Swelling of the heart appears to be a very rare side effect that primarily strikes young people after vaccination for COVID-19, a Centers for Disease Control and Prevention expert reported on June 10, detailing data on cases of myocarditis and pericarditis detected through a government safety system.

The side effect seems to be more common in teen boys and young men than in older adults and women and may occur in 16 cases for every 1 million people who got a second dose, said Tom Shimabukuro, MD, MPH, deputy director of the CDC’s Immunization Safety Office, who presented information on the cases at a meeting of an expert panel that advises the U.S. Food and Drug Administration on vaccines.

Telltale symptoms include chest pain, shortness of breath, and fever.

William Schaffner, MD, an infectious diseases specialist from Vanderbilt University, Nashville, Tenn., thinks certain characteristics are pointing toward a “rare, but real” signal. First, the events are clustering, occurring within days of vaccination. Second, they tend to be more common in males and younger people. Third, he says, the number of events is above the so-called “background rate” – the cases that could be expected in this age group even without vaccination.

“I don’t think we’re quite there yet. We haven’t tied a ribbon around it, but I think the data are trending in that direction,” he said.

The issue of myocarditis weighed heavily on the Vaccines and Related Biological Products Advisory Committee’s considerations of what kind and how much data might be needed to green light use of a vaccine for COVID in children. 

Because the rates of hospitalization for COVID are low in kids, some felt that the FDA should require at least a year of study of the vaccines in clinical trials, the amount of data typically required for full approval, instead of the 2 months currently required for emergency use authorization.  Others wondered whether the risks of vaccination – as low as they are – might outweigh the benefits in this age group.

“I don’t really see this as an emergency in children,” said committee member Michael Kurilla, MD, PhD, the director of clinical innovation at the National Institutes of Health. Dr. Kurilla, however, did say he thought having an expanded access program for children at high risk might make sense.

Most of the young adults who experienced myocarditis recovered quickly, though three needed intensive care and rehabilitation after their episodes. Among cases with known outcomes, 81% got better and 19% still have ongoing symptoms.
 

Adverse events reports

The data on myocarditis come from the Vaccine Adverse Events Reporting System, or VAERS, a database of health problems reported after vaccination. This reporting system, open to anyone, has benefits and limits. It gives the CDC and FDA the ability to rapidly detect potential safety issues, and it is large enough that it can detect rare events, something that’s beyond the power of even large clinical trials. 

But it is observational, so that there’s no way to know if problems reported were caused by the vaccines or a coincidence.

But because VAERS works on an honor system, it can also be spammed, and it carries the bias of the person who’s doing the reporting, from clinicians to average patients. For that reason, Dr. Shimabukuro said they are actively investigating and confirming each report they get. 

Out of more than 12 million doses administered to youth ages 16-24, the CDC says it has 275 reports of heart inflammation following vaccination in this age group. The CDC has analyzed a total 475 cases of myocarditis after vaccination in people under age 30 that were reported to VAERS.

The vaccines linked to the events are the mRNA vaccines made by Pfizer and Moderna. The only vaccines currently authorized for use in adolescents are made by Pfizer. Because the Pfizer vaccine was authorized for use in kids as young as 12 last month, there’s not yet enough data to draw conclusions about the risk of myocarditis in kids ages 12-15.

Younger age groups have only received about 9% of the total doses of the vaccine so far, but they represent about 50% of the myocarditis cases reported after vaccination. “We clearly have an imbalance there,” Dr. Shimabukuro said.

The number of events in this age group appears to be above the rate that would be expected for these age groups without vaccines in the picture, he said, explaining that the number of events are in line with similar adverse events seen in young people in Israel and reported by the Department of Defense. Israel found the incidence of myocarditis after vaccination was 50 cases per million for men ages 18-30.
 

More study needed

Another system tracking adverse events through hospitals, the Vaccine Safety Datalink, didn’t show reports of heart inflammation above numbers that are normally seen in the population, but it did show that inflammation was more likely after a second dose of the vaccine.

“Should this be included in informed consent?” asked Cody Meissner, MD, a pediatric infectious disease specialist at Tufts University, Boston, and a member of the FDA committee. 

“I think it’s hard to deny there seem to be some [events that seem] to be occurring in terms of myocarditis,” he said.

Dr. Meissner said later in the committee’s discussion that his own hospital had recently admitted a 12-year-old boy who developed heart swelling 2 days after the second dose of vaccine with a high level of troponin, an enzyme that indicates damage to the heart. His level was over 9. “A very high level,” Dr. Meissner said.

