs, rather than a true allergy, in persons with SCI. This would be an important effort to combat both individual safety concerns and the public health crisis of antibiotic resistance. Given the available evidence, it is reasonable for SCI health care practitioners to discuss the potential risks and benefits of allergy testing with patients with SCI; this maintains a patient-centered approach that can ensure judicious use of antibiotics when necessary.

Acknowledgments

This material is based on work supported (or supported in part) with resources and the use of facilities at the James A. Haley Veterans’ Hospital

Prostate Cancer

18F-DCFPyL PET/CT Impact on Treatment Strategies for Patients With Prostate Cancer (PROSPYL)

The main purpose of this phase II trial study is to determine whether a positron emission tomography (PET)/computed tomography (CT) scan using 18F-DCFPyL affects the clinical management plan in veterans. In this study, the management plan prior to and after 18F-DCFPyL PET/CT will be recorded by specific questionnaires and corresponding changes in management will be analyzed. The scan will be used to see how the disease has spread. Both the treatment strategies and probable disease outcomes as relevant to clinical endpoints will be assessed. This study is open to veterans only.

ID: NCT04390880

Sponsor: VA Greater Los Angeles Healthcare System

Location: VA Greater Los Angeles Healthcare System

Patient Decision-Making About Precision Oncology in Veterans With Advanced Prostate Cancer

This project proposes to understand and improve veterans’ decision-making in precision oncology (germline testing, somatic tumor testing, and targeted therapy) for advanced prostate cancer. As precision oncology expands, a comprehensive strategy to support patient informed decision-making has not been developed.

ID: NCT05396872

Sponsor; Collaborator: University of California, San Francisco; US Department of Defense

Location: San Francisco VA Medical Center

Intramuscular Mechanisms of Androgen Deprivation-Related Sarcopenia

Prostate cancer is the most common cancer among men and is even more common in the military and veteran population. For patients with advanced prostate cancer, the most common treatment includes lowering the levels of the hormone testosterone as much as possible, which is called androgen deprivation therapy (ADT). Unfortunately, ADT also causes patients to be fatigued, weak, and to lose muscle. This is often referred to as sarcopenia, and it leads to falls, poor quality of life, and higher risk of death. Currently, there is no treatment for sarcopenia because investigators do not understand the mechanisms that cause it. The mitochondria is the part of the cells responsible for providing energy to muscles but to date the investigators do not know if it is affected in prostate cancer patients with sarcopenia due to ADT. The overall goal of this proposal is to establish if the mitochondria is responsible for sarcopenia in patients with prostate cancer receiving ADT. The investigators will measure mitochondrial function, muscle mass and strength, and feelings of fatigue and quality of life in patients with prostate cancer before starting and after 6 months of ADT.

ID: NCT03867357

Sponsor; Collaborator: Seattle Institute for Biomedical and Clinical Research; US Department of Defense

Location: VA Puget Sound Health Care System

VA Seamless Phase II/III Randomized Trial of Standard Systemic Therapy With or Without PET-Directed Local Therapy for OligoRecurrent Prostate Cancer (VA STARPORT)

The primary goal of this study is to determine if adding PET-directed local therapy improves disease control compared to standard systemic therapy alone (SST) in veterans with oligorecurrent prostate cancer on PET/CT. The investigators will conduct a multi-institutional phase II/III randomized trial comparing SST with or without PET-directed local therapy using radiation or surgery to all metastases and if a local recurrence is present.

ID: NCT04787744

Sponsor: VA Office of Research and Development

Locations: VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Kansas City VA Medical Center, St. Louis VA Medical Center John Cochran Division, East Orange Campus of the VA New Jersey Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, Clement J. Zablocki VA Medical Center

Standard Systemic Therapy With or Without Definitive Treatment in Treating Participants With Metastatic Prostate Cancer

This phase III trial studies how well standard systemic therapy with or without definitive treatment (prostate removal surgery or radiation therapy) works in treating participants with prostate cancer that has spread to other places in the body. The addition of prostate removal surgery or radiation therapy to standard systemic therapy for prostate cancer may lower the chance of the cancer growing or spreading.

ID: NCT03678025

Sponsor; Collaborator: Southwest Oncology Group; National Cancer Institute (NCI)

Locations: 328 sites, including Tibor Rubin VA Medical Center, Atlanta VA Medical Center, James J. Peters VA Medical Center, Michael E. DeBakey VA Medical Center, and Audie L. Murphy VA Hospital

A Clinical Study Evaluating the Benefit of Adding Rucaparib to Enzalutamide for Men With Metastatic Prostate Cancer That Has Become Resistant to Testosterone-Deprivation Therapy (CASPAR)

This randomized, placebo-controlled, phase III trial is evaluating the benefit of rucaparib and enzalutamide combination therapy vs enzalutamide alone for the treatment of men with prostate cancer that has spread to other places in the body (metastatic) and has become resistant to testosterone-deprivation therapy (castration-resistant). Enzalutamide helps fight prostate cancer by blocking the use of testosterone by the tumor cells for growth. Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as rucaparib, fight prostate cancer by prevent tumor cells from repairing their DNA. Giving enzalutamide and rucaparib may make patients live longer or prevent their cancer from growing or spreading for a longer time, or both. It may also help doctors learn if a mutation in any of the homologous recombination DNA repair genes is helpful to decide which treatment is best for the patient.

ID: NCT04455750

Sponsor; Collaborator: Alliance for Clinical Trials in Oncology; National Cancer Institute (NCI)

Locations: 413 sites

Digitally Captured Activity Data and PROs to Monitor Physical Function in Prostate Cancer Patients (DigiPRO)

Physical function is a known predictor of quality of life in advanced prostate cancer patients and key measure of treatment tolerability. While treatment with androgen deprivation therapy (ADT) improves survival, it is associated with significant toxicities that lead to physical function (PF) decline. The average age of incident prostate cancer is 66 years, and in this older group of men, chronic comorbid conditions often co-occur with diagnosis, further adding to the risk for PF decline. With over 2.9 million prostate cancer survivors in the US, there is an increasing demand for adequate symptom monitoring and PF assessment throughout cancer care. However, there are currently no validated methods to systematically evaluate and predict PF decline. Thus, the overarching objective of this proposal is to determine whether the use of wearable technology to monitor objective daily activity combined with routine symptom reporting can predict PF decline. To accomplish this, we propose a mixed-methods approach that will provide quantitative information to help identify PC survivors at higher risk for PF decline as well as a qualitative aim gain a deeper understanding of the perceived relationships that PC survivors have with their physical activity levels and treatment symptoms.

ID: NCT04575402

Sponsor; Collaborator: Cedars-Sinai Medical Center; US Department of Defense

Location: Cedars Sinai Medical Center

The BurnAlong Pilot Study for Adolescent and Young Adult Cancer Survivors

The purpose of this prospective, interventional, single-arm pilot study is to evaluate whether virtually delivered group-based physical activity is feasible for adolescent and young adult (AYA) cancer survivors. AYAs who were diagnosed with cancer and have completed cancer treatment will be recruited for this study. This study will enroll 20 participants in total and will last approximately 3 months.

ID: NCT05131815

Sponsor; Collaborator: Cedars-Sinai Medical Center; Walter Reed National Military Medical Center

Location: Cedars-Sinai Medical Center

Lung Cancer

DECAMP 1 PLUS: Prediction of Lung Cancer Using Noninvasive Biomarkers

The Detection of Early lung Cancer Among Military Personnel (DECAMP) consortium is a multidisciplinary and translational research program for lung cancer early detection. DECAMP 1 PLUS aims to improve the efficiency of the diagnostic evaluation of patients with indeterminate pulmonary nodules (8-25 mm). Molecular biomarkers for lung cancer diagnosis measured in minimally invasive and noninvasive biospecimens may be able to distinguish between malignant or benign indeterminate pulmonary nodules in high-risk smokers. Ultimately, this study aims to validate molecular as well as clinical and imaging biomarkers of lung cancer in individuals with indeterminate lung nodules.

ID: NCT04165564

Sponsor: Boston University

Locations: 3 VA medical centers (VA Greater LA Healthcare System, VA Boston Healthcare System, and VA Tennessee Valley Healthcare System), 3 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, and Naval Medical Center Portsmouth) and 12 academic hospitals

DECAMP-2: Screening of Patients With Early Stage Lung Cancer or at High Risk for Developing Lung Cancer (DECAMP-2)

The goal of this project is to improve lung cancer screening in high-risk individuals by identifying biomarkers of preclinical disease and disease risk that are measured in minimally invasive and noninvasive biospecimens. Existing biomarkers for lung cancer diagnosis as well as new biomarkers discovered specifically in this clinical setting will be examined. Biomarkers that identify individuals at highest risk for being diagnosed with lung cancer prior to the appearance of concerning symptoms could increase the utility of lung cancer surveillance and the efficiency of lung cancer chemoprevention clinical trials. Achieving these goals would improve the detection and treatment of early-stage and incipient lung cancer, while restricting the risk of these procedures to those individuals who currently exhibit the early molecular warning signs of impending disease.

