There’s been a push in recent years encouraging doctors to prescribe exercise as medicine, telling their patients how often, how long, and how hard to work out to improve health.

A new study out of Brigham Young University, Provo, Utah, suggests doctors could take that initiative to the next level, prescribing exercise plans that result in a specific health outcome; say, lowering your blood pressure or losing weight. 

“The findings of this study, and others, suggest that we should be able to more consistently and accurately prescribe exercise like medicine,” says senior study author Jayson Gifford, PhD, an exercise sciences professor at BYU. 

These exercise prescriptions would be tailored to patients based on a largely ignored fitness measure called critical power, or maximum steady state – the fastest you can go while maintaining a pace you can sustain for a long time. 

By crafting workouts around critical power instead of the more frequently used VO2 max (maximum effort), we could more accurately predict health outcomes, just as we can with medicine, the researchers wrote in the Journal of Applied Physiology.

“We’ve known for centuries that exercise is part of the way to develop a healthy and long life,” says Jordan Metzl, MD, a sports medicine doctor at the Hospital for Special Surgery in New York and author of The Exercise Cure. “But it’s only in the past 70 years that we’ve recognized the medicinal value of exercise.”

Dr. Metzl, who was not involved in the study, helped develop an annual seminar at Cornell Medical School teaching medical students ways to prescribe exercise that go beyond the “30 minutes per day” cookie-cutter advice. Still, doctors and other health care professionals often struggle to prescribe exercise to prevent or treat disease. And a recent study from Oxford found that when doctors do give weight loss advice, it’s often vague and hard for patients to use. 

“The drug of movement is one of the safest and most effective forms of preventive health,” says Dr. Metzl. “We need to get the medical community fully engaged in prescribing exercise for their patients.” 

This study suggests that a focus on critical power could be key in making that happen. 
 

What the research found

In the study, 22 adults completed 8 weeks of either moderate-intensity training or high-intensity interval training (HIIT).  The intensity levels specified in both plans were based on VO2 max. So, the people in the study trained at given percentages of their VO2 max.

Both groups saw improvements in endurance, but results varied greatly from person to person. Those mixed results could be explained by individual differences in critical power. 

“Improvement was much more correlated with the percentage of critical powers the individuals worked at rather than the percentage of their VO2max, like exercise physiologists have thought for years,” says lead study author Jessica Collins, a researcher at Brigham Young University. 

Not only that but several subjects who did not improve their VO2 max did see an increase in critical power and endurance. 

“People tend to only focus on VO2 max,” Dr. Gifford says. “Many might see the lack of increase in VO2 max for some people and conclude that the training was ineffective. I personally believe that a lot of potentially useful therapies have been ruled out because of an almost exclusive focus on VO2 max.”

Turns out, critical power varies a lot from person to person, even among those with similar VO2 maxes.

“Let’s say you and Jessica had the same VO2 max,” explains Dr. Gifford. “If we had you both going at 70% of [your VO2 max], it could be above your maximum steady state, which would make it really hard for you. And it could be below her maximum steady state, which would make it easy for her.” 

This means you are each stressing your body differently, and that stress is what triggers improvements in fitness and endurance. 

“Below critical power, the metabolic stressors are well-managed and maintained at elevated-but-steady levels,” Dr. Gifford says. “Above critical power, the metabolic stressors are produced so fast that they cannot be controlled, and consistently accrue until reaching very high levels that cause failure.” 

Knowing your critical power means you can predict how those stressors will build up, and you can tailor an exercise program that provides just the right stressor “dose” for you, Dr. Gifford says. 

Such programs could be used for rehab patients recovering from a heart attack or from lung disease, Dr. Gifford suggests. Or they could help older adults improve endurance and physical function, Ms. Collins notes. 

But first, researchers must confirm these results by programming workouts based on people’s critical power and seeing how much different measures improve.
 

How to find your critical power

Critical power is not new, but exercise physiologists and medical professionals have largely ignored it because it’s not easy to measure. 

“People generally train off VO2 max or maximum heart rate, which is even less precise,” Dr. Gifford says. 

Finding people’s critical power in the study involved multiple timed trials and calculating the relationship between speed/power and time, Dr. Gifford explains. 

But for a rough measure of your critical power, you could use an app that measures functional threshold power (FTP), something Dr. Gifford refers to as the “Walmart version” of critical power. “It’s not exactly the same, but it’s close,” he says. (The app Strava features FTP as well as a pretty sophisticated power analysis.) 

Or skip the tech and go by feel. If you’re below your critical power, “it’s going to be challenging, but you’ll feel under control,” Dr. Gifford says. Above your critical power, “your breathing and heart rate will continuously climb until you fail in about 2 to 15 minutes, depending on how far above you are.” Still, you don’t need to know your critical power to start exercising, Ms. Collins notes. 

“The beauty of exercise is that it is such a powerful drug that you can see benefits without fine-tuning the workout this way,” Dr. Gifford explains. “I would hate for this to become a barrier to exercising. The important thing is to do something.”

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

There’s been a push in recent years encouraging doctors to prescribe exercise as medicine, telling their patients how often, how long, and how hard to work out to improve health.

A new study out of Brigham Young University, Provo, Utah, suggests doctors could take that initiative to the next level, prescribing exercise plans that result in a specific health outcome; say, lowering your blood pressure or losing weight. 

“The findings of this study, and others, suggest that we should be able to more consistently and accurately prescribe exercise like medicine,” says senior study author Jayson Gifford, PhD, an exercise sciences professor at BYU. 

These exercise prescriptions would be tailored to patients based on a largely ignored fitness measure called critical power, or maximum steady state – the fastest you can go while maintaining a pace you can sustain for a long time. 

By crafting workouts around critical power instead of the more frequently used VO2 max (maximum effort), we could more accurately predict health outcomes, just as we can with medicine, the researchers wrote in the Journal of Applied Physiology.

“We’ve known for centuries that exercise is part of the way to develop a healthy and long life,” says Jordan Metzl, MD, a sports medicine doctor at the Hospital for Special Surgery in New York and author of The Exercise Cure. “But it’s only in the past 70 years that we’ve recognized the medicinal value of exercise.”

Dr. Metzl, who was not involved in the study, helped develop an annual seminar at Cornell Medical School teaching medical students ways to prescribe exercise that go beyond the “30 minutes per day” cookie-cutter advice. Still, doctors and other health care professionals often struggle to prescribe exercise to prevent or treat disease. And a recent study from Oxford found that when doctors do give weight loss advice, it’s often vague and hard for patients to use. 

“The drug of movement is one of the safest and most effective forms of preventive health,” says Dr. Metzl. “We need to get the medical community fully engaged in prescribing exercise for their patients.” 

This study suggests that a focus on critical power could be key in making that happen. 
 

What the research found

In the study, 22 adults completed 8 weeks of either moderate-intensity training or high-intensity interval training (HIIT).  The intensity levels specified in both plans were based on VO2 max. So, the people in the study trained at given percentages of their VO2 max.

Both groups saw improvements in endurance, but results varied greatly from person to person. Those mixed results could be explained by individual differences in critical power. 

“Improvement was much more correlated with the percentage of critical powers the individuals worked at rather than the percentage of their VO2max, like exercise physiologists have thought for years,” says lead study author Jessica Collins, a researcher at Brigham Young University. 

Not only that but several subjects who did not improve their VO2 max did see an increase in critical power and endurance. 

“People tend to only focus on VO2 max,” Dr. Gifford says. “Many might see the lack of increase in VO2 max for some people and conclude that the training was ineffective. I personally believe that a lot of potentially useful therapies have been ruled out because of an almost exclusive focus on VO2 max.”

Turns out, critical power varies a lot from person to person, even among those with similar VO2 maxes.

“Let’s say you and Jessica had the same VO2 max,” explains Dr. Gifford. “If we had you both going at 70% of [your VO2 max], it could be above your maximum steady state, which would make it really hard for you. And it could be below her maximum steady state, which would make it easy for her.” 

This means you are each stressing your body differently, and that stress is what triggers improvements in fitness and endurance. 

“Below critical power, the metabolic stressors are well-managed and maintained at elevated-but-steady levels,” Dr. Gifford says. “Above critical power, the metabolic stressors are produced so fast that they cannot be controlled, and consistently accrue until reaching very high levels that cause failure.” 

Knowing your critical power means you can predict how those stressors will build up, and you can tailor an exercise program that provides just the right stressor “dose” for you, Dr. Gifford says. 

Such programs could be used for rehab patients recovering from a heart attack or from lung disease, Dr. Gifford suggests. Or they could help older adults improve endurance and physical function, Ms. Collins notes. 

But first, researchers must confirm these results by programming workouts based on people’s critical power and seeing how much different measures improve.
 

How to find your critical power

Critical power is not new, but exercise physiologists and medical professionals have largely ignored it because it’s not easy to measure. 

“People generally train off VO2 max or maximum heart rate, which is even less precise,” Dr. Gifford says. 

Finding people’s critical power in the study involved multiple timed trials and calculating the relationship between speed/power and time, Dr. Gifford explains. 

But for a rough measure of your critical power, you could use an app that measures functional threshold power (FTP), something Dr. Gifford refers to as the “Walmart version” of critical power. “It’s not exactly the same, but it’s close,” he says. (The app Strava features FTP as well as a pretty sophisticated power analysis.) 

Or skip the tech and go by feel. If you’re below your critical power, “it’s going to be challenging, but you’ll feel under control,” Dr. Gifford says. Above your critical power, “your breathing and heart rate will continuously climb until you fail in about 2 to 15 minutes, depending on how far above you are.” Still, you don’t need to know your critical power to start exercising, Ms. Collins notes. 

“The beauty of exercise is that it is such a powerful drug that you can see benefits without fine-tuning the workout this way,” Dr. Gifford explains. “I would hate for this to become a barrier to exercising. The important thing is to do something.”

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

There’s been a push in recent years encouraging doctors to prescribe exercise as medicine, telling their patients how often, how long, and how hard to work out to improve health.

A new study out of Brigham Young University, Provo, Utah, suggests doctors could take that initiative to the next level, prescribing exercise plans that result in a specific health outcome; say, lowering your blood pressure or losing weight. 

“The findings of this study, and others, suggest that we should be able to more consistently and accurately prescribe exercise like medicine,” says senior study author Jayson Gifford, PhD, an exercise sciences professor at BYU. 

These exercise prescriptions would be tailored to patients based on a largely ignored fitness measure called critical power, or maximum steady state – the fastest you can go while maintaining a pace you can sustain for a long time. 

By crafting workouts around critical power instead of the more frequently used VO2 max (maximum effort), we could more accurately predict health outcomes, just as we can with medicine, the researchers wrote in the Journal of Applied Physiology.

“We’ve known for centuries that exercise is part of the way to develop a healthy and long life,” says Jordan Metzl, MD, a sports medicine doctor at the Hospital for Special Surgery in New York and author of The Exercise Cure. “But it’s only in the past 70 years that we’ve recognized the medicinal value of exercise.”

Dr. Metzl, who was not involved in the study, helped develop an annual seminar at Cornell Medical School teaching medical students ways to prescribe exercise that go beyond the “30 minutes per day” cookie-cutter advice. Still, doctors and other health care professionals often struggle to prescribe exercise to prevent or treat disease. And a recent study from Oxford found that when doctors do give weight loss advice, it’s often vague and hard for patients to use. 

“The drug of movement is one of the safest and most effective forms of preventive health,” says Dr. Metzl. “We need to get the medical community fully engaged in prescribing exercise for their patients.” 

This study suggests that a focus on critical power could be key in making that happen. 
 

What the research found

In the study, 22 adults completed 8 weeks of either moderate-intensity training or high-intensity interval training (HIIT).  The intensity levels specified in both plans were based on VO2 max. So, the people in the study trained at given percentages of their VO2 max.

Both groups saw improvements in endurance, but results varied greatly from person to person. Those mixed results could be explained by individual differences in critical power. 

“Improvement was much more correlated with the percentage of critical powers the individuals worked at rather than the percentage of their VO2max, like exercise physiologists have thought for years,” says lead study author Jessica Collins, a researcher at Brigham Young University. 

Not only that but several subjects who did not improve their VO2 max did see an increase in critical power and endurance. 

“People tend to only focus on VO2 max,” Dr. Gifford says. “Many might see the lack of increase in VO2 max for some people and conclude that the training was ineffective. I personally believe that a lot of potentially useful therapies have been ruled out because of an almost exclusive focus on VO2 max.”

Turns out, critical power varies a lot from person to person, even among those with similar VO2 maxes.

“Let’s say you and Jessica had the same VO2 max,” explains Dr. Gifford. “If we had you both going at 70% of [your VO2 max], it could be above your maximum steady state, which would make it really hard for you. And it could be below her maximum steady state, which would make it easy for her.” 

This means you are each stressing your body differently, and that stress is what triggers improvements in fitness and endurance. 

“Below critical power, the metabolic stressors are well-managed and maintained at elevated-but-steady levels,” Dr. Gifford says. “Above critical power, the metabolic stressors are produced so fast that they cannot be controlled, and consistently accrue until reaching very high levels that cause failure.” 

Knowing your critical power means you can predict how those stressors will build up, and you can tailor an exercise program that provides just the right stressor “dose” for you, Dr. Gifford says. 

Such programs could be used for rehab patients recovering from a heart attack or from lung disease, Dr. Gifford suggests. Or they could help older adults improve endurance and physical function, Ms. Collins notes. 