“Will there be scarring to the myocardium? Will there be a predisposition to arrhythmias later on? Will there be an early onset of heart failure? We think that’s unlikely, but [we] don’t know that,” he said.

The CDC has scheduled an emergency meeting next week to convene an expert panel on immunization practices to further review the events.

In addition to the information presented at the FDA’s meeting, doctors at Oregon Health & Science University, Portland, recently described seven cases in teens – all boys – who developed heart inflammation within 4 days of getting the second dose of the Pfizer vaccine.

The study was published June 10 in Pediatrics. All the boys were hospitalized and treated with anti-inflammatory medications including NSAIDs and steroids. Most were discharged within a few days and all recovered from their symptoms.

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

Swelling of the heart appears to be a very rare side effect that primarily strikes young people after vaccination for COVID-19, a Centers for Disease Control and Prevention expert reported on June 10, detailing data on cases of myocarditis and pericarditis detected through a government safety system.

The side effect seems to be more common in teen boys and young men than in older adults and women and may occur in 16 cases for every 1 million people who got a second dose, said Tom Shimabukuro, MD, MPH, deputy director of the CDC’s Immunization Safety Office, who presented information on the cases at a meeting of an expert panel that advises the U.S. Food and Drug Administration on vaccines.

Telltale symptoms include chest pain, shortness of breath, and fever.

William Schaffner, MD, an infectious diseases specialist from Vanderbilt University, Nashville, Tenn., thinks certain characteristics are pointing toward a “rare, but real” signal. First, the events are clustering, occurring within days of vaccination. Second, they tend to be more common in males and younger people. Third, he says, the number of events is above the so-called “background rate” – the cases that could be expected in this age group even without vaccination.

“I don’t think we’re quite there yet. We haven’t tied a ribbon around it, but I think the data are trending in that direction,” he said.

The issue of myocarditis weighed heavily on the Vaccines and Related Biological Products Advisory Committee’s considerations of what kind and how much data might be needed to green light use of a vaccine for COVID in children. 

Because the rates of hospitalization for COVID are low in kids, some felt that the FDA should require at least a year of study of the vaccines in clinical trials, the amount of data typically required for full approval, instead of the 2 months currently required for emergency use authorization.  Others wondered whether the risks of vaccination – as low as they are – might outweigh the benefits in this age group.

“I don’t really see this as an emergency in children,” said committee member Michael Kurilla, MD, PhD, the director of clinical innovation at the National Institutes of Health. Dr. Kurilla, however, did say he thought having an expanded access program for children at high risk might make sense.

Most of the young adults who experienced myocarditis recovered quickly, though three needed intensive care and rehabilitation after their episodes. Among cases with known outcomes, 81% got better and 19% still have ongoing symptoms.
 

Adverse events reports

The data on myocarditis come from the Vaccine Adverse Events Reporting System, or VAERS, a database of health problems reported after vaccination. This reporting system, open to anyone, has benefits and limits. It gives the CDC and FDA the ability to rapidly detect potential safety issues, and it is large enough that it can detect rare events, something that’s beyond the power of even large clinical trials. 

But it is observational, so that there’s no way to know if problems reported were caused by the vaccines or a coincidence.

But because VAERS works on an honor system, it can also be spammed, and it carries the bias of the person who’s doing the reporting, from clinicians to average patients. For that reason, Dr. Shimabukuro said they are actively investigating and confirming each report they get. 

Out of more than 12 million doses administered to youth ages 16-24, the CDC says it has 275 reports of heart inflammation following vaccination in this age group. The CDC has analyzed a total 475 cases of myocarditis after vaccination in people under age 30 that were reported to VAERS.

The vaccines linked to the events are the mRNA vaccines made by Pfizer and Moderna. The only vaccines currently authorized for use in adolescents are made by Pfizer. Because the Pfizer vaccine was authorized for use in kids as young as 12 last month, there’s not yet enough data to draw conclusions about the risk of myocarditis in kids ages 12-15.

Younger age groups have only received about 9% of the total doses of the vaccine so far, but they represent about 50% of the myocarditis cases reported after vaccination. “We clearly have an imbalance there,” Dr. Shimabukuro said.

The number of events in this age group appears to be above the rate that would be expected for these age groups without vaccines in the picture, he said, explaining that the number of events are in line with similar adverse events seen in young people in Israel and reported by the Department of Defense. Israel found the incidence of myocarditis after vaccination was 50 cases per million for men ages 18-30.
 