ID: NCT02504697

Sponsor: Boston University

Locations: VA medical centers (including Los Angeles VA Healthcare System, Boston VA Research Institute, Inc, Philadelphia VA Medical Center, Veterans Research Foundation of Pittsburgh, and VA North Texas Health Care System), 4 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, San Antonio Military Medical Center, and Naval Medical Center Portsmouth), and 4 academic hospitals

Improving Decision-Making Encounters in Lung Cancer Using a Low-Literacy Conversation Tool (iDECIDE)

This clinical trial evaluates the effectiveness of a conversation tool on patient-centered health and decision-making outcomes in patients with lung cancer making treatment decisions. This research is being conducted to help doctors understand the information patients need to participate in shared decision-making about their lung cancer treatment options. The focus of this research is to study how patients choose lung cancer treatment options and the information needed to make that choice, with a focus on patients with lower health literacy.

ID: NCT05407168

Sponsor: Oregon Health & Science University Knight Cancer Institute

Locations: Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute

VA Lung Cancer Surgery or Stereotactic Radiotherapy (VALOR)

The standard of care for stage I non–small cell lung cancer has historically been surgical resection in patients who are medically fit to tolerate an operation. Recent data now suggest that stereotactic radiotherapy may be a suitable alternative. This includes the results from a pooled analysis of 2 incomplete phase III studies that reported a 15% overall survival advantage with stereotactic radiotherapy at 3 years. While these data are promising, the median follow-up period was short, the results underpowered, and the findings were in contradiction to multiple retrospective studies that demonstrate the outcomes with surgery are likely equal or superior. Therefore, the herein trial aims to evaluate these 2 treatments in a prospective randomized fashion with a goal to compare the overall survival beyond 5 years. It has been designed to enroll patients who have a long life expectancy and are fit enough to tolerate an anatomic pulmonary resection with intraoperative lymph node sampling.

This study is designed to open at VA medical centers with expertise in both treatments. The recruitment process includes shared decision making and multidisciplinary evaluations with lung cancer specialists. Mandatory evaluations before randomization include tissue confirmation of NSCLC, staging with FDG-PET/CT, and biopsies of all hilar and/or mediastinal lymph nodes > 10 mm that have a SUV > 2.5. Prerandomization elective lymph node sampling is strongly encouraged, but not required. Following treatment, patients will be followed for a minimum of 5 years.

ID: NCT02984761

Sponsor: VA Office of Research and Development

Locations: 17 VA medical centers, including VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Miami VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, Baltimore VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Corporal Micheal J. Crescenz VA Medical Center, VA Pittsburgh Healthcare System University Drive Division, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, and Clement J. Zablocki VA Medical Center

Utility of CAML as Diagnostic for Early Stage Lung Cancer

The primary objective of this study is to determine the prevalence of cancer associated macrophage-like cells (CAMLS) in patients with pulmonary nodules. Secondary objectives include the following: determine the positive and negative predictive value of CAMLS in patients with pulmonary nodules who undergo biopsy; model combinations of clinical factors with the presence/absence of CAMLS to refine strategies for assessment of patients with pulmonary nodules; and evaluate whether these measures result in enhanced T-cell activity and/or natural killer cell function and number.

ID: NCT03992183

Sponsor; Collaborators: Fox Chase Cancer Center; US Department of Defense

Locations: Corporal Michael J. Crescenz VA Medical Center and Fox Chase Cancer Center

PROSPECT - Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

This study will use therapeutic target-focused (TTF) profiling, genome-wide mRNA profiling, and assessments of tumor phosphopeptides and DNA that are shed into the bloodstream to define how various molecular factors alone and in combination relate to resistance to therapy, to prognosis, and to metastatic patterns at relapse. This study will examine how the presence of factors that drive cell growth, antagonize apoptosis, or confer resistance in other ways may counter the effect of systemic therapies and/or promote rapid tumor recurrence. In this way, the investigators will identify new, previously unappreciated potential therapeutic targets while also identifying which targets are most likely to increase resistance to therapy and worsen prognosis.

ID: NCT05049837

Sponsor; Collaborators: MD Anderson Cancer Center; US Department of Defense, National Institutes of Health (NIH), and National Cancer Institute (NCI)

Location: MD Anderson Cancer Center

Tribally Engaged Approaches to Lung Screening (TEALS)

Lung cancer is the leading cause of cancer mortality among American Indians and Alaska Natives (AI/AN), and AI/AN have worse lung cancer incidence rates, survival, and death compared to the general population. Because lung cancer screening (LCS) with low-dose computed tomography (LDCT) has been shown to reduce lung cancer mortality by roughly 20%, the US Preventive Services Task Force now recommends LCS for persons aged 55 to 80 years who meet specific eligibility criteria (grade-B evidence), and subsequently the Center for Medicare and Medicaid Services (CMS) opted to cover this test. However, the uptake of LCS implementation has been slow in most health care systems, and LCS implementation among AI/AN has never been studied.

To address this knowledge, the Tribally Engaged Approaches to Lung Screening (TEALS) study, a collaborative effort between the Choctaw Nation of Oklahoma, the Stephenson Cancer Center, and the University of Oklahoma Health Sciences Center, will address the following over the course of 5 years: conduct focus groups and semistructured interviews with Choctaw Nation Health Services Authority (CNHSA) patients, clinicians, and health administrators to elucidate individual- and system-level barriers and facilitators that affect the implementation of LCS; develop an LCS care coordination intervention that will identify eligible persons for LCS, help these patients navigate the screening process, and link them with smoking cessation services, when applicable; measure the impact of the TEALS intervention on the receipt of screening and a set of patient- and practice-level outcomes by conducting a cluster-randomized clinical trial of LCS implementation; and disseminate the TEALS program to other researchers and healthcare systems that serve AI/AN patients. TEALS will bridge the gap between evidence and clinical practice for LCS in a high-need, low-resource setting by intervening at the level of the healthcare system.

System-level interventions for guideline implementation tend to be understudied compared to those evaluating individual-level, behavioral interventions. However, the careful development and evaluation of an LCS screening program at the level of the healthcare system would be critical to ensure that more patients can receive LCS. Our research will create a critically needed platform from which future studies could be launched that will examine how to tailor the application of the LCS guideline to the individual preferences of AI/AN patients. TEALS will establish an effective LCS program in a tribal system and thus provide a direct benefit to the Choctaw Nation by increasing LCS participation. TEALS will serve as a blueprint for establishing a sustainable and accessible infrastructure for LCS in AI/AN and other community health systems. By increasing screening for early stage lung cancer, TEALS could ultimately reduce lung cancer mortality in AI/AN communities.

ID: NCT04948060

Sponsor; Collaborator: University of Oklahoma; Choctaw Nation of Oklahoma

Location: University of Oklahoma Health Sciences Center

Prostate Cancer

18F-DCFPyL PET/CT Impact on Treatment Strategies for Patients With Prostate Cancer (PROSPYL)

The main purpose of this phase II trial study is to determine whether a positron emission tomography (PET)/computed tomography (CT) scan using 18F-DCFPyL affects the clinical management plan in veterans. In this study, the management plan prior to and after 18F-DCFPyL PET/CT will be recorded by specific questionnaires and corresponding changes in management will be analyzed. The scan will be used to see how the disease has spread. Both the treatment strategies and probable disease outcomes as relevant to clinical endpoints will be assessed. This study is open to veterans only.

ID: NCT04390880

Sponsor: VA Greater Los Angeles Healthcare System

Location: VA Greater Los Angeles Healthcare System

Patient Decision-Making About Precision Oncology in Veterans With Advanced Prostate Cancer

This project proposes to understand and improve veterans’ decision-making in precision oncology (germline testing, somatic tumor testing, and targeted therapy) for advanced prostate cancer. As precision oncology expands, a comprehensive strategy to support patient informed decision-making has not been developed.