But first, researchers must confirm these results by programming workouts based on people’s critical power and seeing how much different measures improve.
 

How to find your critical power

Critical power is not new, but exercise physiologists and medical professionals have largely ignored it because it’s not easy to measure. 

“People generally train off VO2 max or maximum heart rate, which is even less precise,” Dr. Gifford says. 

Finding people’s critical power in the study involved multiple timed trials and calculating the relationship between speed/power and time, Dr. Gifford explains. 

But for a rough measure of your critical power, you could use an app that measures functional threshold power (FTP), something Dr. Gifford refers to as the “Walmart version” of critical power. “It’s not exactly the same, but it’s close,” he says. (The app Strava features FTP as well as a pretty sophisticated power analysis.) 

Or skip the tech and go by feel. If you’re below your critical power, “it’s going to be challenging, but you’ll feel under control,” Dr. Gifford says. Above your critical power, “your breathing and heart rate will continuously climb until you fail in about 2 to 15 minutes, depending on how far above you are.” Still, you don’t need to know your critical power to start exercising, Ms. Collins notes. 

“The beauty of exercise is that it is such a powerful drug that you can see benefits without fine-tuning the workout this way,” Dr. Gifford explains. “I would hate for this to become a barrier to exercising. The important thing is to do something.”

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

Current guidelines recommend against screening for prostate cancer in men who are 70 years old and older, as it is considered to be “low value” with little or no benefit for the individual. Yet a new study shows that testing for prostate-specific antigen (PSA) and also digital rectal examinations (DRE) are both carried out frequently in older men, even when there is no indication for such testing.

“As a man ages, the risk for a false-positive result increases,” said lead author Chris Gillette, PhD, associate professor of physician assistant studies at Wake Forest University, Winston-Salem, N.C., in a statement

The study authors looked at primary care visits for men who were age 70 or older, and found that, per 100 visits, there were 6.7 PSA tests and 1.6 DRE performed.

Dr. Gillette and colleagues emphasized the importance of their findings. Whereas prior studies have relied on commercially insured men or patient-reported rates of PSA testing, they used a nationally representative clinical dataset that is much more inclusive, as it includes men who are also uninsured or insured through traditional Medicare.

The study was published online in the Journal of the American Board of Family Medicine.

Screening for prostate cancer has been much debated, and the guidelines have changed in recent years. In the period 2012-2018, the U.S. Preventive Services Task Force recommended against PSA-based screening in all men, but then the guidelines changed, and the USPSTF subsequently endorsed individualized screening in those aged 55-69 years after a shared decision-making discussion. That same 2018 update also recommends against PSA screening in men over the age of 70.

In addition, the American Urological Association has recommended against PSA-based prostate cancer screening for men over the age of 70 since 2013.

Previous studies have shown that clinicians are not adhering to the guidelines. An analysis conducted in March 2022 found that about one in four accredited U.S. cancer centers fails to follow national guidelines for PSA testing to screen for prostate cancer. Contrary to national guidelines, which advocate shared decision-making, 22% of centers recommend all men universally initiate PSA screening at either age 50 or 55 and another 4% of centers recommend this before age 50, earlier than the guidelines advise.

In the current study, Dr. Gillette and colleagues conducted a secondary analysis of the National Ambulatory Medical Care Survey datasets from 2013 to 2016 and 2018. The dataset is a nationally representative sample of visits to nonfederal, office-based physician clinics. This analysis was restricted to male patients aged 70 years and older who visited a primary care clinic.

The team found that health care professionals who order a lot of tests are more likely to order low-value screening such as PSA and DRE.

The data also showed that when there were a higher number of services ordered/provided, the patients were significantly more likely to receive a low-value PSA (odds ratio, 1.49) and a low-value DRE (OR, 1.37). In contrast, patients who had more previous visits to the clinician were less likely to receive a low-value DRE (OR, 0.92).

Overall, there a decline in low-value PSA screening after 2014, but this trend was not seen for DRE during primary care visits.

Speculating as to why these low-value tests are being carried out, Dr. Gillette suggested that health care professionals might be responding to patient requests when ordering these screening tests, or they may be using what’s known as a “shotgun” approach to medical testing where all possible tests are ordered during a medical visit.

“However, as health care systems move toward a more value-based care system – where the benefit of services provided outweighs any risks – clinicians need to engage patients in these discussions on the complexity of this testing,” he commented. “Ultimately, when and if to screen is a decision best left between a provider and the patient.”

There was no outside funding and the authors reported no relevant financial relationships.

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

Current guidelines recommend against screening for prostate cancer in men who are 70 years old and older, as it is considered to be “low value” with little or no benefit for the individual. Yet a new study shows that testing for prostate-specific antigen (PSA) and also digital rectal examinations (DRE) are both carried out frequently in older men, even when there is no indication for such testing.

“As a man ages, the risk for a false-positive result increases,” said lead author Chris Gillette, PhD, associate professor of physician assistant studies at Wake Forest University, Winston-Salem, N.C., in a statement

The study authors looked at primary care visits for men who were age 70 or older, and found that, per 100 visits, there were 6.7 PSA tests and 1.6 DRE performed.

Dr. Gillette and colleagues emphasized the importance of their findings. Whereas prior studies have relied on commercially insured men or patient-reported rates of PSA testing, they used a nationally representative clinical dataset that is much more inclusive, as it includes men who are also uninsured or insured through traditional Medicare.

The study was published online in the Journal of the American Board of Family Medicine.

Screening for prostate cancer has been much debated, and the guidelines have changed in recent years. In the period 2012-2018, the U.S. Preventive Services Task Force recommended against PSA-based screening in all men, but then the guidelines changed, and the USPSTF subsequently endorsed individualized screening in those aged 55-69 years after a shared decision-making discussion. That same 2018 update also recommends against PSA screening in men over the age of 70.

In addition, the American Urological Association has recommended against PSA-based prostate cancer screening for men over the age of 70 since 2013.

Previous studies have shown that clinicians are not adhering to the guidelines. An analysis conducted in March 2022 found that about one in four accredited U.S. cancer centers fails to follow national guidelines for PSA testing to screen for prostate cancer. Contrary to national guidelines, which advocate shared decision-making, 22% of centers recommend all men universally initiate PSA screening at either age 50 or 55 and another 4% of centers recommend this before age 50, earlier than the guidelines advise.

In the current study, Dr. Gillette and colleagues conducted a secondary analysis of the National Ambulatory Medical Care Survey datasets from 2013 to 2016 and 2018. The dataset is a nationally representative sample of visits to nonfederal, office-based physician clinics. This analysis was restricted to male patients aged 70 years and older who visited a primary care clinic.

The team found that health care professionals who order a lot of tests are more likely to order low-value screening such as PSA and DRE.

The data also showed that when there were a higher number of services ordered/provided, the patients were significantly more likely to receive a low-value PSA (odds ratio, 1.49) and a low-value DRE (OR, 1.37). In contrast, patients who had more previous visits to the clinician were less likely to receive a low-value DRE (OR, 0.92).

Overall, there a decline in low-value PSA screening after 2014, but this trend was not seen for DRE during primary care visits.

Speculating as to why these low-value tests are being carried out, Dr. Gillette suggested that health care professionals might be responding to patient requests when ordering these screening tests, or they may be using what’s known as a “shotgun” approach to medical testing where all possible tests are ordered during a medical visit.

“However, as health care systems move toward a more value-based care system – where the benefit of services provided outweighs any risks – clinicians need to engage patients in these discussions on the complexity of this testing,” he commented. “Ultimately, when and if to screen is a decision best left between a provider and the patient.”

There was no outside funding and the authors reported no relevant financial relationships.

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

Current guidelines recommend against screening for prostate cancer in men who are 70 years old and older, as it is considered to be “low value” with little or no benefit for the individual. Yet a new study shows that testing for prostate-specific antigen (PSA) and also digital rectal examinations (DRE) are both carried out frequently in older men, even when there is no indication for such testing.

“As a man ages, the risk for a false-positive result increases,” said lead author Chris Gillette, PhD, associate professor of physician assistant studies at Wake Forest University, Winston-Salem, N.C., in a statement

The study authors looked at primary care visits for men who were age 70 or older, and found that, per 100 visits, there were 6.7 PSA tests and 1.6 DRE performed.

Dr. Gillette and colleagues emphasized the importance of their findings. Whereas prior studies have relied on commercially insured men or patient-reported rates of PSA testing, they used a nationally representative clinical dataset that is much more inclusive, as it includes men who are also uninsured or insured through traditional Medicare.

The study was published online in the Journal of the American Board of Family Medicine.

Screening for prostate cancer has been much debated, and the guidelines have changed in recent years. In the period 2012-2018, the U.S. Preventive Services Task Force recommended against PSA-based screening in all men, but then the guidelines changed, and the USPSTF subsequently endorsed individualized screening in those aged 55-69 years after a shared decision-making discussion. That same 2018 update also recommends against PSA screening in men over the age of 70.

In addition, the American Urological Association has recommended against PSA-based prostate cancer screening for men over the age of 70 since 2013.

Previous studies have shown that clinicians are not adhering to the guidelines. An analysis conducted in March 2022 found that about one in four accredited U.S. cancer centers fails to follow national guidelines for PSA testing to screen for prostate cancer. Contrary to national guidelines, which advocate shared decision-making, 22% of centers recommend all men universally initiate PSA screening at either age 50 or 55 and another 4% of centers recommend this before age 50, earlier than the guidelines advise.

In the current study, Dr. Gillette and colleagues conducted a secondary analysis of the National Ambulatory Medical Care Survey datasets from 2013 to 2016 and 2018. The dataset is a nationally representative sample of visits to nonfederal, office-based physician clinics. This analysis was restricted to male patients aged 70 years and older who visited a primary care clinic.

The team found that health care professionals who order a lot of tests are more likely to order low-value screening such as PSA and DRE.

The data also showed that when there were a higher number of services ordered/provided, the patients were significantly more likely to receive a low-value PSA (odds ratio, 1.49) and a low-value DRE (OR, 1.37). In contrast, patients who had more previous visits to the clinician were less likely to receive a low-value DRE (OR, 0.92).

Overall, there a decline in low-value PSA screening after 2014, but this trend was not seen for DRE during primary care visits.

Speculating as to why these low-value tests are being carried out, Dr. Gillette suggested that health care professionals might be responding to patient requests when ordering these screening tests, or they may be using what’s known as a “shotgun” approach to medical testing where all possible tests are ordered during a medical visit.

“However, as health care systems move toward a more value-based care system – where the benefit of services provided outweighs any risks – clinicians need to engage patients in these discussions on the complexity of this testing,” he commented. “Ultimately, when and if to screen is a decision best left between a provider and the patient.”

There was no outside funding and the authors reported no relevant financial relationships.

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

If you smoke, vape, or ingest cannabis, your anesthesiologist should know before you undergo a surgical procedure, according to new medical guidelines.

All patients who undergo procedures that require regional or general anesthesia should be asked if, how often, and in what forms they use the drug, according to recommendations from the American Society of Regional Anesthesia and Pain Medicine.

One reason: Patients who regularly use cannabis may experience worse pain and nausea after surgery and may require more opioid analgesia, the group said.

The society’s recommendations – published in Regional Anesthesia and Pain Medicine – are the first guidelines in the United States to cover cannabis use as it relates to surgery, the group said.
 

Possible interactions

Use of cannabis has increased in recent years, and researchers have been concerned that the drug may interact with anesthesia and complicate pain management. Few studies have evaluated interactions between cannabis and anesthetic agents, however, according to the authors of the new guidelines.

“With the rising prevalence of both medical and recreational cannabis use in the general population, anesthesiologists, surgeons, and perioperative physicians must have an understanding of the effects of cannabis on physiology in order to provide safe perioperative care,” the guideline said.

“Before surgery, anesthesiologists should ask patients if they use cannabis – whether medicinally or recreationally – and be prepared to possibly change the anesthesia plan or delay the procedure in certain situations,” Samer Narouze, MD, PhD, ASRA president and senior author of the guidelines, said in a news release about the recommendations.

Although some patients may use cannabis to relieve pain, research shows that “regular users may have more pain and nausea after surgery, not less, and may need more medications, including opioids, to manage the discomfort,” said Dr. Narouze, chairman of the Center for Pain Medicine at Western Reserve Hospital in Cuyahoga Falls, Ohio.
 

Risks for vomiting, heart attack

The new recommendations were created by a committee of 13 experts, including anesthesiologists, chronic pain physicians, and a patient advocate. Shalini Shah, MD, vice chair of anesthesiology at the University of California, Irvine, was lead author of the document.

Four of 21 recommendations were classified as grade A, meaning that following them would be expected to provide substantial benefits. Those recommendations are to screen all patients before surgery; postpone elective surgery for patients who have altered mental status or impaired decision-making capacity at the time of surgery; counsel frequent, heavy users about the potential for cannabis use to impair postoperative pain control; and counsel pregnant patients about the risks of cannabis use to unborn children.

The authors cited studies to support their recommendations, including one showing that long-term cannabis use was associated with a 20% increase in the incidence of postoperative nausea and vomiting, a leading complaint of surgery patients. Other research has shown that cannabis use is linked to more pain and use of opioids after surgery.

Other recommendations include delaying elective surgery for at least 2 hours after a patient has smoked cannabis, owing to an increased risk for heart attack, and considering adjustment of ventilation settings during surgery for regular smokers of cannabis. Research has shown that smoking cannabis may be a rare trigger for myocardial infarction and is associated with airway inflammation and self-reported respiratory symptoms.