More study needed

Another system tracking adverse events through hospitals, the Vaccine Safety Datalink, didn’t show reports of heart inflammation above numbers that are normally seen in the population, but it did show that inflammation was more likely after a second dose of the vaccine.

“Should this be included in informed consent?” asked Cody Meissner, MD, a pediatric infectious disease specialist at Tufts University, Boston, and a member of the FDA committee. 

“I think it’s hard to deny there seem to be some [events that seem] to be occurring in terms of myocarditis,” he said.

Dr. Meissner said later in the committee’s discussion that his own hospital had recently admitted a 12-year-old boy who developed heart swelling 2 days after the second dose of vaccine with a high level of troponin, an enzyme that indicates damage to the heart. His level was over 9. “A very high level,” Dr. Meissner said.

“Will there be scarring to the myocardium? Will there be a predisposition to arrhythmias later on? Will there be an early onset of heart failure? We think that’s unlikely, but [we] don’t know that,” he said.

The CDC has scheduled an emergency meeting next week to convene an expert panel on immunization practices to further review the events.

In addition to the information presented at the FDA’s meeting, doctors at Oregon Health & Science University, Portland, recently described seven cases in teens – all boys – who developed heart inflammation within 4 days of getting the second dose of the Pfizer vaccine.

The study was published June 10 in Pediatrics. All the boys were hospitalized and treated with anti-inflammatory medications including NSAIDs and steroids. Most were discharged within a few days and all recovered from their symptoms.

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

Swelling of the heart appears to be a very rare side effect that primarily strikes young people after vaccination for COVID-19, a Centers for Disease Control and Prevention expert reported on June 10, detailing data on cases of myocarditis and pericarditis detected through a government safety system.

The side effect seems to be more common in teen boys and young men than in older adults and women and may occur in 16 cases for every 1 million people who got a second dose, said Tom Shimabukuro, MD, MPH, deputy director of the CDC’s Immunization Safety Office, who presented information on the cases at a meeting of an expert panel that advises the U.S. Food and Drug Administration on vaccines.

Telltale symptoms include chest pain, shortness of breath, and fever.

William Schaffner, MD, an infectious diseases specialist from Vanderbilt University, Nashville, Tenn., thinks certain characteristics are pointing toward a “rare, but real” signal. First, the events are clustering, occurring within days of vaccination. Second, they tend to be more common in males and younger people. Third, he says, the number of events is above the so-called “background rate” – the cases that could be expected in this age group even without vaccination.

“I don’t think we’re quite there yet. We haven’t tied a ribbon around it, but I think the data are trending in that direction,” he said.

The issue of myocarditis weighed heavily on the Vaccines and Related Biological Products Advisory Committee’s considerations of what kind and how much data might be needed to green light use of a vaccine for COVID in children. 

Because the rates of hospitalization for COVID are low in kids, some felt that the FDA should require at least a year of study of the vaccines in clinical trials, the amount of data typically required for full approval, instead of the 2 months currently required for emergency use authorization.  Others wondered whether the risks of vaccination – as low as they are – might outweigh the benefits in this age group.

“I don’t really see this as an emergency in children,” said committee member Michael Kurilla, MD, PhD, the director of clinical innovation at the National Institutes of Health. Dr. Kurilla, however, did say he thought having an expanded access program for children at high risk might make sense.

Most of the young adults who experienced myocarditis recovered quickly, though three needed intensive care and rehabilitation after their episodes. Among cases with known outcomes, 81% got better and 19% still have ongoing symptoms.
 

Adverse events reports

The data on myocarditis come from the Vaccine Adverse Events Reporting System, or VAERS, a database of health problems reported after vaccination. This reporting system, open to anyone, has benefits and limits. It gives the CDC and FDA the ability to rapidly detect potential safety issues, and it is large enough that it can detect rare events, something that’s beyond the power of even large clinical trials. 

But it is observational, so that there’s no way to know if problems reported were caused by the vaccines or a coincidence.

But because VAERS works on an honor system, it can also be spammed, and it carries the bias of the person who’s doing the reporting, from clinicians to average patients. For that reason, Dr. Shimabukuro said they are actively investigating and confirming each report they get. 

Out of more than 12 million doses administered to youth ages 16-24, the CDC says it has 275 reports of heart inflammation following vaccination in this age group. The CDC has analyzed a total 475 cases of myocarditis after vaccination in people under age 30 that were reported to VAERS.

The vaccines linked to the events are the mRNA vaccines made by Pfizer and Moderna. The only vaccines currently authorized for use in adolescents are made by Pfizer. Because the Pfizer vaccine was authorized for use in kids as young as 12 last month, there’s not yet enough data to draw conclusions about the risk of myocarditis in kids ages 12-15.