ID: NCT05396872

Sponsor; Collaborator: University of California, San Francisco; US Department of Defense

Location: San Francisco VA Medical Center

Intramuscular Mechanisms of Androgen Deprivation-Related Sarcopenia

Prostate cancer is the most common cancer among men and is even more common in the military and veteran population. For patients with advanced prostate cancer, the most common treatment includes lowering the levels of the hormone testosterone as much as possible, which is called androgen deprivation therapy (ADT). Unfortunately, ADT also causes patients to be fatigued, weak, and to lose muscle. This is often referred to as sarcopenia, and it leads to falls, poor quality of life, and higher risk of death. Currently, there is no treatment for sarcopenia because investigators do not understand the mechanisms that cause it. The mitochondria is the part of the cells responsible for providing energy to muscles but to date the investigators do not know if it is affected in prostate cancer patients with sarcopenia due to ADT. The overall goal of this proposal is to establish if the mitochondria is responsible for sarcopenia in patients with prostate cancer receiving ADT. The investigators will measure mitochondrial function, muscle mass and strength, and feelings of fatigue and quality of life in patients with prostate cancer before starting and after 6 months of ADT.

ID: NCT03867357

Sponsor; Collaborator: Seattle Institute for Biomedical and Clinical Research; US Department of Defense

Location: VA Puget Sound Health Care System

VA Seamless Phase II/III Randomized Trial of Standard Systemic Therapy With or Without PET-Directed Local Therapy for OligoRecurrent Prostate Cancer (VA STARPORT)

The primary goal of this study is to determine if adding PET-directed local therapy improves disease control compared to standard systemic therapy alone (SST) in veterans with oligorecurrent prostate cancer on PET/CT. The investigators will conduct a multi-institutional phase II/III randomized trial comparing SST with or without PET-directed local therapy using radiation or surgery to all metastases and if a local recurrence is present.

ID: NCT04787744

Sponsor: VA Office of Research and Development

Locations: VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Kansas City VA Medical Center, St. Louis VA Medical Center John Cochran Division, East Orange Campus of the VA New Jersey Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, Clement J. Zablocki VA Medical Center

Standard Systemic Therapy With or Without Definitive Treatment in Treating Participants With Metastatic Prostate Cancer

This phase III trial studies how well standard systemic therapy with or without definitive treatment (prostate removal surgery or radiation therapy) works in treating participants with prostate cancer that has spread to other places in the body. The addition of prostate removal surgery or radiation therapy to standard systemic therapy for prostate cancer may lower the chance of the cancer growing or spreading.

ID: NCT03678025

Sponsor; Collaborator: Southwest Oncology Group; National Cancer Institute (NCI)

Locations: 328 sites, including Tibor Rubin VA Medical Center, Atlanta VA Medical Center, James J. Peters VA Medical Center, Michael E. DeBakey VA Medical Center, and Audie L. Murphy VA Hospital

A Clinical Study Evaluating the Benefit of Adding Rucaparib to Enzalutamide for Men With Metastatic Prostate Cancer That Has Become Resistant to Testosterone-Deprivation Therapy (CASPAR)

This randomized, placebo-controlled, phase III trial is evaluating the benefit of rucaparib and enzalutamide combination therapy vs enzalutamide alone for the treatment of men with prostate cancer that has spread to other places in the body (metastatic) and has become resistant to testosterone-deprivation therapy (castration-resistant). Enzalutamide helps fight prostate cancer by blocking the use of testosterone by the tumor cells for growth. Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as rucaparib, fight prostate cancer by prevent tumor cells from repairing their DNA. Giving enzalutamide and rucaparib may make patients live longer or prevent their cancer from growing or spreading for a longer time, or both. It may also help doctors learn if a mutation in any of the homologous recombination DNA repair genes is helpful to decide which treatment is best for the patient.

ID: NCT04455750

Sponsor; Collaborator: Alliance for Clinical Trials in Oncology; National Cancer Institute (NCI)

Locations: 413 sites

Digitally Captured Activity Data and PROs to Monitor Physical Function in Prostate Cancer Patients (DigiPRO)

Physical function is a known predictor of quality of life in advanced prostate cancer patients and key measure of treatment tolerability. While treatment with androgen deprivation therapy (ADT) improves survival, it is associated with significant toxicities that lead to physical function (PF) decline. The average age of incident prostate cancer is 66 years, and in this older group of men, chronic comorbid conditions often co-occur with diagnosis, further adding to the risk for PF decline. With over 2.9 million prostate cancer survivors in the US, there is an increasing demand for adequate symptom monitoring and PF assessment throughout cancer care. However, there are currently no validated methods to systematically evaluate and predict PF decline. Thus, the overarching objective of this proposal is to determine whether the use of wearable technology to monitor objective daily activity combined with routine symptom reporting can predict PF decline. To accomplish this, we propose a mixed-methods approach that will provide quantitative information to help identify PC survivors at higher risk for PF decline as well as a qualitative aim gain a deeper understanding of the perceived relationships that PC survivors have with their physical activity levels and treatment symptoms.

ID: NCT04575402

Sponsor; Collaborator: Cedars-Sinai Medical Center; US Department of Defense

Location: Cedars Sinai Medical Center

The BurnAlong Pilot Study for Adolescent and Young Adult Cancer Survivors

The purpose of this prospective, interventional, single-arm pilot study is to evaluate whether virtually delivered group-based physical activity is feasible for adolescent and young adult (AYA) cancer survivors. AYAs who were diagnosed with cancer and have completed cancer treatment will be recruited for this study. This study will enroll 20 participants in total and will last approximately 3 months.

ID: NCT05131815

Sponsor; Collaborator: Cedars-Sinai Medical Center; Walter Reed National Military Medical Center

Location: Cedars-Sinai Medical Center

Lung Cancer

DECAMP 1 PLUS: Prediction of Lung Cancer Using Noninvasive Biomarkers

The Detection of Early lung Cancer Among Military Personnel (DECAMP) consortium is a multidisciplinary and translational research program for lung cancer early detection. DECAMP 1 PLUS aims to improve the efficiency of the diagnostic evaluation of patients with indeterminate pulmonary nodules (8-25 mm). Molecular biomarkers for lung cancer diagnosis measured in minimally invasive and noninvasive biospecimens may be able to distinguish between malignant or benign indeterminate pulmonary nodules in high-risk smokers. Ultimately, this study aims to validate molecular as well as clinical and imaging biomarkers of lung cancer in individuals with indeterminate lung nodules.

ID: NCT04165564

Sponsor: Boston University

Locations: 3 VA medical centers (VA Greater LA Healthcare System, VA Boston Healthcare System, and VA Tennessee Valley Healthcare System), 3 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, and Naval Medical Center Portsmouth) and 12 academic hospitals

DECAMP-2: Screening of Patients With Early Stage Lung Cancer or at High Risk for Developing Lung Cancer (DECAMP-2)

The goal of this project is to improve lung cancer screening in high-risk individuals by identifying biomarkers of preclinical disease and disease risk that are measured in minimally invasive and noninvasive biospecimens. Existing biomarkers for lung cancer diagnosis as well as new biomarkers discovered specifically in this clinical setting will be examined. Biomarkers that identify individuals at highest risk for being diagnosed with lung cancer prior to the appearance of concerning symptoms could increase the utility of lung cancer surveillance and the efficiency of lung cancer chemoprevention clinical trials. Achieving these goals would improve the detection and treatment of early-stage and incipient lung cancer, while restricting the risk of these procedures to those individuals who currently exhibit the early molecular warning signs of impending disease.

ID: NCT02504697

Sponsor: Boston University

Locations: VA medical centers (including Los Angeles VA Healthcare System, Boston VA Research Institute, Inc, Philadelphia VA Medical Center, Veterans Research Foundation of Pittsburgh, and VA North Texas Health Care System), 4 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, San Antonio Military Medical Center, and Naval Medical Center Portsmouth), and 4 academic hospitals

Improving Decision-Making Encounters in Lung Cancer Using a Low-Literacy Conversation Tool (iDECIDE)

This clinical trial evaluates the effectiveness of a conversation tool on patient-centered health and decision-making outcomes in patients with lung cancer making treatment decisions. This research is being conducted to help doctors understand the information patients need to participate in shared decision-making about their lung cancer treatment options. The focus of this research is to study how patients choose lung cancer treatment options and the information needed to make that choice, with a focus on patients with lower health literacy.