Nevertheless, doctors should not conduct universal toxicology screening, given a lack of evidence supporting this practice, the guideline stated.

The authors did not have enough information to make recommendations about reducing cannabis use before surgery or adjusting opioid prescriptions after surgery for patients who use cannabis, they said.

Kenneth Finn, MD, president of the American Board of Pain Medicine, welcomed the publication of the new guidelines. Dr. Finn, who practices at Springs Rehabilitation in Colorado Springs, has edited a textbook about cannabis in medicine and founded the International Academy on the Science and Impact of Cannabis.

“The vast majority of medical providers really have no idea about cannabis and what its impacts are on the human body,” Dr. Finn said.

For one, it can interact with numerous other drugs, including warfarin.

Guideline coauthor Eugene R. Viscusi, MD, professor of anesthesiology at the Sidney Kimmel Medical College, Philadelphia, emphasized that, while cannabis may be perceived as “natural,” it should not be considered differently from manufactured drugs.

Cannabis and cannabinoids represent “a class of very potent and pharmacologically active compounds,” Dr. Viscusi said in an interview. While researchers continue to assess possible medically beneficial effects of cannabis compounds, clinicians also need to be aware of the risks.

“The literature continues to emerge, and while we are always hopeful for good news, as physicians, we need to be very well versed on potential risks, especially in a high-risk situation like surgery,” he said.

Dr. Shah has consulted for companies that develop medical devices and drugs. Dr. Finn is the editor of the textbook, “Cannabis in Medicine: An Evidence-Based Approach” (Springer: New York, 2020), for which he receives royalties.

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

If you smoke, vape, or ingest cannabis, your anesthesiologist should know before you undergo a surgical procedure, according to new medical guidelines.

All patients who undergo procedures that require regional or general anesthesia should be asked if, how often, and in what forms they use the drug, according to recommendations from the American Society of Regional Anesthesia and Pain Medicine.

One reason: Patients who regularly use cannabis may experience worse pain and nausea after surgery and may require more opioid analgesia, the group said.

The society’s recommendations – published in Regional Anesthesia and Pain Medicine – are the first guidelines in the United States to cover cannabis use as it relates to surgery, the group said.
 

Possible interactions

Use of cannabis has increased in recent years, and researchers have been concerned that the drug may interact with anesthesia and complicate pain management. Few studies have evaluated interactions between cannabis and anesthetic agents, however, according to the authors of the new guidelines.

“With the rising prevalence of both medical and recreational cannabis use in the general population, anesthesiologists, surgeons, and perioperative physicians must have an understanding of the effects of cannabis on physiology in order to provide safe perioperative care,” the guideline said.

“Before surgery, anesthesiologists should ask patients if they use cannabis – whether medicinally or recreationally – and be prepared to possibly change the anesthesia plan or delay the procedure in certain situations,” Samer Narouze, MD, PhD, ASRA president and senior author of the guidelines, said in a news release about the recommendations.

Although some patients may use cannabis to relieve pain, research shows that “regular users may have more pain and nausea after surgery, not less, and may need more medications, including opioids, to manage the discomfort,” said Dr. Narouze, chairman of the Center for Pain Medicine at Western Reserve Hospital in Cuyahoga Falls, Ohio.
 

Risks for vomiting, heart attack

The new recommendations were created by a committee of 13 experts, including anesthesiologists, chronic pain physicians, and a patient advocate. Shalini Shah, MD, vice chair of anesthesiology at the University of California, Irvine, was lead author of the document.

Four of 21 recommendations were classified as grade A, meaning that following them would be expected to provide substantial benefits. Those recommendations are to screen all patients before surgery; postpone elective surgery for patients who have altered mental status or impaired decision-making capacity at the time of surgery; counsel frequent, heavy users about the potential for cannabis use to impair postoperative pain control; and counsel pregnant patients about the risks of cannabis use to unborn children.

The authors cited studies to support their recommendations, including one showing that long-term cannabis use was associated with a 20% increase in the incidence of postoperative nausea and vomiting, a leading complaint of surgery patients. Other research has shown that cannabis use is linked to more pain and use of opioids after surgery.

Other recommendations include delaying elective surgery for at least 2 hours after a patient has smoked cannabis, owing to an increased risk for heart attack, and considering adjustment of ventilation settings during surgery for regular smokers of cannabis. Research has shown that smoking cannabis may be a rare trigger for myocardial infarction and is associated with airway inflammation and self-reported respiratory symptoms.

Nevertheless, doctors should not conduct universal toxicology screening, given a lack of evidence supporting this practice, the guideline stated.

The authors did not have enough information to make recommendations about reducing cannabis use before surgery or adjusting opioid prescriptions after surgery for patients who use cannabis, they said.

Kenneth Finn, MD, president of the American Board of Pain Medicine, welcomed the publication of the new guidelines. Dr. Finn, who practices at Springs Rehabilitation in Colorado Springs, has edited a textbook about cannabis in medicine and founded the International Academy on the Science and Impact of Cannabis.

“The vast majority of medical providers really have no idea about cannabis and what its impacts are on the human body,” Dr. Finn said.

For one, it can interact with numerous other drugs, including warfarin.

Guideline coauthor Eugene R. Viscusi, MD, professor of anesthesiology at the Sidney Kimmel Medical College, Philadelphia, emphasized that, while cannabis may be perceived as “natural,” it should not be considered differently from manufactured drugs.

Cannabis and cannabinoids represent “a class of very potent and pharmacologically active compounds,” Dr. Viscusi said in an interview. While researchers continue to assess possible medically beneficial effects of cannabis compounds, clinicians also need to be aware of the risks.

“The literature continues to emerge, and while we are always hopeful for good news, as physicians, we need to be very well versed on potential risks, especially in a high-risk situation like surgery,” he said.

Dr. Shah has consulted for companies that develop medical devices and drugs. Dr. Finn is the editor of the textbook, “Cannabis in Medicine: An Evidence-Based Approach” (Springer: New York, 2020), for which he receives royalties.

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

If you smoke, vape, or ingest cannabis, your anesthesiologist should know before you undergo a surgical procedure, according to new medical guidelines.

All patients who undergo procedures that require regional or general anesthesia should be asked if, how often, and in what forms they use the drug, according to recommendations from the American Society of Regional Anesthesia and Pain Medicine.

One reason: Patients who regularly use cannabis may experience worse pain and nausea after surgery and may require more opioid analgesia, the group said.

The society’s recommendations – published in Regional Anesthesia and Pain Medicine – are the first guidelines in the United States to cover cannabis use as it relates to surgery, the group said.
 

Possible interactions

Use of cannabis has increased in recent years, and researchers have been concerned that the drug may interact with anesthesia and complicate pain management. Few studies have evaluated interactions between cannabis and anesthetic agents, however, according to the authors of the new guidelines.

“With the rising prevalence of both medical and recreational cannabis use in the general population, anesthesiologists, surgeons, and perioperative physicians must have an understanding of the effects of cannabis on physiology in order to provide safe perioperative care,” the guideline said.

“Before surgery, anesthesiologists should ask patients if they use cannabis – whether medicinally or recreationally – and be prepared to possibly change the anesthesia plan or delay the procedure in certain situations,” Samer Narouze, MD, PhD, ASRA president and senior author of the guidelines, said in a news release about the recommendations.

Although some patients may use cannabis to relieve pain, research shows that “regular users may have more pain and nausea after surgery, not less, and may need more medications, including opioids, to manage the discomfort,” said Dr. Narouze, chairman of the Center for Pain Medicine at Western Reserve Hospital in Cuyahoga Falls, Ohio.
 

Risks for vomiting, heart attack

The new recommendations were created by a committee of 13 experts, including anesthesiologists, chronic pain physicians, and a patient advocate. Shalini Shah, MD, vice chair of anesthesiology at the University of California, Irvine, was lead author of the document.

Four of 21 recommendations were classified as grade A, meaning that following them would be expected to provide substantial benefits. Those recommendations are to screen all patients before surgery; postpone elective surgery for patients who have altered mental status or impaired decision-making capacity at the time of surgery; counsel frequent, heavy users about the potential for cannabis use to impair postoperative pain control; and counsel pregnant patients about the risks of cannabis use to unborn children.

The authors cited studies to support their recommendations, including one showing that long-term cannabis use was associated with a 20% increase in the incidence of postoperative nausea and vomiting, a leading complaint of surgery patients. Other research has shown that cannabis use is linked to more pain and use of opioids after surgery.

Other recommendations include delaying elective surgery for at least 2 hours after a patient has smoked cannabis, owing to an increased risk for heart attack, and considering adjustment of ventilation settings during surgery for regular smokers of cannabis. Research has shown that smoking cannabis may be a rare trigger for myocardial infarction and is associated with airway inflammation and self-reported respiratory symptoms.

Nevertheless, doctors should not conduct universal toxicology screening, given a lack of evidence supporting this practice, the guideline stated.

The authors did not have enough information to make recommendations about reducing cannabis use before surgery or adjusting opioid prescriptions after surgery for patients who use cannabis, they said.

Kenneth Finn, MD, president of the American Board of Pain Medicine, welcomed the publication of the new guidelines. Dr. Finn, who practices at Springs Rehabilitation in Colorado Springs, has edited a textbook about cannabis in medicine and founded the International Academy on the Science and Impact of Cannabis.

“The vast majority of medical providers really have no idea about cannabis and what its impacts are on the human body,” Dr. Finn said.

For one, it can interact with numerous other drugs, including warfarin.

Guideline coauthor Eugene R. Viscusi, MD, professor of anesthesiology at the Sidney Kimmel Medical College, Philadelphia, emphasized that, while cannabis may be perceived as “natural,” it should not be considered differently from manufactured drugs.

Cannabis and cannabinoids represent “a class of very potent and pharmacologically active compounds,” Dr. Viscusi said in an interview. While researchers continue to assess possible medically beneficial effects of cannabis compounds, clinicians also need to be aware of the risks.

“The literature continues to emerge, and while we are always hopeful for good news, as physicians, we need to be very well versed on potential risks, especially in a high-risk situation like surgery,” he said.

Dr. Shah has consulted for companies that develop medical devices and drugs. Dr. Finn is the editor of the textbook, “Cannabis in Medicine: An Evidence-Based Approach” (Springer: New York, 2020), for which he receives royalties.

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

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

A genome-wide association study (GWAS) of suicidal thoughts and behaviors (SITB) has identified significant cross-ancestry risk loci. The findings provide further evidence of a genetic basis for SITB.

“It’s really important for us to continue to study the genetic risk factors for suicidal behaviors so we can really understand the biology and develop better treatments,” study investigator Allison E. Ashley-Koch, PhD, professor in the department of medicine at Duke University Medical Center, Durham, N.C., told this news organization.

The findings were published online in JAMA Psychiatry).
 

SITB heritability

Suicide is a leading cause of death, particularly among individuals aged 15-29 years. Whereas the global rate of suicide has decreased by 36% in the past 20 years, the rate in the United States has increased by 35%, with the greatest rise in military veterans.

Twin studies suggest heritability for SITB is between 30% and 55%, but the molecular genetic basis of SITB remains elusive.

To address this research gap, investigators conducted a study of 633,778 U.S. military veterans from the Million Veteran Program (MVP) cohort. Of these, 71% had European ancestry, 19% had African ancestry, 8% were Hispanic, and 1% were Asian. Just under 10% of the sample was female.

Study participants donated a blood sample and agreed to have their genetic information linked with their electronic health record data.

From diagnostic codes and other sources, researchers identified 121,211 individuals with SITB. They classified participants with no documented lifetime history of suicidal ideation, suicide attempt, or suicide death as controls.

Rates of SITB differed significantly by ancestry – 25% in those with African or Hispanic ancestry, 21% in those with Asian ancestry, and 16.8% in those with European ancestry. Rates also differed by age and sex; those with SITB were younger and more likely to be female.

In addition to age and sex, covariates included “genetic principal components,” which Dr. Ashley-Koch said accounts for combining data of individuals with different ethnic/racial backgrounds.

Through meta-analysis, the investigators identified seven genome-wide, significant cross-ancestry risk loci.

To evaluate whether the findings could be replicated, researchers used the International Suicide Genetics Consortium (ISGC), a primarily civilian international consortium of roughly 550,000 individuals of mostly European ancestry.

The analysis showed the top replicated cross-ancestry risk locus was rs6557168, an intronic single-nucleotide variant (SNV) in the ESR1 gene that encodes an estrogen receptor. Previous work identified ESR1 as a causal genetic driver gene for development of posttraumatic stress disorder and depression, both of which are risk factors for SITB among veterans.

The second-strongest replicated cross-ancestry locus was rs12808482, an intronic variant in the DRD2 gene, which encodes the D₂ dopamine-receptor subtype. The authors noted DRD2 is highly expressed in brain tissue and has been associated with numerous psychiatric phenotypes.

Research suggests DRD2 is associated with other risk factors for SITB, such as schizophrenia, mood disorders, and attention-deficit/hyperactivity disorder, but DRD2 could also contribute to suicide risk directly. The authors noted it is highly expressed in the prefrontal cortex, nucleus accumbens, substantia nigra, and hippocampus.
 

Outstanding candidate gene

The study revealed a cross-ancestry GWS association for rs10671545, a variant in DCC, which is “also an outstanding candidate gene,” the investigators write.