Younger age groups have only received about 9% of the total doses of the vaccine so far, but they represent about 50% of the myocarditis cases reported after vaccination. “We clearly have an imbalance there,” Dr. Shimabukuro said.

The number of events in this age group appears to be above the rate that would be expected for these age groups without vaccines in the picture, he said, explaining that the number of events are in line with similar adverse events seen in young people in Israel and reported by the Department of Defense. Israel found the incidence of myocarditis after vaccination was 50 cases per million for men ages 18-30.
 

More study needed

Another system tracking adverse events through hospitals, the Vaccine Safety Datalink, didn’t show reports of heart inflammation above numbers that are normally seen in the population, but it did show that inflammation was more likely after a second dose of the vaccine.

“Should this be included in informed consent?” asked Cody Meissner, MD, a pediatric infectious disease specialist at Tufts University, Boston, and a member of the FDA committee. 

“I think it’s hard to deny there seem to be some [events that seem] to be occurring in terms of myocarditis,” he said.

Dr. Meissner said later in the committee’s discussion that his own hospital had recently admitted a 12-year-old boy who developed heart swelling 2 days after the second dose of vaccine with a high level of troponin, an enzyme that indicates damage to the heart. His level was over 9. “A very high level,” Dr. Meissner said.

“Will there be scarring to the myocardium? Will there be a predisposition to arrhythmias later on? Will there be an early onset of heart failure? We think that’s unlikely, but [we] don’t know that,” he said.

The CDC has scheduled an emergency meeting next week to convene an expert panel on immunization practices to further review the events.

In addition to the information presented at the FDA’s meeting, doctors at Oregon Health & Science University, Portland, recently described seven cases in teens – all boys – who developed heart inflammation within 4 days of getting the second dose of the Pfizer vaccine.

The study was published June 10 in Pediatrics. All the boys were hospitalized and treated with anti-inflammatory medications including NSAIDs and steroids. Most were discharged within a few days and all recovered from their symptoms.

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

The optimal first step to address mild to moderately elevated blood pressure and cholesterol in otherwise healthy adults is a “prescription” to sit less and move more, the American Heart Association says in a new scientific statement.

“The current American Heart Association guidelines for diagnosing high blood pressure and cholesterol recognize that otherwise healthy individuals with mildly or moderately elevated levels of these cardiovascular risk factors should actively attempt to reduce these risks,” Bethany Barone Gibbs, PhD, chair of the statement writing group, said in an AHA news release.

“The first treatment strategy for many of these patients should be healthy lifestyle changes beginning with increasing physical activity,” said Dr. Gibbs, from the University of Pittsburgh.

The 12-page AHA scientific statement – Physical Activity as a Critical Component of First-Line Treatment for Elevated Blood Pressure or Cholesterol: Who, What, and How? – was published online June 2 in Hypertension.
 

Every little bit helps

According to the AHA, about 21% of American adults have systolic blood pressure between 120 and 139 mm Hg, or diastolic blood pressure between 80 and 89 mm Hg, which meets the criteria for lifestyle-only treatment for elevated BP outlined in the American College of Cardiology (ACC)/AHA high blood pressure guideline.

In addition, about 28% of American adults have LDL cholesterol above 70 mg/dL and otherwise meet the low-risk criteria for heart disease or stroke. These individuals would meet the criteria for lifestyle-only treatment outlined in the 2018 ACC/AHA cholesterol treatment guidelines, which include increased physical activity, weight loss, better diet, smoking cessation, and moderating alcohol intake.

“Of the recommended lifestyle changes, increasing physical activity has extensive benefits, including improving both blood pressure and blood cholesterol, that are comparable, superior, or complementary to other healthy lifestyle changes,” the writing group says.

“Physical activity assessment and prescription are an excellent lifestyle behavior treatment option for all patients, including for the large population of mild-moderate-risk patients with elevated blood pressure and blood cholesterol,” they note.

Research has shown that increasing physical activity can lead to clinically meaningful 3 or 4 mm Hg reductions in systolic and diastolic blood pressure, and 3 to 6 mg/dL decreases in LDL cholesterol, the authors point out.

Previous evidence also shows that physically active people have a 21% lower risk of developing cardiovascular disease and a 36% lower risk for death from cardiovascular diseases than those who are not physically active.

Physical activity also has benefits beyond heart health, including a lower risk for some cancers; improved bone, brain, and mental health; and better sleep, they note.