ID: NCT05407168

Sponsor: Oregon Health & Science University Knight Cancer Institute

Locations: Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute

VA Lung Cancer Surgery or Stereotactic Radiotherapy (VALOR)

The standard of care for stage I non–small cell lung cancer has historically been surgical resection in patients who are medically fit to tolerate an operation. Recent data now suggest that stereotactic radiotherapy may be a suitable alternative. This includes the results from a pooled analysis of 2 incomplete phase III studies that reported a 15% overall survival advantage with stereotactic radiotherapy at 3 years. While these data are promising, the median follow-up period was short, the results underpowered, and the findings were in contradiction to multiple retrospective studies that demonstrate the outcomes with surgery are likely equal or superior. Therefore, the herein trial aims to evaluate these 2 treatments in a prospective randomized fashion with a goal to compare the overall survival beyond 5 years. It has been designed to enroll patients who have a long life expectancy and are fit enough to tolerate an anatomic pulmonary resection with intraoperative lymph node sampling.

This study is designed to open at VA medical centers with expertise in both treatments. The recruitment process includes shared decision making and multidisciplinary evaluations with lung cancer specialists. Mandatory evaluations before randomization include tissue confirmation of NSCLC, staging with FDG-PET/CT, and biopsies of all hilar and/or mediastinal lymph nodes > 10 mm that have a SUV > 2.5. Prerandomization elective lymph node sampling is strongly encouraged, but not required. Following treatment, patients will be followed for a minimum of 5 years.

ID: NCT02984761

Sponsor: VA Office of Research and Development

Locations: 17 VA medical centers, including VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Miami VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, Baltimore VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Corporal Micheal J. Crescenz VA Medical Center, VA Pittsburgh Healthcare System University Drive Division, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, and Clement J. Zablocki VA Medical Center

Utility of CAML as Diagnostic for Early Stage Lung Cancer

The primary objective of this study is to determine the prevalence of cancer associated macrophage-like cells (CAMLS) in patients with pulmonary nodules. Secondary objectives include the following: determine the positive and negative predictive value of CAMLS in patients with pulmonary nodules who undergo biopsy; model combinations of clinical factors with the presence/absence of CAMLS to refine strategies for assessment of patients with pulmonary nodules; and evaluate whether these measures result in enhanced T-cell activity and/or natural killer cell function and number.

ID: NCT03992183

Sponsor; Collaborators: Fox Chase Cancer Center; US Department of Defense

Locations: Corporal Michael J. Crescenz VA Medical Center and Fox Chase Cancer Center

PROSPECT - Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

This study will use therapeutic target-focused (TTF) profiling, genome-wide mRNA profiling, and assessments of tumor phosphopeptides and DNA that are shed into the bloodstream to define how various molecular factors alone and in combination relate to resistance to therapy, to prognosis, and to metastatic patterns at relapse. This study will examine how the presence of factors that drive cell growth, antagonize apoptosis, or confer resistance in other ways may counter the effect of systemic therapies and/or promote rapid tumor recurrence. In this way, the investigators will identify new, previously unappreciated potential therapeutic targets while also identifying which targets are most likely to increase resistance to therapy and worsen prognosis.

ID: NCT05049837

Sponsor; Collaborators: MD Anderson Cancer Center; US Department of Defense, National Institutes of Health (NIH), and National Cancer Institute (NCI)

Location: MD Anderson Cancer Center

Tribally Engaged Approaches to Lung Screening (TEALS)

Lung cancer is the leading cause of cancer mortality among American Indians and Alaska Natives (AI/AN), and AI/AN have worse lung cancer incidence rates, survival, and death compared to the general population. Because lung cancer screening (LCS) with low-dose computed tomography (LDCT) has been shown to reduce lung cancer mortality by roughly 20%, the US Preventive Services Task Force now recommends LCS for persons aged 55 to 80 years who meet specific eligibility criteria (grade-B evidence), and subsequently the Center for Medicare and Medicaid Services (CMS) opted to cover this test. However, the uptake of LCS implementation has been slow in most health care systems, and LCS implementation among AI/AN has never been studied.

To address this knowledge, the Tribally Engaged Approaches to Lung Screening (TEALS) study, a collaborative effort between the Choctaw Nation of Oklahoma, the Stephenson Cancer Center, and the University of Oklahoma Health Sciences Center, will address the following over the course of 5 years: conduct focus groups and semistructured interviews with Choctaw Nation Health Services Authority (CNHSA) patients, clinicians, and health administrators to elucidate individual- and system-level barriers and facilitators that affect the implementation of LCS; develop an LCS care coordination intervention that will identify eligible persons for LCS, help these patients navigate the screening process, and link them with smoking cessation services, when applicable; measure the impact of the TEALS intervention on the receipt of screening and a set of patient- and practice-level outcomes by conducting a cluster-randomized clinical trial of LCS implementation; and disseminate the TEALS program to other researchers and healthcare systems that serve AI/AN patients. TEALS will bridge the gap between evidence and clinical practice for LCS in a high-need, low-resource setting by intervening at the level of the healthcare system.

System-level interventions for guideline implementation tend to be understudied compared to those evaluating individual-level, behavioral interventions. However, the careful development and evaluation of an LCS screening program at the level of the healthcare system would be critical to ensure that more patients can receive LCS. Our research will create a critically needed platform from which future studies could be launched that will examine how to tailor the application of the LCS guideline to the individual preferences of AI/AN patients. TEALS will establish an effective LCS program in a tribal system and thus provide a direct benefit to the Choctaw Nation by increasing LCS participation. TEALS will serve as a blueprint for establishing a sustainable and accessible infrastructure for LCS in AI/AN and other community health systems. By increasing screening for early stage lung cancer, TEALS could ultimately reduce lung cancer mortality in AI/AN communities.

ID: NCT04948060

Sponsor; Collaborator: University of Oklahoma; Choctaw Nation of Oklahoma

Location: University of Oklahoma Health Sciences Center

Prostate Cancer

18F-DCFPyL PET/CT Impact on Treatment Strategies for Patients With Prostate Cancer (PROSPYL)

The main purpose of this phase II trial study is to determine whether a positron emission tomography (PET)/computed tomography (CT) scan using 18F-DCFPyL affects the clinical management plan in veterans. In this study, the management plan prior to and after 18F-DCFPyL PET/CT will be recorded by specific questionnaires and corresponding changes in management will be analyzed. The scan will be used to see how the disease has spread. Both the treatment strategies and probable disease outcomes as relevant to clinical endpoints will be assessed. This study is open to veterans only.

ID: NCT04390880

Sponsor: VA Greater Los Angeles Healthcare System

Location: VA Greater Los Angeles Healthcare System

Patient Decision-Making About Precision Oncology in Veterans With Advanced Prostate Cancer

This project proposes to understand and improve veterans’ decision-making in precision oncology (germline testing, somatic tumor testing, and targeted therapy) for advanced prostate cancer. As precision oncology expands, a comprehensive strategy to support patient informed decision-making has not been developed.

ID: NCT05396872

Sponsor; Collaborator: University of California, San Francisco; US Department of Defense

Location: San Francisco VA Medical Center

Intramuscular Mechanisms of Androgen Deprivation-Related Sarcopenia

Prostate cancer is the most common cancer among men and is even more common in the military and veteran population. For patients with advanced prostate cancer, the most common treatment includes lowering the levels of the hormone testosterone as much as possible, which is called androgen deprivation therapy (ADT). Unfortunately, ADT also causes patients to be fatigued, weak, and to lose muscle. This is often referred to as sarcopenia, and it leads to falls, poor quality of life, and higher risk of death. Currently, there is no treatment for sarcopenia because investigators do not understand the mechanisms that cause it. The mitochondria is the part of the cells responsible for providing energy to muscles but to date the investigators do not know if it is affected in prostate cancer patients with sarcopenia due to ADT. The overall goal of this proposal is to establish if the mitochondria is responsible for sarcopenia in patients with prostate cancer receiving ADT. The investigators will measure mitochondrial function, muscle mass and strength, and feelings of fatigue and quality of life in patients with prostate cancer before starting and after 6 months of ADT.

ID: NCT03867357

Sponsor; Collaborator: Seattle Institute for Biomedical and Clinical Research; US Department of Defense

Location: VA Puget Sound Health Care System

VA Seamless Phase II/III Randomized Trial of Standard Systemic Therapy With or Without PET-Directed Local Therapy for OligoRecurrent Prostate Cancer (VA STARPORT)

The primary goal of this study is to determine if adding PET-directed local therapy improves disease control compared to standard systemic therapy alone (SST) in veterans with oligorecurrent prostate cancer on PET/CT. The investigators will conduct a multi-institutional phase II/III randomized trial comparing SST with or without PET-directed local therapy using radiation or surgery to all metastases and if a local recurrence is present.