They note it is expressed in brain tissue, is involved in synaptic plasticity, axon guidance, and circadian entrainment, and has been associated with multiple psychiatric phenotypes.

Researchers also found what they called “intriguing” cross-ancestry GWS associations for the TRAF3 gene, which regulates type-1 interferon production. Many patients receiving interferon therapy develop major depressive disorder and suicidal ideation.

TRAF3 is also associated with antisocial behavior, substance use, and ADHD. Lithium – a standard treatment for bipolar disorder that reduces suicide risk – modulates the expression of TRAF3.

Dr. Ashley-Koch noted the replication of these loci (ESR1, DRD2, TRAF3, and DCC) was in a population of mostly White civilians. “This suggests to us that at least some of the risk for suicidal thoughts and behaviors does cross ancestry and also crosses military and civilian populations.”

It was “exciting” that all four genes the study focused on had previously been implicated in other psychiatric disorders, said Dr. Ashley-Koch. “What gave us a little more confidence, above and beyond the replication, was that these genes are somehow important for psychiatric disorders, and not any psychiatric disorders, but the ones that are also associated with a high risk of suicide behavior, such as depression, PTSD, schizophrenia, and ADHD.”

The findings will not have an immediate impact on clinical practice, said Dr. Ashley-Koch.

“We need to take the next step, which is to try to understand how these genetic factors may impact risk and what else is happening biologically to increase that risk. Then once we do that, hopefully we can develop some new treatments,” she added.
 

‘Valuable and noble’ research

Commenting on the study, Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, said this kind of genetic research is “valuable and noble.”

Researchers have long been interested in risk factors for suicide among military personnel and veterans, said Dr. Ritchie. Evidence to date suggests being a young male is a risk factor as is feeling excluded or not fitting into the unit, and drug or alcohol addiction.

Dr. Ritchie noted other psychiatric disorders, including schizophrenia, depression, and bipolar disorder, are at least partially inherited.

She noted the study’s findings should not be used to discriminate against those who might have the identified genetic loci without clearer evidence of their impact.

“If we were able to identify these genes, would we start screening everybody who joins the military to see if they have these genes, and how would that impact the ability to recruit or retain personnel?”

She agreed additional work is needed to determine if and how carrying these genes might impact clinical care.

In addition, she pointed out that behavior is influenced not only by genetic load but also by environment. “This study may show the impact of the genetic load a little bit more clearly; right now, we tend to look at environmental factors.”

The study was supported by an award from the Clinical Science Research and Development (CSR&D) service of the Veterans Health Administration’s Office of Research and Development. The work was also supported in part by the joint U.S. Department of Veterans Affairs and U.S. Department of Energy MVP CHAMPION program.

Dr. Ashley-Koch reported grants from Veterans Administration during the conduct of the study. Several other coauthors report relationships with industry, nonprofit organizations, and government agencies. The full list can be found with the original article. Dr. Ritchie reports no relevant financial relationships.

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

Stroke patients receiving thrombolysis do not appear to be at increased risk of symptomatic intracerebral hemorrhage (sICH) if they are taking direct oral anticoagulants (DOACs), a new study has found.

The study, the largest ever regarding the safety of thrombolysis in patients on DOACs, actually found a lower rate of sICH among patients taking DOACs than among those not taking anticoagulants.

“Thrombolysis is a backbone therapy in stroke, but the large population of patients who take DOACs are currently excluded from this treatment because DOAC use is a contraindication to treatment with thrombolysis. This is based on the presumption of an increased risk of sICH, but data to support or refute this presumption are lacking,” said senior author David J. Seiffge, MD, Bern University Hospital, Switzerland.

“Our results suggest that current guidelines need to be revised to remove the absolute contraindication of thrombolysis in patients on DOACs. The guidelines need to be more liberal on the use of thrombolysis in these patients,” he added.

“This study provides the basis for extending vital thrombolysis treatment to this substantial population of patients who take DOACs,” Dr. Seiffge said.

He estimates that 1 of every 6 stroke patients are taking a DOAC and that 1% to 2% of patients taking DOACs have a stroke each year. “As millions of patients are on DOACs, this is a large number of people who are not getting potentially life-saving thrombolysis therapy.”

Dr. Seiffge comments: “In our hospital we see at least one stroke patient on DOACs every day. It is a very frequent scenario. With this new data, we believe many of these patients could now benefit from thrombolysis without an increased bleeding risk.”

The study was published online  in JAMA Neurology.
 

An international investigation

While thrombolysis is currently contraindicated for patients taking DOACs, some clinicians still administer thrombolysis to these patients. Different selection strategies are used, including the use of DOAC reversal agents prior to thrombolysis or the selection of patients with low anticoagulant activity, the authors noted.

The current study involved an international collaboration. The investigators compared the risk of sICH among patients who had recently taken DOACs and who underwent thrombolysis as treatment for acute ischemic stroke with the risk among control stroke patients who underwent thrombolysis but who had not been taking DOACs.

Potential contributing centers were identified by a systematic search of the literature based on published studies on the use of thrombolysis for patients who had recently taken DOACs or prospective stroke registries that may include patients who had recently taken DOACs.

The study included 832 patients from 64 centers worldwide who were confirmed to have taken a DOAC within 48 hours of receiving thrombolysis for acute ischemic stroke. The comparison group was made up of 32,375 patients who had experienced ischemic stroke that was treated with thrombolysis but who had received no prior anticoagulation therapy.

Compared with control patients, patients who had recently taken DOACs were older; the incidence of hypertension among them was higher; they had a higher degree of prestroke disability; they were less likely to be smokers; the time from symptom onset to treatment was longer; they had experienced more severe stroke; and they were more likely to have a large-vessel occlusion.

Of the patients taking DOACs, 30.3% received DOAC reversal prior to thrombolysis. For 27.0%, DOAC plasma levels were measured. The remainder were treated with thrombolysis without either of these selection methods.

Results showed that the unadjusted rate of sICH was 2.5% among patients taking DOACs, compared with 4.1% among control patients who were not taking anticoagulants.

After adjustment for stroke severity and other baseline sICH predictors, patients who had recently taken DOACs and who received thrombolysis had lower odds of developing sICH (adjusted odds ratio, 0.57; 95% confidence interval, 0.36-0.92; P = .02).

There was no difference between the selection strategies, and results were consistent in different sensitivity analyses.

The secondary outcome of any ICH occurred in 18.0% in patients taking DOACs, compared with 17.4% among control patients who used no anticoagulants. After adjustment, there was no difference in the odds for any ICH between the groups (aOR, 1.18; 95% CI, 0.95-1.45; P = .14).

The unadjusted rate of functional independence was 45% among patients taking DOACs, compared with 57% among control patients. After adjustment, patients who had recently taken DOACs and who underwent thrombolysis had numerically higher odds of being functionally independent than control patients, although this difference did not reach statistical significance (aOR, 1.13; 95% CI, 0.94-1.36; P = .20).

The association of DOAC therapy with lower odds of sICH remained when mechanical thrombectomy, large-vessel occlusion, or concomitant antiplatelet therapy was added to the model.

“This is by far the largest study to look at this issue of thrombolytic use in patients on DOACs, and we did not find any group on DOACs that had an excess ICH rate with thrombolysis,” Dr. Seiffge said,

He explained that receiving warfarin was at one time an absolute contraindication for thrombolysis, but after a 2014 study suggested that the risk was not increased for patients with an international normalized ratio below 117, this was downgraded to a relative contraindication.

“We think our study is comparable and should lead to a guideline change,” Dr. Seiffge commented.

“A relative contraindication allows clinicians the space to make a considered decision on an individual basis,” he added.

Dr. Seiffge said that at his hospital, local guidelines regarding this issue have already been changed on the basis of these data, and use of DOACs is now considered a relative contraindication.

“International guidelines can take years to update, so in the meantime, I think other centers will also go ahead with a more liberal approach. There are always some centers that are ahead of the guidelines,” he added.

Although the lower risk of sICH seen in patients who have recently used DOACs seems counterintuitive at first glance, there could be a pathophysiologic explanation for this finding, the authors suggest.

They point out that thrombin inhibition, either directly or via the coagulation cascade, might be protective against the occurrence of sICH.

“Anticoagulants may allow the clot to respond better to thrombolysis – the clot is not as solid and is easier to recanalize. This leads to smaller strokes and a lower bleeding risk. Thrombin generation is also a major driver for blood brain barrier breakdown. DOACs reduce thrombin generation, so reduce blood brain barrier breakdown and reduce bleeding,” Dr. Seiffge explained. “But these are hypotheses,” he added.
 

Study ‘meaningfully advances the field’

In an accompanying editorial, Eva A. Mistry, MBBS, University of Cincinnati, said the current study “meaningfully advances the field” and provides an estimation of safety of intravenous thrombolysis among patients who have taken DOACs within 48 hours of hospital admission.

She lists strengths of the study as inclusion of a large number of patients across several geographically diverse institutions with heterogeneous standard practices for thrombolysis with recent DOAC use and narrow confidence intervals regarding observed rates of sICH.

“Further, the upper bound of this confidence interval for the DOAC group is below 4%, which is a welcome result and provides supportive data for clinicians who already practice thrombolysis for patients with recent DOAC ingestion,” Dr. Mistry adds.

However, she points out several study limitations, which she says limit immediate, widespread clinical applicability.

These include use of a nonconcurrent control population, which included patients from centers that did not contribute to the DOAC group and the inclusion of Asian patients who likely received a lower thrombolytic dose.

Dr. Seiffge noted that the researchers did adjust for Asian patients but not for the thrombolytic dosage. “I personally do not think this affects the results, as Asian patients have a lower dosage because they have a higher bleeding risk. The lower bleeding risk with DOACs was seen in all continents.”

Dr. Mistry also suggests that the DOAC group itself is prone to selection bias from preferential thrombolysis of patients receiving DOAC who are at lower risk of sICH.

But Dr. Seiffge argued: “I think, actually, the opposite is true. The DOAC patients were older, had more severe comorbidities, and an increased bleeding risk.”

Dr. Mistry concluded, “Despite the limitations of the study design and enrolled population, these data may be used by clinicians to make individualized decisions regarding thrombolysis among patients with recent DOAC use. Importantly, this study lays the foundation for prospective, well-powered studies that definitively determine the safety of thrombolysis in this population.”

The study was supported by a grant from the Bangerter-Rhyner Foundation. Dr. Seiffge received grants from Bangerter Rhyner Foundation during the conduct of the study and personal fees from Bayer, Alexion, and VarmX outside the submitted work. Dr. Mistry receives grant funding from the National Institute of Neurological Disorders and Stroke and serves as a consultant for RAPID AI.

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

Stroke patients receiving thrombolysis do not appear to be at increased risk of symptomatic intracerebral hemorrhage (sICH) if they are taking direct oral anticoagulants (DOACs), a new study has found.

The study, the largest ever regarding the safety of thrombolysis in patients on DOACs, actually found a lower rate of sICH among patients taking DOACs than among those not taking anticoagulants.

“Thrombolysis is a backbone therapy in stroke, but the large population of patients who take DOACs are currently excluded from this treatment because DOAC use is a contraindication to treatment with thrombolysis. This is based on the presumption of an increased risk of sICH, but data to support or refute this presumption are lacking,” said senior author David J. Seiffge, MD, Bern University Hospital, Switzerland.

“Our results suggest that current guidelines need to be revised to remove the absolute contraindication of thrombolysis in patients on DOACs. The guidelines need to be more liberal on the use of thrombolysis in these patients,” he added.

“This study provides the basis for extending vital thrombolysis treatment to this substantial population of patients who take DOACs,” Dr. Seiffge said.

He estimates that 1 of every 6 stroke patients are taking a DOAC and that 1% to 2% of patients taking DOACs have a stroke each year. “As millions of patients are on DOACs, this is a large number of people who are not getting potentially life-saving thrombolysis therapy.”

Dr. Seiffge comments: “In our hospital we see at least one stroke patient on DOACs every day. It is a very frequent scenario. With this new data, we believe many of these patients could now benefit from thrombolysis without an increased bleeding risk.”

The study was published online  in JAMA Neurology.
 

An international investigation

While thrombolysis is currently contraindicated for patients taking DOACs, some clinicians still administer thrombolysis to these patients. Different selection strategies are used, including the use of DOAC reversal agents prior to thrombolysis or the selection of patients with low anticoagulant activity, the authors noted.

The current study involved an international collaboration. The investigators compared the risk of sICH among patients who had recently taken DOACs and who underwent thrombolysis as treatment for acute ischemic stroke with the risk among control stroke patients who underwent thrombolysis but who had not been taking DOACs.

Potential contributing centers were identified by a systematic search of the literature based on published studies on the use of thrombolysis for patients who had recently taken DOACs or prospective stroke registries that may include patients who had recently taken DOACs.

The study included 832 patients from 64 centers worldwide who were confirmed to have taken a DOAC within 48 hours of receiving thrombolysis for acute ischemic stroke. The comparison group was made up of 32,375 patients who had experienced ischemic stroke that was treated with thrombolysis but who had received no prior anticoagulation therapy.

Compared with control patients, patients who had recently taken DOACs were older; the incidence of hypertension among them was higher; they had a higher degree of prestroke disability; they were less likely to be smokers; the time from symptom onset to treatment was longer; they had experienced more severe stroke; and they were more likely to have a large-vessel occlusion.