The U.S. Department of Health and Human Services 2018 physical activity guidelines advise Americans to log 150 minutes of moderate-intensity aerobic exercise or 75 minutes of vigorous aerobic activity each week and to participate in two or more weekly strength training sessions.

However, there is no minimum amount of time to receive benefits from physical activity.

“Every little bit of activity is better than none. Even small initial increases of 5 to 10 minutes a day can yield health benefits,” Dr. Gibbs said.
 

Translational advice for clinicians

The AHA statement encourages clinicians to ask patients about their physical activity at every interaction; provide ideas and resources to help patients improve and sustain regular life-long physical activity; and encourage and celebrate small increases in activity, such as walking more or taking the stairs, to help with motivation.

“In our world where physical activity is increasingly engineered out of our lives and the overwhelming default is to sit – and even more so now as the nation and the world is practicing quarantine and isolation to reduce the spread of coronavirus – the message that we must be relentless in our pursuit to ‘sit less and move more’ throughout the day is more important than ever,” said Dr. Gibbs.

The statement was prepared by a volunteer writing group on behalf of the AHA Council on Lifestyle and Cardiometabolic Health; the Council on Cardiovascular and Stroke Nursing; and the Council on Clinical Cardiology.

This research had no commercial funding. A list of disclosures for the writing group is available with the original article.

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

The optimal first step to address mild to moderately elevated blood pressure and cholesterol in otherwise healthy adults is a “prescription” to sit less and move more, the American Heart Association says in a new scientific statement.

“The current American Heart Association guidelines for diagnosing high blood pressure and cholesterol recognize that otherwise healthy individuals with mildly or moderately elevated levels of these cardiovascular risk factors should actively attempt to reduce these risks,” Bethany Barone Gibbs, PhD, chair of the statement writing group, said in an AHA news release.

“The first treatment strategy for many of these patients should be healthy lifestyle changes beginning with increasing physical activity,” said Dr. Gibbs, from the University of Pittsburgh.

The 12-page AHA scientific statement – Physical Activity as a Critical Component of First-Line Treatment for Elevated Blood Pressure or Cholesterol: Who, What, and How? – was published online June 2 in Hypertension.
 

Every little bit helps

According to the AHA, about 21% of American adults have systolic blood pressure between 120 and 139 mm Hg, or diastolic blood pressure between 80 and 89 mm Hg, which meets the criteria for lifestyle-only treatment for elevated BP outlined in the American College of Cardiology (ACC)/AHA high blood pressure guideline.

In addition, about 28% of American adults have LDL cholesterol above 70 mg/dL and otherwise meet the low-risk criteria for heart disease or stroke. These individuals would meet the criteria for lifestyle-only treatment outlined in the 2018 ACC/AHA cholesterol treatment guidelines, which include increased physical activity, weight loss, better diet, smoking cessation, and moderating alcohol intake.

“Of the recommended lifestyle changes, increasing physical activity has extensive benefits, including improving both blood pressure and blood cholesterol, that are comparable, superior, or complementary to other healthy lifestyle changes,” the writing group says.

“Physical activity assessment and prescription are an excellent lifestyle behavior treatment option for all patients, including for the large population of mild-moderate-risk patients with elevated blood pressure and blood cholesterol,” they note.

Research has shown that increasing physical activity can lead to clinically meaningful 3 or 4 mm Hg reductions in systolic and diastolic blood pressure, and 3 to 6 mg/dL decreases in LDL cholesterol, the authors point out.

Previous evidence also shows that physically active people have a 21% lower risk of developing cardiovascular disease and a 36% lower risk for death from cardiovascular diseases than those who are not physically active.

Physical activity also has benefits beyond heart health, including a lower risk for some cancers; improved bone, brain, and mental health; and better sleep, they note.

The U.S. Department of Health and Human Services 2018 physical activity guidelines advise Americans to log 150 minutes of moderate-intensity aerobic exercise or 75 minutes of vigorous aerobic activity each week and to participate in two or more weekly strength training sessions.

However, there is no minimum amount of time to receive benefits from physical activity.

“Every little bit of activity is better than none. Even small initial increases of 5 to 10 minutes a day can yield health benefits,” Dr. Gibbs said.
 

Translational advice for clinicians

The AHA statement encourages clinicians to ask patients about their physical activity at every interaction; provide ideas and resources to help patients improve and sustain regular life-long physical activity; and encourage and celebrate small increases in activity, such as walking more or taking the stairs, to help with motivation.