ID: NCT04787744

Sponsor: VA Office of Research and Development

Locations: VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Kansas City VA Medical Center, St. Louis VA Medical Center John Cochran Division, East Orange Campus of the VA New Jersey Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, Clement J. Zablocki VA Medical Center

Standard Systemic Therapy With or Without Definitive Treatment in Treating Participants With Metastatic Prostate Cancer

This phase III trial studies how well standard systemic therapy with or without definitive treatment (prostate removal surgery or radiation therapy) works in treating participants with prostate cancer that has spread to other places in the body. The addition of prostate removal surgery or radiation therapy to standard systemic therapy for prostate cancer may lower the chance of the cancer growing or spreading.

ID: NCT03678025

Sponsor; Collaborator: Southwest Oncology Group; National Cancer Institute (NCI)

Locations: 328 sites, including Tibor Rubin VA Medical Center, Atlanta VA Medical Center, James J. Peters VA Medical Center, Michael E. DeBakey VA Medical Center, and Audie L. Murphy VA Hospital

A Clinical Study Evaluating the Benefit of Adding Rucaparib to Enzalutamide for Men With Metastatic Prostate Cancer That Has Become Resistant to Testosterone-Deprivation Therapy (CASPAR)

This randomized, placebo-controlled, phase III trial is evaluating the benefit of rucaparib and enzalutamide combination therapy vs enzalutamide alone for the treatment of men with prostate cancer that has spread to other places in the body (metastatic) and has become resistant to testosterone-deprivation therapy (castration-resistant). Enzalutamide helps fight prostate cancer by blocking the use of testosterone by the tumor cells for growth. Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as rucaparib, fight prostate cancer by prevent tumor cells from repairing their DNA. Giving enzalutamide and rucaparib may make patients live longer or prevent their cancer from growing or spreading for a longer time, or both. It may also help doctors learn if a mutation in any of the homologous recombination DNA repair genes is helpful to decide which treatment is best for the patient.

ID: NCT04455750

Sponsor; Collaborator: Alliance for Clinical Trials in Oncology; National Cancer Institute (NCI)

Locations: 413 sites

Digitally Captured Activity Data and PROs to Monitor Physical Function in Prostate Cancer Patients (DigiPRO)

Physical function is a known predictor of quality of life in advanced prostate cancer patients and key measure of treatment tolerability. While treatment with androgen deprivation therapy (ADT) improves survival, it is associated with significant toxicities that lead to physical function (PF) decline. The average age of incident prostate cancer is 66 years, and in this older group of men, chronic comorbid conditions often co-occur with diagnosis, further adding to the risk for PF decline. With over 2.9 million prostate cancer survivors in the US, there is an increasing demand for adequate symptom monitoring and PF assessment throughout cancer care. However, there are currently no validated methods to systematically evaluate and predict PF decline. Thus, the overarching objective of this proposal is to determine whether the use of wearable technology to monitor objective daily activity combined with routine symptom reporting can predict PF decline. To accomplish this, we propose a mixed-methods approach that will provide quantitative information to help identify PC survivors at higher risk for PF decline as well as a qualitative aim gain a deeper understanding of the perceived relationships that PC survivors have with their physical activity levels and treatment symptoms.

ID: NCT04575402

Sponsor; Collaborator: Cedars-Sinai Medical Center; US Department of Defense

Location: Cedars Sinai Medical Center

The BurnAlong Pilot Study for Adolescent and Young Adult Cancer Survivors

The purpose of this prospective, interventional, single-arm pilot study is to evaluate whether virtually delivered group-based physical activity is feasible for adolescent and young adult (AYA) cancer survivors. AYAs who were diagnosed with cancer and have completed cancer treatment will be recruited for this study. This study will enroll 20 participants in total and will last approximately 3 months.

ID: NCT05131815

Sponsor; Collaborator: Cedars-Sinai Medical Center; Walter Reed National Military Medical Center

Location: Cedars-Sinai Medical Center

Lung Cancer

DECAMP 1 PLUS: Prediction of Lung Cancer Using Noninvasive Biomarkers

The Detection of Early lung Cancer Among Military Personnel (DECAMP) consortium is a multidisciplinary and translational research program for lung cancer early detection. DECAMP 1 PLUS aims to improve the efficiency of the diagnostic evaluation of patients with indeterminate pulmonary nodules (8-25 mm). Molecular biomarkers for lung cancer diagnosis measured in minimally invasive and noninvasive biospecimens may be able to distinguish between malignant or benign indeterminate pulmonary nodules in high-risk smokers. Ultimately, this study aims to validate molecular as well as clinical and imaging biomarkers of lung cancer in individuals with indeterminate lung nodules.

ID: NCT04165564

Sponsor: Boston University

Locations: 3 VA medical centers (VA Greater LA Healthcare System, VA Boston Healthcare System, and VA Tennessee Valley Healthcare System), 3 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, and Naval Medical Center Portsmouth) and 12 academic hospitals

DECAMP-2: Screening of Patients With Early Stage Lung Cancer or at High Risk for Developing Lung Cancer (DECAMP-2)

The goal of this project is to improve lung cancer screening in high-risk individuals by identifying biomarkers of preclinical disease and disease risk that are measured in minimally invasive and noninvasive biospecimens. Existing biomarkers for lung cancer diagnosis as well as new biomarkers discovered specifically in this clinical setting will be examined. Biomarkers that identify individuals at highest risk for being diagnosed with lung cancer prior to the appearance of concerning symptoms could increase the utility of lung cancer surveillance and the efficiency of lung cancer chemoprevention clinical trials. Achieving these goals would improve the detection and treatment of early-stage and incipient lung cancer, while restricting the risk of these procedures to those individuals who currently exhibit the early molecular warning signs of impending disease.

ID: NCT02504697

Sponsor: Boston University

Locations: VA medical centers (including Los Angeles VA Healthcare System, Boston VA Research Institute, Inc, Philadelphia VA Medical Center, Veterans Research Foundation of Pittsburgh, and VA North Texas Health Care System), 4 military treatment facilities (Naval Medical Center San Diego, Walter Reed National Military Medical Center, San Antonio Military Medical Center, and Naval Medical Center Portsmouth), and 4 academic hospitals

Improving Decision-Making Encounters in Lung Cancer Using a Low-Literacy Conversation Tool (iDECIDE)

This clinical trial evaluates the effectiveness of a conversation tool on patient-centered health and decision-making outcomes in patients with lung cancer making treatment decisions. This research is being conducted to help doctors understand the information patients need to participate in shared decision-making about their lung cancer treatment options. The focus of this research is to study how patients choose lung cancer treatment options and the information needed to make that choice, with a focus on patients with lower health literacy.

ID: NCT05407168

Sponsor: Oregon Health & Science University Knight Cancer Institute

Locations: Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute

VA Lung Cancer Surgery or Stereotactic Radiotherapy (VALOR)

The standard of care for stage I non–small cell lung cancer has historically been surgical resection in patients who are medically fit to tolerate an operation. Recent data now suggest that stereotactic radiotherapy may be a suitable alternative. This includes the results from a pooled analysis of 2 incomplete phase III studies that reported a 15% overall survival advantage with stereotactic radiotherapy at 3 years. While these data are promising, the median follow-up period was short, the results underpowered, and the findings were in contradiction to multiple retrospective studies that demonstrate the outcomes with surgery are likely equal or superior. Therefore, the herein trial aims to evaluate these 2 treatments in a prospective randomized fashion with a goal to compare the overall survival beyond 5 years. It has been designed to enroll patients who have a long life expectancy and are fit enough to tolerate an anatomic pulmonary resection with intraoperative lymph node sampling.

This study is designed to open at VA medical centers with expertise in both treatments. The recruitment process includes shared decision making and multidisciplinary evaluations with lung cancer specialists. Mandatory evaluations before randomization include tissue confirmation of NSCLC, staging with FDG-PET/CT, and biopsies of all hilar and/or mediastinal lymph nodes > 10 mm that have a SUV > 2.5. Prerandomization elective lymph node sampling is strongly encouraged, but not required. Following treatment, patients will be followed for a minimum of 5 years.