Of the patients taking DOACs, 30.3% received DOAC reversal prior to thrombolysis. For 27.0%, DOAC plasma levels were measured. The remainder were treated with thrombolysis without either of these selection methods.

Results showed that the unadjusted rate of sICH was 2.5% among patients taking DOACs, compared with 4.1% among control patients who were not taking anticoagulants.

After adjustment for stroke severity and other baseline sICH predictors, patients who had recently taken DOACs and who received thrombolysis had lower odds of developing sICH (adjusted odds ratio, 0.57; 95% confidence interval, 0.36-0.92; P = .02).

There was no difference between the selection strategies, and results were consistent in different sensitivity analyses.

The secondary outcome of any ICH occurred in 18.0% in patients taking DOACs, compared with 17.4% among control patients who used no anticoagulants. After adjustment, there was no difference in the odds for any ICH between the groups (aOR, 1.18; 95% CI, 0.95-1.45; P = .14).

The unadjusted rate of functional independence was 45% among patients taking DOACs, compared with 57% among control patients. After adjustment, patients who had recently taken DOACs and who underwent thrombolysis had numerically higher odds of being functionally independent than control patients, although this difference did not reach statistical significance (aOR, 1.13; 95% CI, 0.94-1.36; P = .20).

The association of DOAC therapy with lower odds of sICH remained when mechanical thrombectomy, large-vessel occlusion, or concomitant antiplatelet therapy was added to the model.

“This is by far the largest study to look at this issue of thrombolytic use in patients on DOACs, and we did not find any group on DOACs that had an excess ICH rate with thrombolysis,” Dr. Seiffge said,

He explained that receiving warfarin was at one time an absolute contraindication for thrombolysis, but after a 2014 study suggested that the risk was not increased for patients with an international normalized ratio below 117, this was downgraded to a relative contraindication.

“We think our study is comparable and should lead to a guideline change,” Dr. Seiffge commented.

“A relative contraindication allows clinicians the space to make a considered decision on an individual basis,” he added.

Dr. Seiffge said that at his hospital, local guidelines regarding this issue have already been changed on the basis of these data, and use of DOACs is now considered a relative contraindication.

“International guidelines can take years to update, so in the meantime, I think other centers will also go ahead with a more liberal approach. There are always some centers that are ahead of the guidelines,” he added.

Although the lower risk of sICH seen in patients who have recently used DOACs seems counterintuitive at first glance, there could be a pathophysiologic explanation for this finding, the authors suggest.

They point out that thrombin inhibition, either directly or via the coagulation cascade, might be protective against the occurrence of sICH.

“Anticoagulants may allow the clot to respond better to thrombolysis – the clot is not as solid and is easier to recanalize. This leads to smaller strokes and a lower bleeding risk. Thrombin generation is also a major driver for blood brain barrier breakdown. DOACs reduce thrombin generation, so reduce blood brain barrier breakdown and reduce bleeding,” Dr. Seiffge explained. “But these are hypotheses,” he added.
 

Study ‘meaningfully advances the field’

In an accompanying editorial, Eva A. Mistry, MBBS, University of Cincinnati, said the current study “meaningfully advances the field” and provides an estimation of safety of intravenous thrombolysis among patients who have taken DOACs within 48 hours of hospital admission.

She lists strengths of the study as inclusion of a large number of patients across several geographically diverse institutions with heterogeneous standard practices for thrombolysis with recent DOAC use and narrow confidence intervals regarding observed rates of sICH.

“Further, the upper bound of this confidence interval for the DOAC group is below 4%, which is a welcome result and provides supportive data for clinicians who already practice thrombolysis for patients with recent DOAC ingestion,” Dr. Mistry adds.

However, she points out several study limitations, which she says limit immediate, widespread clinical applicability.

These include use of a nonconcurrent control population, which included patients from centers that did not contribute to the DOAC group and the inclusion of Asian patients who likely received a lower thrombolytic dose.

Dr. Seiffge noted that the researchers did adjust for Asian patients but not for the thrombolytic dosage. “I personally do not think this affects the results, as Asian patients have a lower dosage because they have a higher bleeding risk. The lower bleeding risk with DOACs was seen in all continents.”

Dr. Mistry also suggests that the DOAC group itself is prone to selection bias from preferential thrombolysis of patients receiving DOAC who are at lower risk of sICH.

But Dr. Seiffge argued: “I think, actually, the opposite is true. The DOAC patients were older, had more severe comorbidities, and an increased bleeding risk.”

Dr. Mistry concluded, “Despite the limitations of the study design and enrolled population, these data may be used by clinicians to make individualized decisions regarding thrombolysis among patients with recent DOAC use. Importantly, this study lays the foundation for prospective, well-powered studies that definitively determine the safety of thrombolysis in this population.”

The study was supported by a grant from the Bangerter-Rhyner Foundation. Dr. Seiffge received grants from Bangerter Rhyner Foundation during the conduct of the study and personal fees from Bayer, Alexion, and VarmX outside the submitted work. Dr. Mistry receives grant funding from the National Institute of Neurological Disorders and Stroke and serves as a consultant for RAPID AI.

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

Stroke patients receiving thrombolysis do not appear to be at increased risk of symptomatic intracerebral hemorrhage (sICH) if they are taking direct oral anticoagulants (DOACs), a new study has found.

The study, the largest ever regarding the safety of thrombolysis in patients on DOACs, actually found a lower rate of sICH among patients taking DOACs than among those not taking anticoagulants.

“Thrombolysis is a backbone therapy in stroke, but the large population of patients who take DOACs are currently excluded from this treatment because DOAC use is a contraindication to treatment with thrombolysis. This is based on the presumption of an increased risk of sICH, but data to support or refute this presumption are lacking,” said senior author David J. Seiffge, MD, Bern University Hospital, Switzerland.

“Our results suggest that current guidelines need to be revised to remove the absolute contraindication of thrombolysis in patients on DOACs. The guidelines need to be more liberal on the use of thrombolysis in these patients,” he added.

“This study provides the basis for extending vital thrombolysis treatment to this substantial population of patients who take DOACs,” Dr. Seiffge said.

He estimates that 1 of every 6 stroke patients are taking a DOAC and that 1% to 2% of patients taking DOACs have a stroke each year. “As millions of patients are on DOACs, this is a large number of people who are not getting potentially life-saving thrombolysis therapy.”

Dr. Seiffge comments: “In our hospital we see at least one stroke patient on DOACs every day. It is a very frequent scenario. With this new data, we believe many of these patients could now benefit from thrombolysis without an increased bleeding risk.”

The study was published online  in JAMA Neurology.
 

An international investigation

While thrombolysis is currently contraindicated for patients taking DOACs, some clinicians still administer thrombolysis to these patients. Different selection strategies are used, including the use of DOAC reversal agents prior to thrombolysis or the selection of patients with low anticoagulant activity, the authors noted.

The current study involved an international collaboration. The investigators compared the risk of sICH among patients who had recently taken DOACs and who underwent thrombolysis as treatment for acute ischemic stroke with the risk among control stroke patients who underwent thrombolysis but who had not been taking DOACs.

Potential contributing centers were identified by a systematic search of the literature based on published studies on the use of thrombolysis for patients who had recently taken DOACs or prospective stroke registries that may include patients who had recently taken DOACs.

The study included 832 patients from 64 centers worldwide who were confirmed to have taken a DOAC within 48 hours of receiving thrombolysis for acute ischemic stroke. The comparison group was made up of 32,375 patients who had experienced ischemic stroke that was treated with thrombolysis but who had received no prior anticoagulation therapy.

Compared with control patients, patients who had recently taken DOACs were older; the incidence of hypertension among them was higher; they had a higher degree of prestroke disability; they were less likely to be smokers; the time from symptom onset to treatment was longer; they had experienced more severe stroke; and they were more likely to have a large-vessel occlusion.

Of the patients taking DOACs, 30.3% received DOAC reversal prior to thrombolysis. For 27.0%, DOAC plasma levels were measured. The remainder were treated with thrombolysis without either of these selection methods.

Results showed that the unadjusted rate of sICH was 2.5% among patients taking DOACs, compared with 4.1% among control patients who were not taking anticoagulants.

After adjustment for stroke severity and other baseline sICH predictors, patients who had recently taken DOACs and who received thrombolysis had lower odds of developing sICH (adjusted odds ratio, 0.57; 95% confidence interval, 0.36-0.92; P = .02).

There was no difference between the selection strategies, and results were consistent in different sensitivity analyses.

The secondary outcome of any ICH occurred in 18.0% in patients taking DOACs, compared with 17.4% among control patients who used no anticoagulants. After adjustment, there was no difference in the odds for any ICH between the groups (aOR, 1.18; 95% CI, 0.95-1.45; P = .14).

The unadjusted rate of functional independence was 45% among patients taking DOACs, compared with 57% among control patients. After adjustment, patients who had recently taken DOACs and who underwent thrombolysis had numerically higher odds of being functionally independent than control patients, although this difference did not reach statistical significance (aOR, 1.13; 95% CI, 0.94-1.36; P = .20).

The association of DOAC therapy with lower odds of sICH remained when mechanical thrombectomy, large-vessel occlusion, or concomitant antiplatelet therapy was added to the model.

“This is by far the largest study to look at this issue of thrombolytic use in patients on DOACs, and we did not find any group on DOACs that had an excess ICH rate with thrombolysis,” Dr. Seiffge said,

He explained that receiving warfarin was at one time an absolute contraindication for thrombolysis, but after a 2014 study suggested that the risk was not increased for patients with an international normalized ratio below 117, this was downgraded to a relative contraindication.

“We think our study is comparable and should lead to a guideline change,” Dr. Seiffge commented.

“A relative contraindication allows clinicians the space to make a considered decision on an individual basis,” he added.

Dr. Seiffge said that at his hospital, local guidelines regarding this issue have already been changed on the basis of these data, and use of DOACs is now considered a relative contraindication.

“International guidelines can take years to update, so in the meantime, I think other centers will also go ahead with a more liberal approach. There are always some centers that are ahead of the guidelines,” he added.

Although the lower risk of sICH seen in patients who have recently used DOACs seems counterintuitive at first glance, there could be a pathophysiologic explanation for this finding, the authors suggest.

They point out that thrombin inhibition, either directly or via the coagulation cascade, might be protective against the occurrence of sICH.

“Anticoagulants may allow the clot to respond better to thrombolysis – the clot is not as solid and is easier to recanalize. This leads to smaller strokes and a lower bleeding risk. Thrombin generation is also a major driver for blood brain barrier breakdown. DOACs reduce thrombin generation, so reduce blood brain barrier breakdown and reduce bleeding,” Dr. Seiffge explained. “But these are hypotheses,” he added.
 

Study ‘meaningfully advances the field’

In an accompanying editorial, Eva A. Mistry, MBBS, University of Cincinnati, said the current study “meaningfully advances the field” and provides an estimation of safety of intravenous thrombolysis among patients who have taken DOACs within 48 hours of hospital admission.

She lists strengths of the study as inclusion of a large number of patients across several geographically diverse institutions with heterogeneous standard practices for thrombolysis with recent DOAC use and narrow confidence intervals regarding observed rates of sICH.

“Further, the upper bound of this confidence interval for the DOAC group is below 4%, which is a welcome result and provides supportive data for clinicians who already practice thrombolysis for patients with recent DOAC ingestion,” Dr. Mistry adds.

However, she points out several study limitations, which she says limit immediate, widespread clinical applicability.

These include use of a nonconcurrent control population, which included patients from centers that did not contribute to the DOAC group and the inclusion of Asian patients who likely received a lower thrombolytic dose.

Dr. Seiffge noted that the researchers did adjust for Asian patients but not for the thrombolytic dosage. “I personally do not think this affects the results, as Asian patients have a lower dosage because they have a higher bleeding risk. The lower bleeding risk with DOACs was seen in all continents.”

Dr. Mistry also suggests that the DOAC group itself is prone to selection bias from preferential thrombolysis of patients receiving DOAC who are at lower risk of sICH.

But Dr. Seiffge argued: “I think, actually, the opposite is true. The DOAC patients were older, had more severe comorbidities, and an increased bleeding risk.”

Dr. Mistry concluded, “Despite the limitations of the study design and enrolled population, these data may be used by clinicians to make individualized decisions regarding thrombolysis among patients with recent DOAC use. Importantly, this study lays the foundation for prospective, well-powered studies that definitively determine the safety of thrombolysis in this population.”

The study was supported by a grant from the Bangerter-Rhyner Foundation. Dr. Seiffge received grants from Bangerter Rhyner Foundation during the conduct of the study and personal fees from Bayer, Alexion, and VarmX outside the submitted work. Dr. Mistry receives grant funding from the National Institute of Neurological Disorders and Stroke and serves as a consultant for RAPID AI.

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

U.S. News & World Report recently released its annual ratings of the best diets based on medical and nutritional data. It was the Mediterranean diet for the sixth year in a row.

Does this surprise anyone?

Although first publicized in 1975, the diet really didn’t gain attention until the 1990s. But, since then, the evidence in its favor has steadily grown.

Granted, while it was codified into a diet then, the benefits of fruits and vegetables weren’t exactly a secret beforehand. I’m pretty sure all of us remember being told to eat our vegetables (often repeatedly) while growing up.

So it’s not like we, both medical and nonmedical people, should be surprised at the results.

Is it really going to change anyone’s dietary habits?

Of course it will! It’s the beginning of the new year, and this time people are actually going to stick with their resolutions! For the first time they understand that ... who am I kidding?