“In our world where physical activity is increasingly engineered out of our lives and the overwhelming default is to sit – and even more so now as the nation and the world is practicing quarantine and isolation to reduce the spread of coronavirus – the message that we must be relentless in our pursuit to ‘sit less and move more’ throughout the day is more important than ever,” said Dr. Gibbs.

The statement was prepared by a volunteer writing group on behalf of the AHA Council on Lifestyle and Cardiometabolic Health; the Council on Cardiovascular and Stroke Nursing; and the Council on Clinical Cardiology.

This research had no commercial funding. A list of disclosures for the writing group is available with the original article.

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

The optimal first step to address mild to moderately elevated blood pressure and cholesterol in otherwise healthy adults is a “prescription” to sit less and move more, the American Heart Association says in a new scientific statement.

“The current American Heart Association guidelines for diagnosing high blood pressure and cholesterol recognize that otherwise healthy individuals with mildly or moderately elevated levels of these cardiovascular risk factors should actively attempt to reduce these risks,” Bethany Barone Gibbs, PhD, chair of the statement writing group, said in an AHA news release.

“The first treatment strategy for many of these patients should be healthy lifestyle changes beginning with increasing physical activity,” said Dr. Gibbs, from the University of Pittsburgh.

The 12-page AHA scientific statement – Physical Activity as a Critical Component of First-Line Treatment for Elevated Blood Pressure or Cholesterol: Who, What, and How? – was published online June 2 in Hypertension.
 

Every little bit helps

According to the AHA, about 21% of American adults have systolic blood pressure between 120 and 139 mm Hg, or diastolic blood pressure between 80 and 89 mm Hg, which meets the criteria for lifestyle-only treatment for elevated BP outlined in the American College of Cardiology (ACC)/AHA high blood pressure guideline.

In addition, about 28% of American adults have LDL cholesterol above 70 mg/dL and otherwise meet the low-risk criteria for heart disease or stroke. These individuals would meet the criteria for lifestyle-only treatment outlined in the 2018 ACC/AHA cholesterol treatment guidelines, which include increased physical activity, weight loss, better diet, smoking cessation, and moderating alcohol intake.

“Of the recommended lifestyle changes, increasing physical activity has extensive benefits, including improving both blood pressure and blood cholesterol, that are comparable, superior, or complementary to other healthy lifestyle changes,” the writing group says.

“Physical activity assessment and prescription are an excellent lifestyle behavior treatment option for all patients, including for the large population of mild-moderate-risk patients with elevated blood pressure and blood cholesterol,” they note.

Research has shown that increasing physical activity can lead to clinically meaningful 3 or 4 mm Hg reductions in systolic and diastolic blood pressure, and 3 to 6 mg/dL decreases in LDL cholesterol, the authors point out.

Previous evidence also shows that physically active people have a 21% lower risk of developing cardiovascular disease and a 36% lower risk for death from cardiovascular diseases than those who are not physically active.

Physical activity also has benefits beyond heart health, including a lower risk for some cancers; improved bone, brain, and mental health; and better sleep, they note.

The U.S. Department of Health and Human Services 2018 physical activity guidelines advise Americans to log 150 minutes of moderate-intensity aerobic exercise or 75 minutes of vigorous aerobic activity each week and to participate in two or more weekly strength training sessions.

However, there is no minimum amount of time to receive benefits from physical activity.

“Every little bit of activity is better than none. Even small initial increases of 5 to 10 minutes a day can yield health benefits,” Dr. Gibbs said.
 

Translational advice for clinicians

The AHA statement encourages clinicians to ask patients about their physical activity at every interaction; provide ideas and resources to help patients improve and sustain regular life-long physical activity; and encourage and celebrate small increases in activity, such as walking more or taking the stairs, to help with motivation.

“In our world where physical activity is increasingly engineered out of our lives and the overwhelming default is to sit – and even more so now as the nation and the world is practicing quarantine and isolation to reduce the spread of coronavirus – the message that we must be relentless in our pursuit to ‘sit less and move more’ throughout the day is more important than ever,” said Dr. Gibbs.

The statement was prepared by a volunteer writing group on behalf of the AHA Council on Lifestyle and Cardiometabolic Health; the Council on Cardiovascular and Stroke Nursing; and the Council on Clinical Cardiology.

This research had no commercial funding. A list of disclosures for the writing group is available with the original article.

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

For many people, being told that they are HIV positive is no longer a death sentence. But for Robert Suttle, a Black gay man and social justice educator, it is a life sentence.