ID: NCT02984761

Sponsor: VA Office of Research and Development

Locations: 17 VA medical centers, including VA Long Beach Healthcare System, VA Greater Los Angeles Healthcare System, Bay Pines VA Healthcare System, Miami VA Healthcare System, Edward Hines Jr. VA Hospital, Richard L. Roudebush VA Medical Center, Baltimore VA Medical Center, VA Boston Healthcare System Jamaica Plain Campus, VA Ann Arbor Healthcare System, Minneapolis VA Health Care System, Durham VA Medical Center, Louis Stokes VA Medical Center, Corporal Micheal J. Crescenz VA Medical Center, VA Pittsburgh Healthcare System University Drive Division, Michael E. DeBakey VA Medical Center, Hunter Holmes McGuire VA Medical Center, and Clement J. Zablocki VA Medical Center

Utility of CAML as Diagnostic for Early Stage Lung Cancer

The primary objective of this study is to determine the prevalence of cancer associated macrophage-like cells (CAMLS) in patients with pulmonary nodules. Secondary objectives include the following: determine the positive and negative predictive value of CAMLS in patients with pulmonary nodules who undergo biopsy; model combinations of clinical factors with the presence/absence of CAMLS to refine strategies for assessment of patients with pulmonary nodules; and evaluate whether these measures result in enhanced T-cell activity and/or natural killer cell function and number.

ID: NCT03992183

Sponsor; Collaborators: Fox Chase Cancer Center; US Department of Defense

Locations: Corporal Michael J. Crescenz VA Medical Center and Fox Chase Cancer Center

PROSPECT - Profiling of Resistance Patterns & Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax and Therapeutic Target Identification

This study will use therapeutic target-focused (TTF) profiling, genome-wide mRNA profiling, and assessments of tumor phosphopeptides and DNA that are shed into the bloodstream to define how various molecular factors alone and in combination relate to resistance to therapy, to prognosis, and to metastatic patterns at relapse. This study will examine how the presence of factors that drive cell growth, antagonize apoptosis, or confer resistance in other ways may counter the effect of systemic therapies and/or promote rapid tumor recurrence. In this way, the investigators will identify new, previously unappreciated potential therapeutic targets while also identifying which targets are most likely to increase resistance to therapy and worsen prognosis.

ID: NCT05049837

Sponsor; Collaborators: MD Anderson Cancer Center; US Department of Defense, National Institutes of Health (NIH), and National Cancer Institute (NCI)

Location: MD Anderson Cancer Center

Tribally Engaged Approaches to Lung Screening (TEALS)

Lung cancer is the leading cause of cancer mortality among American Indians and Alaska Natives (AI/AN), and AI/AN have worse lung cancer incidence rates, survival, and death compared to the general population. Because lung cancer screening (LCS) with low-dose computed tomography (LDCT) has been shown to reduce lung cancer mortality by roughly 20%, the US Preventive Services Task Force now recommends LCS for persons aged 55 to 80 years who meet specific eligibility criteria (grade-B evidence), and subsequently the Center for Medicare and Medicaid Services (CMS) opted to cover this test. However, the uptake of LCS implementation has been slow in most health care systems, and LCS implementation among AI/AN has never been studied.

To address this knowledge, the Tribally Engaged Approaches to Lung Screening (TEALS) study, a collaborative effort between the Choctaw Nation of Oklahoma, the Stephenson Cancer Center, and the University of Oklahoma Health Sciences Center, will address the following over the course of 5 years: conduct focus groups and semistructured interviews with Choctaw Nation Health Services Authority (CNHSA) patients, clinicians, and health administrators to elucidate individual- and system-level barriers and facilitators that affect the implementation of LCS; develop an LCS care coordination intervention that will identify eligible persons for LCS, help these patients navigate the screening process, and link them with smoking cessation services, when applicable; measure the impact of the TEALS intervention on the receipt of screening and a set of patient- and practice-level outcomes by conducting a cluster-randomized clinical trial of LCS implementation; and disseminate the TEALS program to other researchers and healthcare systems that serve AI/AN patients. TEALS will bridge the gap between evidence and clinical practice for LCS in a high-need, low-resource setting by intervening at the level of the healthcare system.

System-level interventions for guideline implementation tend to be understudied compared to those evaluating individual-level, behavioral interventions. However, the careful development and evaluation of an LCS screening program at the level of the healthcare system would be critical to ensure that more patients can receive LCS. Our research will create a critically needed platform from which future studies could be launched that will examine how to tailor the application of the LCS guideline to the individual preferences of AI/AN patients. TEALS will establish an effective LCS program in a tribal system and thus provide a direct benefit to the Choctaw Nation by increasing LCS participation. TEALS will serve as a blueprint for establishing a sustainable and accessible infrastructure for LCS in AI/AN and other community health systems. By increasing screening for early stage lung cancer, TEALS could ultimately reduce lung cancer mortality in AI/AN communities.

ID: NCT04948060

Sponsor; Collaborator: University of Oklahoma; Choctaw Nation of Oklahoma

Location: University of Oklahoma Health Sciences Center

Since 1983, the correlation between head and neck squamous cell carcinoma (SCC) and human papillomavirus (HPV) has been of great interest to head and neck oncologists.¹ In 1998, Smith and colleagues provided evidence of HPV as an independent risk factor for the development of head and neck SCC.² HPV-associated head and neck SCC accounts for between 30% and 64% of oropharyngeal SCC, depending on the published study; tonsil primaries account for the majority of these cancers.^3,4

The presence of HPV E6 and E7 oncoproteins leads to the inactivation of p53 and pRb tumor suppressors. Furthermore, Ragin and colleagues discussed a distinct molecular pathway specific to HPV-associated head and neck SCC, which was different from non–HPV-associated head and neck SCC, involving genetic mutations in CDKN2A/p16.⁵

Current methods in correlating the presence of HPV infection in head and neck SCC have centered on p16^INK4a (p16) immunohistochemistry (IHC) staining and DNA in situ hybridization (ISH) for specific HPV DNA types. IHC staining for p16 involves a monoclonal antibody specific to p16. The usefulness of this test relies on p16 overexpression due to the inactivation of pRb by the HPV E7 oncoprotein. This test is readily performed on archived tissue and has a documented sensitivity and specificity of 100% and 79%, respectively, as reported by Singhi and Westra in 2010.⁶ HPV DNA fluorescence in situ hybridization is the gold standard for determining the presence of specific types of HPV DNA; however, p16IHC can serve as a rapid, less costly means of studying archived tissue, lending its utility to retrospective population-based studies.

METHODS

A retrospective study was designed to determine the proportion of HPV-associated oropharyngeal SCC in a US Department of Veterans Affairs (VA) population, using p16antigen IHC on paraffin-embedded tissue as the surrogate marker for the presence of HPV infection. Patients consisted of veterans who were treated for oropharyngeal SCC at Veterans Affairs Memphis Healthcare System (VAMHS) in Tennessee between January 1, 2000, and December 31, 2008. This data range allowed for at least 5 years of follow-up. Patients were excluded who lacked enough tissue specimens for analysis. Measurement outcomes included p16expression, with subset analysis by race and ethnicity, degree of tobacco and alcohol use, tumor location, stage, age at diagnosis, and survival outcome. Microsoft Excel was used to calculate Fisher exact test, Student t test, and χ² statistics. Significance was set at P < .05. This study received institutional review board approval from the University of Tennessee Health Science Center and the VAMHS.

RESULTS

We identified 66 total cases of oropharyngeal SCC; 19 cases (29%) were positive for p16. The mean age at diagnosis for the p16-positive cohort was 59 years vs 61 years for the p16-negative cohort (P = .22; Table 1).

Although the tonsil was the most common site of tumor origin in both the p16-positive and negative cohorts (63% vs 51%, respectively), our analysis showed no statistically significant difference in sites of origin (P = .69) (Table 2).

DISCUSSION

The VAMHS population in our study had a lower proportion of HPV-associated oropharyngeal SCC compared with studies on nonveteran populations (29% vs 40%-80%, respectively).^5,6 This disparity may indicate a true difference in these populations or may be related to a decreased prevalence of HPV infection in the population served by the VAMHS. This single-institution population did not completely correlate with previous population studies. Specifically, age at presentation (equivalent to patients with p16-negative status rather than earlier age at onset), disease stage at presentation (lower stage for patients with p16-positive status), and disease-specific survival (not improved compared with patients with p16-negative status in other studies) were dissimilar to previous investigations.^2,3

The increased age and staging at presentation could be related in these patients with p16-positive status, which may further account for the lack of improved survival. Furthermore, both groups tended to use alcohol at a high proportion; whereas other populations have had a lesser degree of alcohol intake with p16 positivity.^1-4 These differences may be due to variations in the habits and behavior of VA patients compared with non-VA patients.^3,4

HPV-associated oropharyngeal SCC in published data has been associated with high-risk sexual behavior, lower age, and less tobacco and alcohol use.^5,6 No difference was noted in tumor site predilection; however, the small size of our study could explain the lack of finding site preference shown in previous studies.^2,3Other veteran-specific factors are absent in the at-large population, such as Agent Orange exposure. More than 8 million veterans (22%) from the Vietnam era self-reported Agent Orange exposure.⁷ Agent Orange exposure significantly predicted developing upper aerodigestive tract cancer. Oropharyngeal, nasopharyngeal, laryngeal, and thyroid cancers were significantly associated with Agent Orange exposure. Interestingly, these patients experienced an improved 10-year survival rate compared with patients not exposed to Agent Orange. This finding contrasts with our patients, who did not experience improved outcomes vs nonveteran patients with head and neck cancer.⁷

Suicide in veterans with head and neck cancer has been evaluated and was found at an incidence of 0.7%. Survivors of head and neck cancer are almost twice as likely to die by suicide compared with other cancer survivors. These patients have a higher rate of mental health disorders, substance misuse, and use of palliative care services.⁸ Sixty-five of 66 of our patients died during the 5-year observation period, although none died by suicide.