For some people (hopefully myself included) there will be success at eating better and taking care of themselves. For most it will be Groundhog Day, both literally and figuratively, when February comes around.

It makes me wonder why this is. We all know what’s good for us. The evidence to support the Mediterranean diet is solid. The foods on it are widely available, often at lower cost than the usual American protein-heavy and processed foods habits. They’re flexible, and, generally taste good.

Yet, for all the evidence behind it, most won’t stick with it. Too many years of habits. Too many stressful days at work that lower our willpower to stick with it. Too many convenient reasons to count.

The question really isn’t “what’s the best diet?” That’s been answered. Realistically I don’t see that changing anytime soon.

The real question is “how do I stick with it?”

And another 5, 10, or 20 years of annually trying to figure out what the best diet is won’t change that.

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

U.S. News & World Report recently released its annual ratings of the best diets based on medical and nutritional data. It was the Mediterranean diet for the sixth year in a row.

Does this surprise anyone?

Although first publicized in 1975, the diet really didn’t gain attention until the 1990s. But, since then, the evidence in its favor has steadily grown.

Granted, while it was codified into a diet then, the benefits of fruits and vegetables weren’t exactly a secret beforehand. I’m pretty sure all of us remember being told to eat our vegetables (often repeatedly) while growing up.

So it’s not like we, both medical and nonmedical people, should be surprised at the results.

Is it really going to change anyone’s dietary habits?

Of course it will! It’s the beginning of the new year, and this time people are actually going to stick with their resolutions! For the first time they understand that ... who am I kidding?

For some people (hopefully myself included) there will be success at eating better and taking care of themselves. For most it will be Groundhog Day, both literally and figuratively, when February comes around.

It makes me wonder why this is. We all know what’s good for us. The evidence to support the Mediterranean diet is solid. The foods on it are widely available, often at lower cost than the usual American protein-heavy and processed foods habits. They’re flexible, and, generally taste good.

Yet, for all the evidence behind it, most won’t stick with it. Too many years of habits. Too many stressful days at work that lower our willpower to stick with it. Too many convenient reasons to count.

The question really isn’t “what’s the best diet?” That’s been answered. Realistically I don’t see that changing anytime soon.

The real question is “how do I stick with it?”

And another 5, 10, or 20 years of annually trying to figure out what the best diet is won’t change that.

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

U.S. News & World Report recently released its annual ratings of the best diets based on medical and nutritional data. It was the Mediterranean diet for the sixth year in a row.

Does this surprise anyone?

Although first publicized in 1975, the diet really didn’t gain attention until the 1990s. But, since then, the evidence in its favor has steadily grown.

Granted, while it was codified into a diet then, the benefits of fruits and vegetables weren’t exactly a secret beforehand. I’m pretty sure all of us remember being told to eat our vegetables (often repeatedly) while growing up.

So it’s not like we, both medical and nonmedical people, should be surprised at the results.

Is it really going to change anyone’s dietary habits?

Of course it will! It’s the beginning of the new year, and this time people are actually going to stick with their resolutions! For the first time they understand that ... who am I kidding?

For some people (hopefully myself included) there will be success at eating better and taking care of themselves. For most it will be Groundhog Day, both literally and figuratively, when February comes around.

It makes me wonder why this is. We all know what’s good for us. The evidence to support the Mediterranean diet is solid. The foods on it are widely available, often at lower cost than the usual American protein-heavy and processed foods habits. They’re flexible, and, generally taste good.

Yet, for all the evidence behind it, most won’t stick with it. Too many years of habits. Too many stressful days at work that lower our willpower to stick with it. Too many convenient reasons to count.

The question really isn’t “what’s the best diet?” That’s been answered. Realistically I don’t see that changing anytime soon.

The real question is “how do I stick with it?”

And another 5, 10, or 20 years of annually trying to figure out what the best diet is won’t change that.

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

A new consensus statement from the American Thyroid Association (ATA) and European Thyroid Association (ETA) offers recommendations for endocrinologists on the management of thyroid eye disease (TED), addressing key questions, including about important novel treatments, that transcend international borders.

The consensus statement is important as new therapies transform the treatment of TED that, notably, have even played a key role in simplifying the name of the disease, which has had numerous other, often confusing names over the years, ranging from thyrotropic exophthalmos to Graves ophthalmopathy, Terry F. Davies, MD, of the thyroid research unit, department of medicine, Icahn School of Medicine at Mount Sinai, New York, said in an editorial published along with the statement in Thyroid.

“The emergence of novel therapies has changed the entire discussion concerning TED and not just its name,” he wrote. “These are early and exciting days in the treatment of TED, which is likely to be a much more manageable disease in the years to come.”

However, Dr. Davies stressed to this news organization that there are still a lot of unanswered questions, particularly when it comes to newer therapies. For example, teprotumumab can cost up to $300,000 for one course of treatment for one patient, the consensus statement notes.
 

When to consult an ophthalmologist

Graves disease is the most common cause of hyperthyroidism and affects > 1% of the U.S. population. TED is the most common complication of Graves disease that occurs outside of the thyroid gland. TED causes a variety of eye-related signs and symptoms, which can be disfiguring and negatively affect quality of life, and in rare cases, threaten vision.

Key issues covered in the consensus statement include timely diagnosis of TED, assessment of disease activity and severity, initial care and referral for specialty care, and treatment recommendations for moderate to severe TED.

In terms of disease assessment, for instance, the statement authors noted the important distinction in TED “between the two interdependent components of inflammatory activity, manifested by pain, redness, and edema, and disease severity, including proptosis, lid malposition, exposure keratopathy, impaired ocular motility, and optic neuropathy.”

“The presence of multiple features of inflammation usually signifies active disease,” they explained.

For initial care, input from endocrinologists as well as ophthalmologists with experience in TED management is urged, and “an ophthalmologist should be consulted when the diagnosis of TED is uncertain, in cases of moderate to severe TED, and when surgical intervention needs to be considered.”

Furthermore, “urgent referral is required when sight-threatening TED is suspected or confirmed,” the authors noted.
 

Debate over some treatment recommendations

In terms of therapy, for initial care, “a single course of selenium selenite 100 mcg twice daily for 6 months may be considered for patients with mild, active TED, particularly in regions of selenium insufficiency,” the consensus statement recommends.

Intravenous glucocorticoid (IVGC) therapy is meanwhile recommended as a preferred treatment for active moderate to severe TED specifically when disease activity is the prominent feature in the absence of significant proptosis or diplopia.

For patients with active moderate to severe TED who are glucocorticoid-resistant, the authors noted that rituximab and tocilizumab may be considered and that teprotumumab has not been evaluated in this setting.

Teprotumumab, if available, is a preferred therapy for patients with active moderate to severe TED who have significant proptosis.

There is, however, some debate over the issue, editorial author Dr. Davies told this news organization.

“It is still argued over how bad the eyes need to be before recommending this new treatment,” he said. “I think the answer is in the proptosis – the amount of bulging present rather than just inflammation,” Dr. Davies said.

“There is also a real clinical problem in that we have no specific biomarker for the disease, however, high levels of TSH receptor antibody are often a good indicator of eye disease.”

The authors cautioned, however, that clinical trials with medical therapies have been limited by inclusion criteria and other factors, and biologics have meanwhile increased the cost of treatment “many-fold” compared with conventional agents.

Therefore, “clinicians should balance the demonstrated efficacy of recently introduced therapies [such as teprotumumab] against the absence of experience on sustained long-term efficacy, safety, and cost-effectiveness,” they noted.

Importantly, “one course consisting of eight infusions of teprotumumab has a retail cost of approximately $300,000, depending on patient weight, [which is] approximately 2,000 times that of IVGC,” they noted.

“The process involved in selecting therapy with these drugs and other drugs includes a consideration of both short- and long-term efficacy, adverse effects that are both known and unknown, the likelihood of disease aggravation or relapse after a previously beneficial response, and the relative cost and availability,” said Henry B. Burch, MD, who is at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, in Bethesda, Md., and is on the consensus statement task force.

To help with those decisions, the consensus statement provides comprehensive tables that compare drug efficacy for key outcomes including inflammation, proptosis, diplopia, and quality of life, and importantly, comparisons also of drug costs and potential adverse effects for each of the current TED therapies.
 

Consensus statement not a guideline

The groups noted that the consensus statement is not meant to be a clinical practice guideline and was not written to “establish a standard of care, replace sound clinical judgment, or capture all nuances likely to be present in any particular patient,” and “specific outcomes are not guaranteed.”

What the statement is intended for is to “provide a concise and timely appraisal of a rapidly changing therapeutic arena” for practicing endocrinologists, they explained.

Overall, the authors recommend an individualized management approach, based on factors ranging from disease severity, duration, its impact on daily living, patient age, comorbidities, and importantly, the costs of therapies.

Ultimately, patient satisfaction is essential in TED management, Dr. Burch added.

“Consideration of the impact of TED on patient’s satisfaction with their appearance and visual functioning is a key component in management decisions concerning TED.”A version of this article first appeared on Medscape.com.

A new consensus statement from the American Thyroid Association (ATA) and European Thyroid Association (ETA) offers recommendations for endocrinologists on the management of thyroid eye disease (TED), addressing key questions, including about important novel treatments, that transcend international borders.

The consensus statement is important as new therapies transform the treatment of TED that, notably, have even played a key role in simplifying the name of the disease, which has had numerous other, often confusing names over the years, ranging from thyrotropic exophthalmos to Graves ophthalmopathy, Terry F. Davies, MD, of the thyroid research unit, department of medicine, Icahn School of Medicine at Mount Sinai, New York, said in an editorial published along with the statement in Thyroid.

“The emergence of novel therapies has changed the entire discussion concerning TED and not just its name,” he wrote. “These are early and exciting days in the treatment of TED, which is likely to be a much more manageable disease in the years to come.”

However, Dr. Davies stressed to this news organization that there are still a lot of unanswered questions, particularly when it comes to newer therapies. For example, teprotumumab can cost up to $300,000 for one course of treatment for one patient, the consensus statement notes.
 

When to consult an ophthalmologist

Graves disease is the most common cause of hyperthyroidism and affects > 1% of the U.S. population. TED is the most common complication of Graves disease that occurs outside of the thyroid gland. TED causes a variety of eye-related signs and symptoms, which can be disfiguring and negatively affect quality of life, and in rare cases, threaten vision.

Key issues covered in the consensus statement include timely diagnosis of TED, assessment of disease activity and severity, initial care and referral for specialty care, and treatment recommendations for moderate to severe TED.

In terms of disease assessment, for instance, the statement authors noted the important distinction in TED “between the two interdependent components of inflammatory activity, manifested by pain, redness, and edema, and disease severity, including proptosis, lid malposition, exposure keratopathy, impaired ocular motility, and optic neuropathy.”

“The presence of multiple features of inflammation usually signifies active disease,” they explained.

For initial care, input from endocrinologists as well as ophthalmologists with experience in TED management is urged, and “an ophthalmologist should be consulted when the diagnosis of TED is uncertain, in cases of moderate to severe TED, and when surgical intervention needs to be considered.”

Furthermore, “urgent referral is required when sight-threatening TED is suspected or confirmed,” the authors noted.
 

Debate over some treatment recommendations

In terms of therapy, for initial care, “a single course of selenium selenite 100 mcg twice daily for 6 months may be considered for patients with mild, active TED, particularly in regions of selenium insufficiency,” the consensus statement recommends.

Intravenous glucocorticoid (IVGC) therapy is meanwhile recommended as a preferred treatment for active moderate to severe TED specifically when disease activity is the prominent feature in the absence of significant proptosis or diplopia.

For patients with active moderate to severe TED who are glucocorticoid-resistant, the authors noted that rituximab and tocilizumab may be considered and that teprotumumab has not been evaluated in this setting.

Teprotumumab, if available, is a preferred therapy for patients with active moderate to severe TED who have significant proptosis.

There is, however, some debate over the issue, editorial author Dr. Davies told this news organization.

“It is still argued over how bad the eyes need to be before recommending this new treatment,” he said. “I think the answer is in the proptosis – the amount of bulging present rather than just inflammation,” Dr. Davies said.

“There is also a real clinical problem in that we have no specific biomarker for the disease, however, high levels of TSH receptor antibody are often a good indicator of eye disease.”

The authors cautioned, however, that clinical trials with medical therapies have been limited by inclusion criteria and other factors, and biologics have meanwhile increased the cost of treatment “many-fold” compared with conventional agents.

Therefore, “clinicians should balance the demonstrated efficacy of recently introduced therapies [such as teprotumumab] against the absence of experience on sustained long-term efficacy, safety, and cost-effectiveness,” they noted.

Importantly, “one course consisting of eight infusions of teprotumumab has a retail cost of approximately $300,000, depending on patient weight, [which is] approximately 2,000 times that of IVGC,” they noted.

“The process involved in selecting therapy with these drugs and other drugs includes a consideration of both short- and long-term efficacy, adverse effects that are both known and unknown, the likelihood of disease aggravation or relapse after a previously beneficial response, and the relative cost and availability,” said Henry B. Burch, MD, who is at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, in Bethesda, Md., and is on the consensus statement task force.

To help with those decisions, the consensus statement provides comprehensive tables that compare drug efficacy for key outcomes including inflammation, proptosis, diplopia, and quality of life, and importantly, comparisons also of drug costs and potential adverse effects for each of the current TED therapies.
 