Unexpectedly caught up in the HIV criminalization web at the age of 30, Mr. Suttle spent 6 months in a Louisiana state prison for a consensual sexual relationship with an adult partner. The crime? Not disclosing his HIV-positive status, a charge that Mr. Suttle says is untrue.

“I did disclose my status to my partner; however, I can’t really answer how they might have received it,” he said.

Today, at the age of 42, Mr. Suttle still carries the indelible stain of a conviction and of being a registered sex offender. “After their diagnosis, criminal charge, and/or conviction, many people think they’re done – either ‘I’ve gotten out of prison’ or ‘I’m still on probation’ – whatever the case may be,” he explained. “But we’re still living out these collateral consequences, be it with housing, moving to another state, or finding a job.”

The same is true for HIV-positive people who are charged and tried but manage to dodge prison for one reason or another. Monique Howell, a straight, 40-year-old former army soldier and single mother of five children, said that she was afraid to disclose her HIV status to a sexual partner but did advise him to wear a condom.* She points to her DD14 discharge papers (i.e., forms that verify that someone served in the military) that were issued when her military duty was rescinded following the dismissal of her court case.

“I was going to reenlist, but I got in trouble,” she said. She explained that although a DD14 separation helps to ensure that she can receive benefits and care, the papers were issued with a caveat stating “serious offense,” an indelible stain that, like Mr. Suttle’s, will follow her for the rest of her life.
 

Laws criminalize myths and misconceptions

HIV criminalization laws subject persons whose behaviors may expose others to HIV to felony or misdemeanor charges. Depending on the state, they can carry prison terms ranging from less than 10 years to life, according to the Centers for Disease Control and Prevention.

Originally enacted at the height of the AIDS epidemic in 1986, when fear was rampant and hundreds were dying, the laws were intended to reduce HIV transmission. But they’ve had unintended consequences: Amplifying stigmatization and discrimination and perpetuating HIV myths and misconceptions, including how HIV is transmitted.

Decades of scientific advances challenge the most basic reasoning behind laws (for example, that transmission is possible via biting or spitting or through a single sexual act, which studies have shown poses a risk as low as 0%-1.4%). In addition, few laws reflect one of the most important HIV research findings of the past decade: undetectable equals untransmittable, meaning that the virus cannot be sexually transmitted by people who are taking antiretroviral therapy and whose viral loads are undetectable.

In most of these cases, individuals who are positive for HIV are charged and punished for unintentional exposure, not deliberate intent to harm. Moreover, for the charge to stick, sexual partners don’t need to have acquired the virus or prove the transmission source if they do become HIV positive.

Ms. Howell noted that it was the Army that brought the charges against her, not her sexual partner at that time (who, incidentally, tested negative). He even testified on her behalf at the trial. “I’ll never forget it,” she said. “He said, ‘I don’t want anything to happen to Monique; even if you put her behind bars, she’s still HIV-positive and she’s still got those children. She told me to get a condom, and I chose not to.’ ”
 

Criminal vs. clinical fallout

In 2018, 20 scientists across the world issued a consensus statement underscoring the fact that HIV criminalization laws are based on fallacies and faulty science. The statement (which remains one of the most accessed in the Journal of the International AIDS Society) also points out that 33 countries (including the United States) use general criminal statutes such as attempted murder or reckless endangerment to lengthen sentences when people with HIV commit crimes.

When the laws were created, “many were the equivalent [to general criminal laws], because HIV was seen as a death sentence,” explained Chris Beyrer MD, MPH, professor of public health and human rights at Johns Hopkins Bloomberg School of Public Health, Baltimore. “So, failure to disclose your status, to wear a condom was seen as risking someone else’s life, which is no longer the case,” he added.

In fact, “from the perspective of the kinds of impact that these laws have had on transmission, or risk, or behavior, what you find is that they really have no public health benefit and they have real public harms,” said Dr. Beyrer.

Claire Farel, MD, assistant professor and medical director of the UNC Infectious Diseases Clinic at the University of North Carolina at Chapel Hill, concurs. “Because of the criminalization undercurrent, there are people who don’t get tested, meaning that they are at risk for worse health outcomes, such as cancer, vascular disease, and of course HIV-related poor outcomes, including progression to AIDS.”

Farel also points to the residual stigma associated with HIV. “Much of this is inextricable from that surrounding homophobia, especially among young men of color who have sex with men. It opens up a larger conversation that a lot of people don’t want to engage in,” she said.
 