In a 2022 cohort study by Sun and colleagues, upfront surgical treatment was associated with a 23% reduced risk of stroke compared with definitive chemoradiotherapy in US veterans with oropharyngeal carcinoma.⁹ In our study, 58 of 66 patients (88%) received concurrent chemoradiation, possibly reflecting the more advanced stage of diagnosis in our study population. This was due to comorbidities and other health and economic factors. In our study, 43 patients (65%) died of factors not related to the disease, reflecting the overall comorbidity burden of this population. Seven patients (11%) in our 5-year study died of a documented stroke. In the study of veterans by Sun and colleagues, the 10-year cumulative incidence of stroke was 12.5% and death was 57.3%.⁹ Our veteran population experienced a similar incidence of strokes. These findings may need to be included when discussing the risk-benefit aspects of different treatment options with our veteran patients with oropharyngeal cancer.

To understand the influence of HPV infection on the course of oropharyngeal SCC in the VA patient population and to apply this understanding to future individualized treatment paradigms, this study can be expanded to a greater number of VA patients. p16 immunoexpression appears to be a useful surrogate for high-risk HPV infection in oropharyngeal SCC, and its ease of use supports its feasibility in further VA population analysis.¹⁰ While realizing that the veteran HPV-associated oropharyngeal SCC population differs from the civilian HPV-associated oropharyngeal SCC population, we also have realized that other unique considerations in the veteran population, such as chemical warfare exposure, mental illness, and vascular disease, complicate treatment decisions in these patients.

CONCLUSIONS

Disparities in racial distribution and tobacco use between patients with p16-positive and p16-negative status are similar to those reported in non-VA populations. In contrast, the frequently reported younger age at presentation and better disease outcomes seen in non-VA patients were not observed, perhaps due to the lower percentage of p16expression in VA patients with oropharyngeal SCC. Whereas de-intensification of therapy may be considered for many patients with oropharygeal cancer that is HPV-associated because of improved prognosis, this approach should be undertaken with great care in this group of patients. Personalization of therapy for these HPV-associated oropharyngeal SCC in the veteran population must be adapted to mitigate this critical disparity.

Since 1983, the correlation between head and neck squamous cell carcinoma (SCC) and human papillomavirus (HPV) has been of great interest to head and neck oncologists.¹ In 1998, Smith and colleagues provided evidence of HPV as an independent risk factor for the development of head and neck SCC.² HPV-associated head and neck SCC accounts for between 30% and 64% of oropharyngeal SCC, depending on the published study; tonsil primaries account for the majority of these cancers.^3,4

The presence of HPV E6 and E7 oncoproteins leads to the inactivation of p53 and pRb tumor suppressors. Furthermore, Ragin and colleagues discussed a distinct molecular pathway specific to HPV-associated head and neck SCC, which was different from non–HPV-associated head and neck SCC, involving genetic mutations in CDKN2A/p16.⁵

Current methods in correlating the presence of HPV infection in head and neck SCC have centered on p16^INK4a (p16) immunohistochemistry (IHC) staining and DNA in situ hybridization (ISH) for specific HPV DNA types. IHC staining for p16 involves a monoclonal antibody specific to p16. The usefulness of this test relies on p16 overexpression due to the inactivation of pRb by the HPV E7 oncoprotein. This test is readily performed on archived tissue and has a documented sensitivity and specificity of 100% and 79%, respectively, as reported by Singhi and Westra in 2010.⁶ HPV DNA fluorescence in situ hybridization is the gold standard for determining the presence of specific types of HPV DNA; however, p16IHC can serve as a rapid, less costly means of studying archived tissue, lending its utility to retrospective population-based studies.

METHODS

A retrospective study was designed to determine the proportion of HPV-associated oropharyngeal SCC in a US Department of Veterans Affairs (VA) population, using p16antigen IHC on paraffin-embedded tissue as the surrogate marker for the presence of HPV infection. Patients consisted of veterans who were treated for oropharyngeal SCC at Veterans Affairs Memphis Healthcare System (VAMHS) in Tennessee between January 1, 2000, and December 31, 2008. This data range allowed for at least 5 years of follow-up. Patients were excluded who lacked enough tissue specimens for analysis. Measurement outcomes included p16expression, with subset analysis by race and ethnicity, degree of tobacco and alcohol use, tumor location, stage, age at diagnosis, and survival outcome. Microsoft Excel was used to calculate Fisher exact test, Student t test, and χ² statistics. Significance was set at P < .05. This study received institutional review board approval from the University of Tennessee Health Science Center and the VAMHS.

RESULTS

We identified 66 total cases of oropharyngeal SCC; 19 cases (29%) were positive for p16. The mean age at diagnosis for the p16-positive cohort was 59 years vs 61 years for the p16-negative cohort (P = .22; Table 1).

Although the tonsil was the most common site of tumor origin in both the p16-positive and negative cohorts (63% vs 51%, respectively), our analysis showed no statistically significant difference in sites of origin (P = .69) (Table 2).

DISCUSSION

The VAMHS population in our study had a lower proportion of HPV-associated oropharyngeal SCC compared with studies on nonveteran populations (29% vs 40%-80%, respectively).^5,6 This disparity may indicate a true difference in these populations or may be related to a decreased prevalence of HPV infection in the population served by the VAMHS. This single-institution population did not completely correlate with previous population studies. Specifically, age at presentation (equivalent to patients with p16-negative status rather than earlier age at onset), disease stage at presentation (lower stage for patients with p16-positive status), and disease-specific survival (not improved compared with patients with p16-negative status in other studies) were dissimilar to previous investigations.^2,3

The increased age and staging at presentation could be related in these patients with p16-positive status, which may further account for the lack of improved survival. Furthermore, both groups tended to use alcohol at a high proportion; whereas other populations have had a lesser degree of alcohol intake with p16 positivity.^1-4 These differences may be due to variations in the habits and behavior of VA patients compared with non-VA patients.^3,4

HPV-associated oropharyngeal SCC in published data has been associated with high-risk sexual behavior, lower age, and less tobacco and alcohol use.^5,6 No difference was noted in tumor site predilection; however, the small size of our study could explain the lack of finding site preference shown in previous studies.^2,3Other veteran-specific factors are absent in the at-large population, such as Agent Orange exposure. More than 8 million veterans (22%) from the Vietnam era self-reported Agent Orange exposure.⁷ Agent Orange exposure significantly predicted developing upper aerodigestive tract cancer. Oropharyngeal, nasopharyngeal, laryngeal, and thyroid cancers were significantly associated with Agent Orange exposure. Interestingly, these patients experienced an improved 10-year survival rate compared with patients not exposed to Agent Orange. This finding contrasts with our patients, who did not experience improved outcomes vs nonveteran patients with head and neck cancer.⁷

Suicide in veterans with head and neck cancer has been evaluated and was found at an incidence of 0.7%. Survivors of head and neck cancer are almost twice as likely to die by suicide compared with other cancer survivors. These patients have a higher rate of mental health disorders, substance misuse, and use of palliative care services.⁸ Sixty-five of 66 of our patients died during the 5-year observation period, although none died by suicide.

In a 2022 cohort study by Sun and colleagues, upfront surgical treatment was associated with a 23% reduced risk of stroke compared with definitive chemoradiotherapy in US veterans with oropharyngeal carcinoma.⁹ In our study, 58 of 66 patients (88%) received concurrent chemoradiation, possibly reflecting the more advanced stage of diagnosis in our study population. This was due to comorbidities and other health and economic factors. In our study, 43 patients (65%) died of factors not related to the disease, reflecting the overall comorbidity burden of this population. Seven patients (11%) in our 5-year study died of a documented stroke. In the study of veterans by Sun and colleagues, the 10-year cumulative incidence of stroke was 12.5% and death was 57.3%.⁹ Our veteran population experienced a similar incidence of strokes. These findings may need to be included when discussing the risk-benefit aspects of different treatment options with our veteran patients with oropharyngeal cancer.