Consensus statement not a guideline

The groups noted that the consensus statement is not meant to be a clinical practice guideline and was not written to “establish a standard of care, replace sound clinical judgment, or capture all nuances likely to be present in any particular patient,” and “specific outcomes are not guaranteed.”

What the statement is intended for is to “provide a concise and timely appraisal of a rapidly changing therapeutic arena” for practicing endocrinologists, they explained.

Overall, the authors recommend an individualized management approach, based on factors ranging from disease severity, duration, its impact on daily living, patient age, comorbidities, and importantly, the costs of therapies.

Ultimately, patient satisfaction is essential in TED management, Dr. Burch added.

“Consideration of the impact of TED on patient’s satisfaction with their appearance and visual functioning is a key component in management decisions concerning TED.”A version of this article first appeared on Medscape.com.

A new consensus statement from the American Thyroid Association (ATA) and European Thyroid Association (ETA) offers recommendations for endocrinologists on the management of thyroid eye disease (TED), addressing key questions, including about important novel treatments, that transcend international borders.

The consensus statement is important as new therapies transform the treatment of TED that, notably, have even played a key role in simplifying the name of the disease, which has had numerous other, often confusing names over the years, ranging from thyrotropic exophthalmos to Graves ophthalmopathy, Terry F. Davies, MD, of the thyroid research unit, department of medicine, Icahn School of Medicine at Mount Sinai, New York, said in an editorial published along with the statement in Thyroid.

“The emergence of novel therapies has changed the entire discussion concerning TED and not just its name,” he wrote. “These are early and exciting days in the treatment of TED, which is likely to be a much more manageable disease in the years to come.”

However, Dr. Davies stressed to this news organization that there are still a lot of unanswered questions, particularly when it comes to newer therapies. For example, teprotumumab can cost up to $300,000 for one course of treatment for one patient, the consensus statement notes.
 

When to consult an ophthalmologist

Graves disease is the most common cause of hyperthyroidism and affects > 1% of the U.S. population. TED is the most common complication of Graves disease that occurs outside of the thyroid gland. TED causes a variety of eye-related signs and symptoms, which can be disfiguring and negatively affect quality of life, and in rare cases, threaten vision.

Key issues covered in the consensus statement include timely diagnosis of TED, assessment of disease activity and severity, initial care and referral for specialty care, and treatment recommendations for moderate to severe TED.

In terms of disease assessment, for instance, the statement authors noted the important distinction in TED “between the two interdependent components of inflammatory activity, manifested by pain, redness, and edema, and disease severity, including proptosis, lid malposition, exposure keratopathy, impaired ocular motility, and optic neuropathy.”

“The presence of multiple features of inflammation usually signifies active disease,” they explained.

For initial care, input from endocrinologists as well as ophthalmologists with experience in TED management is urged, and “an ophthalmologist should be consulted when the diagnosis of TED is uncertain, in cases of moderate to severe TED, and when surgical intervention needs to be considered.”

Furthermore, “urgent referral is required when sight-threatening TED is suspected or confirmed,” the authors noted.
 

Debate over some treatment recommendations

In terms of therapy, for initial care, “a single course of selenium selenite 100 mcg twice daily for 6 months may be considered for patients with mild, active TED, particularly in regions of selenium insufficiency,” the consensus statement recommends.

Intravenous glucocorticoid (IVGC) therapy is meanwhile recommended as a preferred treatment for active moderate to severe TED specifically when disease activity is the prominent feature in the absence of significant proptosis or diplopia.

For patients with active moderate to severe TED who are glucocorticoid-resistant, the authors noted that rituximab and tocilizumab may be considered and that teprotumumab has not been evaluated in this setting.

Teprotumumab, if available, is a preferred therapy for patients with active moderate to severe TED who have significant proptosis.

There is, however, some debate over the issue, editorial author Dr. Davies told this news organization.

“It is still argued over how bad the eyes need to be before recommending this new treatment,” he said. “I think the answer is in the proptosis – the amount of bulging present rather than just inflammation,” Dr. Davies said.

“There is also a real clinical problem in that we have no specific biomarker for the disease, however, high levels of TSH receptor antibody are often a good indicator of eye disease.”

The authors cautioned, however, that clinical trials with medical therapies have been limited by inclusion criteria and other factors, and biologics have meanwhile increased the cost of treatment “many-fold” compared with conventional agents.

Therefore, “clinicians should balance the demonstrated efficacy of recently introduced therapies [such as teprotumumab] against the absence of experience on sustained long-term efficacy, safety, and cost-effectiveness,” they noted.

Importantly, “one course consisting of eight infusions of teprotumumab has a retail cost of approximately $300,000, depending on patient weight, [which is] approximately 2,000 times that of IVGC,” they noted.

“The process involved in selecting therapy with these drugs and other drugs includes a consideration of both short- and long-term efficacy, adverse effects that are both known and unknown, the likelihood of disease aggravation or relapse after a previously beneficial response, and the relative cost and availability,” said Henry B. Burch, MD, who is at the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, in Bethesda, Md., and is on the consensus statement task force.

To help with those decisions, the consensus statement provides comprehensive tables that compare drug efficacy for key outcomes including inflammation, proptosis, diplopia, and quality of life, and importantly, comparisons also of drug costs and potential adverse effects for each of the current TED therapies.
 

Consensus statement not a guideline

The groups noted that the consensus statement is not meant to be a clinical practice guideline and was not written to “establish a standard of care, replace sound clinical judgment, or capture all nuances likely to be present in any particular patient,” and “specific outcomes are not guaranteed.”

What the statement is intended for is to “provide a concise and timely appraisal of a rapidly changing therapeutic arena” for practicing endocrinologists, they explained.

Overall, the authors recommend an individualized management approach, based on factors ranging from disease severity, duration, its impact on daily living, patient age, comorbidities, and importantly, the costs of therapies.

Ultimately, patient satisfaction is essential in TED management, Dr. Burch added.

“Consideration of the impact of TED on patient’s satisfaction with their appearance and visual functioning is a key component in management decisions concerning TED.”A version of this article first appeared on Medscape.com.

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

Readjudication of mortality data from the FOURIER trial suggests a higher risk for cardiovascular death with evolocumab (Repatha) among patients with established atherosclerotic cardiovascular disease than originally reported for the first-in-class PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor.

The Restoring Invisible and Abandoned Trials (RIAT) investigators launched this review in 2018, citing “significant inconsistencies and misreporting” between information in death narratives in the trial’s clinical study report (CSR) and the 2017 New England Journal of Medicine publication of the primary trial results.

“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the researchers conclude in the new report published online in BMJ Open. “At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our adjudication.

“Our findings indicate that complete restoration of all clinical outcomes from the FOURIER trial is required,” they wrote. “Meanwhile, clinicians should be skeptical about benefits vs harms of prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.”

Asked to comment on the reanalysis, FOURIER lead investigator Marc Sabatine, MD, MPH, a professor of medicine at Harvard Medical School and the Lewis Dexter distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital, both in Boston, said: “It’s hard to call this science. I think it lacks all scientific rigor and is fundamentally flawed and, because their process was flawed, it has led them to erroneous conclusions.”

Reached for comment, Sanjay Kaul, MD, a cardiologist and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, who was not involved with either study, said: “If I were to describe this in one sentence, I would say much ado about nothing. A tempest in a teapot.”
 

Evaluating hard outcomes

The Food and Drug Administration approved evolocumab in 2015 for lowering LDL cholesterol levels, but without results from any trial evaluating hard outcomes.

As previously reported in 2017, FOURIER showed that adding evolocumab to high-intensity statins slashed LDL cholesterol by 59% and was associated with a 15% reduction in the primary composite cardiovascular events endpoint, compared with placebo, but numerically more all-cause and CV mortality.

The NEJM data analysis reported the risk for cardiovascular mortality was 5% (hazard ratio, 1.05; 95% confidence interval, 0.88-1.25), whereas the new review found a still nonsignificant 20% relative risk (R95% CI, 0.95-1.51).

Cardiac deaths were also numerically higher in the evolocumab group (113 vs. 88), corresponding to a 28% higher relative risk (95% CI, 0.97-1.69). Vascular deaths were similar at 37 in both groups (RR, 1.00; 95% CI, 0.63-1.58).

For 360 of the 870 deaths, the cause of death adjudicated by the FOURIER clinical events committee differs from that identified by the local clinical investigators in the CSR death narrative, the authors said.

The RIAT investigators found 11 more deaths from myocardial infarction in the evolocumab group (36 vs. 25 in NEJM) and 3 fewer deaths in the placebo group (27 vs. 30). In addition, their review indicated that deaths as a result of cardiac failure in the evolocumab group were almost double those in the placebo group, at 31 versus 16, respectively.
 

An ‘obvious disconnect’

Thomas L. Perry, MD, a coauthor of the BMJ Open paper and a general internist in the department of anesthesiology, pharmacology, and therapeutics at the University of British Columbia, Vancouver, said in an interview that the team repeatedly sought information from the FOURIER investigators but never received a response.

They petitioned and received the FOURIER CSR from the European Medicines Agency and Health Canada and made a similar request with the FDA but were told in October 2019 it would take up to 7 years to release the information. Case report forms were also requested but not received from all three agencies.

Dr. Perry noted that no autopsies were performed in the trial, a claim Dr. Sabatine rejected, and that their review of the death narratives in the CSR found 91 deaths classified by the local investigator as “undetermined” but subsequently adjudicated by the FOURIER clinical events committee as “sudden cardiac” deaths without any documented evidence to support the change.

At his request, Dr. Perry said they included two case examples (figures 1 and 2) in the BMJ Open paper of the “obvious disconnect” in death endpoints. Both of these were identified by the local investigator as a myocardial infarction but later “misreported” according to Dr. Perry, as a sudden cardiac death and noncardiovascular death (trauma), respectively.

“What’s so important about this is not only that it throws into doubt the reliability of what the people at Harvard and elsewhere reported in the New England Journal of Medicine in 2017, but also raises a question about any other large study like this where you rely on supposedly ethical local investigators to run the trial well and to report accurately what happens to people,” Dr. Perry said in an interview.

Although he never prescribed evolocumab after the initial results were published, Dr. Perry said he’s even less convinced of a benefit now. “Basically, I don’t believe that they are telling us the facts. I have no reason to say there’s an element of deliberately misleading us. I think it’s sloppiness, incompetence, laziness.”

Dr. Perry also favors readjudication of the mortality data in the ODYSSEY trial, which showed an all-cause mortality benefit with the PCSK9 inhibitor alirocumab (Praluent).
 

The ‘full picture’

Dr. Sabatine explained that when a patient had a cardiovascular event, including a death, it triggered the collection of a full dossier containing all available source documents, such as discharge summaries, laboratory and imaging data, and autopsy reports, that were independently reviewed by two board certified physicians blinded to treatment. To suggest, as the RIAT investigators have, that no autopsies were performed is “obviously ridiculous and wrong.”

In contrast, he said the new analysis was post hoc, involved unblinded individuals, and relied on serious adverse event narratives, which include a small text box that must be filled out with the site’s initial impression of the case and sent within 24 hours of the event.

Further, when the FOURIER investigators pulled the dossiers for the two more egregious examples cited in the paper, they found that the first patient died in his sleep at home. “The investigator then just said, ‘oh, I assume it’s an MI,’ but there’s no biochemical data, there’s no ECGs, there’s nothing to make the diagnosis of MI. So that’s why that is a sudden cardiac death per the FDA definition,” Dr. Sabatine said.

When the FOURIER investigators reviewed the full dossier for the second case example, they found the patient had slipped in his kitchen at home, sustained a serious head trauma, was brought into the emergency department, and died.

“That’s why we rely on the source documents. That gives the full picture,” he said. The FDA also reviewed the death narratives.

“They comment, ironically, that they were surprised at the inconsistencies between the investigator-reported causes of death and the central events committee-adjudicated ones, making it sound like something nefarious has happened. But that’s the whole point of adjudication, right? That you have a central events committee that reviews and then classifies based on all the data,” Dr. Sabatine said.

Dr. Sabatine said he sees no reason to reevaluate the ODYSSEY mortality data and that the RIAT analysis should not change the overall interpretation of FOURIER.

“I think this is in fact a disservice to the medical community because it’s not real science,” he said. “It’s just sensationalism and sends the wrong message. But I completely stand by the results that we published, as the FDA has.”

Dr. Kaul also thought the new analysis doesn’t materially change the overall benefit–risk balance. He observed that there isn’t a major difference between the reanalysis and the original evaluation. Total mortality was similar and, for cardiovascular deaths, the original NEJM paper lists 251 for evolocumab versus 240 for placebo and the reanalysis lists 150 versus 125, respectively.

Undetermined deaths were 144 for evolocumab and 164 for placebo in the reanalysis. “The conservative approach is to count them as presumed cardiovascular deaths,” Dr. Kaul said. “So, if you do the math and add those undetermined as cardiovascular deaths, we get a total of 294 (150 + 144) versus 289 (125 + 164). That’s five excess deaths with evolocumab.”
 

Open access

Although the RIAT group has called for the public release of the FOURIER data, commercial and legal issues will complicate that process, Steven Grover, MD, professor of medicine and director of the comprehensive health improvement program at McGill University, Montreal, said in an interview. Amgen is back in court over patent protection, filing an appeal with the Supreme Court after losing in the lower courts in a protracted battle, Reuters reported.