To understand the influence of HPV infection on the course of oropharyngeal SCC in the VA patient population and to apply this understanding to future individualized treatment paradigms, this study can be expanded to a greater number of VA patients. p16 immunoexpression appears to be a useful surrogate for high-risk HPV infection in oropharyngeal SCC, and its ease of use supports its feasibility in further VA population analysis.¹⁰ While realizing that the veteran HPV-associated oropharyngeal SCC population differs from the civilian HPV-associated oropharyngeal SCC population, we also have realized that other unique considerations in the veteran population, such as chemical warfare exposure, mental illness, and vascular disease, complicate treatment decisions in these patients.

CONCLUSIONS

Disparities in racial distribution and tobacco use between patients with p16-positive and p16-negative status are similar to those reported in non-VA populations. In contrast, the frequently reported younger age at presentation and better disease outcomes seen in non-VA patients were not observed, perhaps due to the lower percentage of p16expression in VA patients with oropharyngeal SCC. Whereas de-intensification of therapy may be considered for many patients with oropharygeal cancer that is HPV-associated because of improved prognosis, this approach should be undertaken with great care in this group of patients. Personalization of therapy for these HPV-associated oropharyngeal SCC in the veteran population must be adapted to mitigate this critical disparity.

Since 1983, the correlation between head and neck squamous cell carcinoma (SCC) and human papillomavirus (HPV) has been of great interest to head and neck oncologists.¹ In 1998, Smith and colleagues provided evidence of HPV as an independent risk factor for the development of head and neck SCC.² HPV-associated head and neck SCC accounts for between 30% and 64% of oropharyngeal SCC, depending on the published study; tonsil primaries account for the majority of these cancers.^3,4

The presence of HPV E6 and E7 oncoproteins leads to the inactivation of p53 and pRb tumor suppressors. Furthermore, Ragin and colleagues discussed a distinct molecular pathway specific to HPV-associated head and neck SCC, which was different from non–HPV-associated head and neck SCC, involving genetic mutations in CDKN2A/p16.⁵

Current methods in correlating the presence of HPV infection in head and neck SCC have centered on p16^INK4a (p16) immunohistochemistry (IHC) staining and DNA in situ hybridization (ISH) for specific HPV DNA types. IHC staining for p16 involves a monoclonal antibody specific to p16. The usefulness of this test relies on p16 overexpression due to the inactivation of pRb by the HPV E7 oncoprotein. This test is readily performed on archived tissue and has a documented sensitivity and specificity of 100% and 79%, respectively, as reported by Singhi and Westra in 2010.⁶ HPV DNA fluorescence in situ hybridization is the gold standard for determining the presence of specific types of HPV DNA; however, p16IHC can serve as a rapid, less costly means of studying archived tissue, lending its utility to retrospective population-based studies.

METHODS

A retrospective study was designed to determine the proportion of HPV-associated oropharyngeal SCC in a US Department of Veterans Affairs (VA) population, using p16antigen IHC on paraffin-embedded tissue as the surrogate marker for the presence of HPV infection. Patients consisted of veterans who were treated for oropharyngeal SCC at Veterans Affairs Memphis Healthcare System (VAMHS) in Tennessee between January 1, 2000, and December 31, 2008. This data range allowed for at least 5 years of follow-up. Patients were excluded who lacked enough tissue specimens for analysis. Measurement outcomes included p16expression, with subset analysis by race and ethnicity, degree of tobacco and alcohol use, tumor location, stage, age at diagnosis, and survival outcome. Microsoft Excel was used to calculate Fisher exact test, Student t test, and χ² statistics. Significance was set at P < .05. This study received institutional review board approval from the University of Tennessee Health Science Center and the VAMHS.

RESULTS

We identified 66 total cases of oropharyngeal SCC; 19 cases (29%) were positive for p16. The mean age at diagnosis for the p16-positive cohort was 59 years vs 61 years for the p16-negative cohort (P = .22; Table 1).

Although the tonsil was the most common site of tumor origin in both the p16-positive and negative cohorts (63% vs 51%, respectively), our analysis showed no statistically significant difference in sites of origin (P = .69) (Table 2).

DISCUSSION

The VAMHS population in our study had a lower proportion of HPV-associated oropharyngeal SCC compared with studies on nonveteran populations (29% vs 40%-80%, respectively).^5,6 This disparity may indicate a true difference in these populations or may be related to a decreased prevalence of HPV infection in the population served by the VAMHS. This single-institution population did not completely correlate with previous population studies. Specifically, age at presentation (equivalent to patients with p16-negative status rather than earlier age at onset), disease stage at presentation (lower stage for patients with p16-positive status), and disease-specific survival (not improved compared with patients with p16-negative status in other studies) were dissimilar to previous investigations.^2,3

The increased age and staging at presentation could be related in these patients with p16-positive status, which may further account for the lack of improved survival. Furthermore, both groups tended to use alcohol at a high proportion; whereas other populations have had a lesser degree of alcohol intake with p16 positivity.^1-4 These differences may be due to variations in the habits and behavior of VA patients compared with non-VA patients.^3,4

HPV-associated oropharyngeal SCC in published data has been associated with high-risk sexual behavior, lower age, and less tobacco and alcohol use.^5,6 No difference was noted in tumor site predilection; however, the small size of our study could explain the lack of finding site preference shown in previous studies.^2,3Other veteran-specific factors are absent in the at-large population, such as Agent Orange exposure. More than 8 million veterans (22%) from the Vietnam era self-reported Agent Orange exposure.⁷ Agent Orange exposure significantly predicted developing upper aerodigestive tract cancer. Oropharyngeal, nasopharyngeal, laryngeal, and thyroid cancers were significantly associated with Agent Orange exposure. Interestingly, these patients experienced an improved 10-year survival rate compared with patients not exposed to Agent Orange. This finding contrasts with our patients, who did not experience improved outcomes vs nonveteran patients with head and neck cancer.⁷

Suicide in veterans with head and neck cancer has been evaluated and was found at an incidence of 0.7%. Survivors of head and neck cancer are almost twice as likely to die by suicide compared with other cancer survivors. These patients have a higher rate of mental health disorders, substance misuse, and use of palliative care services.⁸ Sixty-five of 66 of our patients died during the 5-year observation period, although none died by suicide.

In a 2022 cohort study by Sun and colleagues, upfront surgical treatment was associated with a 23% reduced risk of stroke compared with definitive chemoradiotherapy in US veterans with oropharyngeal carcinoma.⁹ In our study, 58 of 66 patients (88%) received concurrent chemoradiation, possibly reflecting the more advanced stage of diagnosis in our study population. This was due to comorbidities and other health and economic factors. In our study, 43 patients (65%) died of factors not related to the disease, reflecting the overall comorbidity burden of this population. Seven patients (11%) in our 5-year study died of a documented stroke. In the study of veterans by Sun and colleagues, the 10-year cumulative incidence of stroke was 12.5% and death was 57.3%.⁹ Our veteran population experienced a similar incidence of strokes. These findings may need to be included when discussing the risk-benefit aspects of different treatment options with our veteran patients with oropharyngeal cancer.

To understand the influence of HPV infection on the course of oropharyngeal SCC in the VA patient population and to apply this understanding to future individualized treatment paradigms, this study can be expanded to a greater number of VA patients. p16 immunoexpression appears to be a useful surrogate for high-risk HPV infection in oropharyngeal SCC, and its ease of use supports its feasibility in further VA population analysis.¹⁰ While realizing that the veteran HPV-associated oropharyngeal SCC population differs from the civilian HPV-associated oropharyngeal SCC population, we also have realized that other unique considerations in the veteran population, such as chemical warfare exposure, mental illness, and vascular disease, complicate treatment decisions in these patients.

CONCLUSIONS

Disparities in racial distribution and tobacco use between patients with p16-positive and p16-negative status are similar to those reported in non-VA populations. In contrast, the frequently reported younger age at presentation and better disease outcomes seen in non-VA patients were not observed, perhaps due to the lower percentage of p16expression in VA patients with oropharyngeal SCC. Whereas de-intensification of therapy may be considered for many patients with oropharygeal cancer that is HPV-associated because of improved prognosis, this approach should be undertaken with great care in this group of patients. Personalization of therapy for these HPV-associated oropharyngeal SCC in the veteran population must be adapted to mitigate this critical disparity.