“One thing that’s for sure after they’ve raised questions about the results of this study [is that] somebody needs to take a good hard look at the adjudicated results,” said Dr. Grover, who coauthored several iterations of the Canadian Cardiovascular Society dyslipidemia guidelines, including the latest in 2021.

“I think the thing that got so many of us back in 2017 when the study was first published is the mortality data stuck out like a sore thumb,” he said in an interview. “It didn’t have to be statistically significant, but it did need to move in the same direction as the nonfatal coronary events. That’s what we’ve seen happen time and again and, in this case, it was going in the opposite direction.”

Dr. Sabatine said he doesn’t know whether the data will be released but that the FOURIER trialists plan to submit a rebuttal to BMJ Open to the RIAT analysis, which has caused a stir on CardioTwitter. “Now that people live with tweets of information, it necessitates then dispelling the misinformation that comes out. So yes, we will draft a rebuttal pointing out all the flaws in this analysis.”

Dr. Kaul commented that the FDA’s response not to provide the data was “rather curious” and that Dr. Sabatine and colleagues had the opportunity to address the RIAT group’s concerns, but the paper notes they did not even bother to respond. “You can’t be holier than thou in medicine. You have to treat every question with respect and humility and can’t be dismissive. ... He could have nipped the evil in the bud, so to speak.”

The study was funded by a grant from the University of Maryland, Baltimore. The authors, Dr. Kaul, and Dr. Grover reported having no relevant financial relationships.

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

Participation in the first 2 years of Maryland’s Advanced Primary Care Program (MDPCP) was associated with better COVID-19 outcomes compared with a matched group not involved with the program, new data indicate.

The better outcomes were seen in higher vaccination rates and fewer infections, hospitalizations, and deaths from the disease, according to study authors, led by Emily Gruber, MBA, MPH, with the Maryland Primary Care Program, Maryland Department of Health in Baltimore.

The results were published online in JAMA Network Open.

The study population was divided into MDPCP participants (n = 208,146) and a matched cohort (n = 37,203) of beneficiaries not attributed to MDPCP practices but who met eligibility criteria for study participation from Jan. 1, 2020, through Dec. 31, 2021.
 

More vaccinations, more antibody treatments

Researchers broke down the comparisons of better outcomes: 84.47% of MDPCP beneficiaries were fully vaccinated vs. 77.93% of nonparticipating beneficiaries (P less than .001). COVID-19–positive program beneficiaries also received monoclonal antibody treatment more often (8.45% vs. 6.11%; P less than .001).

Plus, program participants received more care via telehealth (62.95% vs. 54.53%; P less than .001) compared with those not participating.

Regarding secondary outcomes, MDPCP beneficiaries had lower rates of COVID cases (6.55% vs. 7.09%; P less than .001), lower rates of COVID-19 hospitalizations (1.81% vs. 2.06%; P = .001), and lower rates of death due to COVID-19 (0.56% vs. 0.77%; P less than .001).
 

Program components

Enrollment in the MDPCP is voluntary, and primary care practices can apply each year to be part of the program.

The model integrates primary care and public health in the pandemic response. It was created by the Maryland Department of Health (MDH) and the Centers for Medicare & Medicaid Services (CMS).

It expands the role of primary care to include services such as expanded care management, integrated behavioral health, data-driven care, and screenings and referrals to address social needs.

Coauthor Howard Haft, MD, MMM, with the Maryland Department of Public Health, said in an interview that among the most important factors in the program’s success were giving providers vaccines to distribute and then giving providers data on how many patients are vaccinated, and who’s not vaccinated but at high risk, and how those rates compare to other practices.

As to whether this could be a widespread model, Dr. Haft said, “It’s highly replicable.”

“Every state in the nation overall has all of these resources. It’s a matter of having the operational and political will to put those resources together. Almost every state has the technological ability to use their health information exchange to help tie pieces together.”
 

Vaccines and testing made available to providers

Making ample vaccines and testing available to providers in their offices helped patients get those services in a place they trust, Dr. Haft said.

The model also included a payment system for providers that included a significant amount of non–visit-based payments when many locations were closed in the height of the pandemic.

“That helped financially,” as did providing free telehealth platforms to practices with training on how to use them, Dr. Haft said.
 

‘Innovative and important’

Renu Tipirneni, MD, an assistant professor of internal medicine at the University of Michigan and at the Institute for Healthcare Policy and Innovation in Ann Arbor, said Maryland is out front putting into practice what practices nationwide aspire to do – coordinating physical and mental health and social needs and integrating primary and public health. Dr. Tipirneni, who was not involved with the study, said she was impressed the researchers were able to show statistically significant improvement with COVID-19 outcomes in the first 2 years.

“In terms of health outcomes, we often have to wait longer to see good outcomes,” she said. “It’s a really innovative and important model.”

She said states can learn from each other and this model is an example.

Integrating primary care and public health and addressing social needs may be the biggest challenges for states, she said, as those realms typically have been siloed.

“But they may be the key components to achieving these outcomes,” she said.
 

Take-home message

The most important benefit of the program is that data suggest it saves lives, according to Dr. Haft. While the actual difference between COVID deaths in the program and nonprogram groups was small, multiplying that savings across the nation shows substantial potential benefit, he explained.

“At a time when we were losing lives at an unconscionable rate, we were able to make a difference in saving lives,” Dr. Haft said.

Authors report no relevant financial disclosures.

The study received financial support from the Maryland Department of Health.

Dr. Tiperneni is helping evaluate Michigan’s Medicaid contract.
 

Participation in the first 2 years of Maryland’s Advanced Primary Care Program (MDPCP) was associated with better COVID-19 outcomes compared with a matched group not involved with the program, new data indicate.

The better outcomes were seen in higher vaccination rates and fewer infections, hospitalizations, and deaths from the disease, according to study authors, led by Emily Gruber, MBA, MPH, with the Maryland Primary Care Program, Maryland Department of Health in Baltimore.

The results were published online in JAMA Network Open.

The study population was divided into MDPCP participants (n = 208,146) and a matched cohort (n = 37,203) of beneficiaries not attributed to MDPCP practices but who met eligibility criteria for study participation from Jan. 1, 2020, through Dec. 31, 2021.
 

More vaccinations, more antibody treatments

Researchers broke down the comparisons of better outcomes: 84.47% of MDPCP beneficiaries were fully vaccinated vs. 77.93% of nonparticipating beneficiaries (P less than .001). COVID-19–positive program beneficiaries also received monoclonal antibody treatment more often (8.45% vs. 6.11%; P less than .001).

Plus, program participants received more care via telehealth (62.95% vs. 54.53%; P less than .001) compared with those not participating.

Regarding secondary outcomes, MDPCP beneficiaries had lower rates of COVID cases (6.55% vs. 7.09%; P less than .001), lower rates of COVID-19 hospitalizations (1.81% vs. 2.06%; P = .001), and lower rates of death due to COVID-19 (0.56% vs. 0.77%; P less than .001).
 

Program components

Enrollment in the MDPCP is voluntary, and primary care practices can apply each year to be part of the program.

The model integrates primary care and public health in the pandemic response. It was created by the Maryland Department of Health (MDH) and the Centers for Medicare & Medicaid Services (CMS).

It expands the role of primary care to include services such as expanded care management, integrated behavioral health, data-driven care, and screenings and referrals to address social needs.

Coauthor Howard Haft, MD, MMM, with the Maryland Department of Public Health, said in an interview that among the most important factors in the program’s success were giving providers vaccines to distribute and then giving providers data on how many patients are vaccinated, and who’s not vaccinated but at high risk, and how those rates compare to other practices.

As to whether this could be a widespread model, Dr. Haft said, “It’s highly replicable.”

“Every state in the nation overall has all of these resources. It’s a matter of having the operational and political will to put those resources together. Almost every state has the technological ability to use their health information exchange to help tie pieces together.”
 

Vaccines and testing made available to providers

Making ample vaccines and testing available to providers in their offices helped patients get those services in a place they trust, Dr. Haft said.

The model also included a payment system for providers that included a significant amount of non–visit-based payments when many locations were closed in the height of the pandemic.

“That helped financially,” as did providing free telehealth platforms to practices with training on how to use them, Dr. Haft said.
 

‘Innovative and important’

Renu Tipirneni, MD, an assistant professor of internal medicine at the University of Michigan and at the Institute for Healthcare Policy and Innovation in Ann Arbor, said Maryland is out front putting into practice what practices nationwide aspire to do – coordinating physical and mental health and social needs and integrating primary and public health. Dr. Tipirneni, who was not involved with the study, said she was impressed the researchers were able to show statistically significant improvement with COVID-19 outcomes in the first 2 years.

“In terms of health outcomes, we often have to wait longer to see good outcomes,” she said. “It’s a really innovative and important model.”

She said states can learn from each other and this model is an example.

Integrating primary care and public health and addressing social needs may be the biggest challenges for states, she said, as those realms typically have been siloed.

“But they may be the key components to achieving these outcomes,” she said.
 

Take-home message

The most important benefit of the program is that data suggest it saves lives, according to Dr. Haft. While the actual difference between COVID deaths in the program and nonprogram groups was small, multiplying that savings across the nation shows substantial potential benefit, he explained.

“At a time when we were losing lives at an unconscionable rate, we were able to make a difference in saving lives,” Dr. Haft said.

Authors report no relevant financial disclosures.

The study received financial support from the Maryland Department of Health.

Dr. Tiperneni is helping evaluate Michigan’s Medicaid contract.
 

Participation in the first 2 years of Maryland’s Advanced Primary Care Program (MDPCP) was associated with better COVID-19 outcomes compared with a matched group not involved with the program, new data indicate.

The better outcomes were seen in higher vaccination rates and fewer infections, hospitalizations, and deaths from the disease, according to study authors, led by Emily Gruber, MBA, MPH, with the Maryland Primary Care Program, Maryland Department of Health in Baltimore.

The results were published online in JAMA Network Open.

The study population was divided into MDPCP participants (n = 208,146) and a matched cohort (n = 37,203) of beneficiaries not attributed to MDPCP practices but who met eligibility criteria for study participation from Jan. 1, 2020, through Dec. 31, 2021.
 

More vaccinations, more antibody treatments

Researchers broke down the comparisons of better outcomes: 84.47% of MDPCP beneficiaries were fully vaccinated vs. 77.93% of nonparticipating beneficiaries (P less than .001). COVID-19–positive program beneficiaries also received monoclonal antibody treatment more often (8.45% vs. 6.11%; P less than .001).

Plus, program participants received more care via telehealth (62.95% vs. 54.53%; P less than .001) compared with those not participating.

Regarding secondary outcomes, MDPCP beneficiaries had lower rates of COVID cases (6.55% vs. 7.09%; P less than .001), lower rates of COVID-19 hospitalizations (1.81% vs. 2.06%; P = .001), and lower rates of death due to COVID-19 (0.56% vs. 0.77%; P less than .001).
 

Program components

Enrollment in the MDPCP is voluntary, and primary care practices can apply each year to be part of the program.

The model integrates primary care and public health in the pandemic response. It was created by the Maryland Department of Health (MDH) and the Centers for Medicare & Medicaid Services (CMS).

It expands the role of primary care to include services such as expanded care management, integrated behavioral health, data-driven care, and screenings and referrals to address social needs.

Coauthor Howard Haft, MD, MMM, with the Maryland Department of Public Health, said in an interview that among the most important factors in the program’s success were giving providers vaccines to distribute and then giving providers data on how many patients are vaccinated, and who’s not vaccinated but at high risk, and how those rates compare to other practices.

As to whether this could be a widespread model, Dr. Haft said, “It’s highly replicable.”

“Every state in the nation overall has all of these resources. It’s a matter of having the operational and political will to put those resources together. Almost every state has the technological ability to use their health information exchange to help tie pieces together.”
 

Vaccines and testing made available to providers

Making ample vaccines and testing available to providers in their offices helped patients get those services in a place they trust, Dr. Haft said.

The model also included a payment system for providers that included a significant amount of non–visit-based payments when many locations were closed in the height of the pandemic.

“That helped financially,” as did providing free telehealth platforms to practices with training on how to use them, Dr. Haft said.
 

‘Innovative and important’

Renu Tipirneni, MD, an assistant professor of internal medicine at the University of Michigan and at the Institute for Healthcare Policy and Innovation in Ann Arbor, said Maryland is out front putting into practice what practices nationwide aspire to do – coordinating physical and mental health and social needs and integrating primary and public health. Dr. Tipirneni, who was not involved with the study, said she was impressed the researchers were able to show statistically significant improvement with COVID-19 outcomes in the first 2 years.

“In terms of health outcomes, we often have to wait longer to see good outcomes,” she said. “It’s a really innovative and important model.”

She said states can learn from each other and this model is an example.

Integrating primary care and public health and addressing social needs may be the biggest challenges for states, she said, as those realms typically have been siloed.

“But they may be the key components to achieving these outcomes,” she said.
 

Take-home message

The most important benefit of the program is that data suggest it saves lives, according to Dr. Haft. While the actual difference between COVID deaths in the program and nonprogram groups was small, multiplying that savings across the nation shows substantial potential benefit, he explained.

“At a time when we were losing lives at an unconscionable rate, we were able to make a difference in saving lives,” Dr. Haft said.

Authors report no relevant financial disclosures.

The study received financial support from the Maryland Department of Health.

Dr. Tiperneni is helping evaluate Michigan’s Medicaid contract.
 

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.