Laws broaden existing disparities even further

The CDC released a study June 4 showing substantial declines in the overall incidence of HIV in the United States, with an important caveat: There’s been a worsening disparity in cases. Access to care and engagement with care remain poor among certain populations. For example, Black individuals accounted for 41% of new HIV infections in 2019, but they represent only 12% of the U.S. population; Hispanic/Latinx persons accounted for 29% of new infections, although they represent only 17% of the entire population.

The same is true for HIV criminalization: In 2020, more than 50% of defendants were people of color, according to U.S. case data collated by the HIV Justice Network.

Still, the momentum to change these antiquated laws is gaining speed. In May, the Illinois State Senate passed a bill repealing HIV criminalization, and this past March, Virginia’s Governor Ralph Northam signed a bill lowering HIV-related criminalization charges from a felony to a misdemeanor and changing the wording of its law to include both intent and transmission.** California, Colorado, Iowa, Michigan, Nevada, and North Carolina have also modernized or repealed their laws.
 

Ending the U.S. HIV epidemic: Patients first

Without true HIV criminalization reform, efforts to change the public and clinical mindset regarding HIV from its being a highly stigmatized disease to a preventable, treatable infection are likely to fall short. Dr. Beyrer emphasized that the onus lies with the scientific and activist communities working together. “I don’t know how you can end the epidemic if you are still stigmatizing the people who are actually acquiring these infections,” he said.

There are steps that patients can take while these forces push for change.

“As people first process their diagnosis, they need to learn as much about HIV and the science behind it as possible,” advised Mr. Suttle. He said that to protect oneself, it’s essential to learn about HIV criminalization and the laws in one’s state.

“Find someone you can trust, starting with your medical provider if possible, and if you have a significant other, bring that person to your appointments so they can see that you are in care and doing all that you can do to lower viral loads and protect others,” he added.

Ms. Howell said that although people should be in treatment and care, attitudes also need to change on the clinician side. “We’re just given these meds, told to take them, and are sent on our merry ways, but they don’t tell us how to live our lives properly; nobody grabs us and says, hey, these are the laws and you need to know this or that.”

When a person who is HIV positive does get caught up in the system, if possible, that person should consult an attorney who understands these laws. Mr. Suttle suggested reaching out to organizations in the movement to end HIV criminalization (e.g., the Sero Project, the Center for HIV Law and Policy, or the Positive Women’s Network) for further support, help with cases (including providing experts to testify), social services, and other resources. Mr. Suttle also encourages people who need help and direction to reach out to him directly at [email protected].

Forty years ago, the CDC published its first report of an illness in five healthy gay men living in Los Angeles. The first cases in women were reported shortly thereafter. Over the years, there have been many scientific advances in prevention and treatment. But as Dr. Beyrer aptly noted in an editorial published January 2021 in The Lancet HIV, “time has not lessened the sting of the early decades of AIDS.”

“We should not have to be afraid of who we are because we are HIV positive,” said Ms. Howell.

Dr. Farel, Mr. Suttle, and Ms. Howell report no relevant financial relationships. Dr. Beyrer has a consulting agreement with Merck.
 

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

*Correction, 6/14/2021: An earlier version of this story misstated Ms. Howell's age. She is 40.

**Correction, 6/14/2021: An earlier version of this story misspelled Gov. Northam's name.

For many people, being told that they are HIV positive is no longer a death sentence. But for Robert Suttle, a Black gay man and social justice educator, it is a life sentence.

Unexpectedly caught up in the HIV criminalization web at the age of 30, Mr. Suttle spent 6 months in a Louisiana state prison for a consensual sexual relationship with an adult partner. The crime? Not disclosing his HIV-positive status, a charge that Mr. Suttle says is untrue.

“I did disclose my status to my partner; however, I can’t really answer how they might have received it,” he said.

Today, at the age of 42, Mr. Suttle still carries the indelible stain of a conviction and of being a registered sex offender. “After their diagnosis, criminal charge, and/or conviction, many people think they’re done – either ‘I’ve gotten out of prison’ or ‘I’m still on probation’ – whatever the case may be,” he explained. “But we’re still living out these collateral consequences, be it with housing, moving to another state, or finding a job.”

The same is true for HIV-positive people who are charged and tried but manage to dodge prison for one reason or another. Monique Howell, a straight, 40-year-old former army soldier and single mother of five children, said that she was afraid to disclose her HIV status to a sexual partner but did advise him to wear a condom.* She points to her DD14 discharge papers (i.e., forms that verify that someone served in the military) that were issued when her military duty was rescinded following the dismissal of her court case.

“I was going to reenlist, but I got in trouble,” she said. She explained that although a DD14 separation helps to ensure that she can receive benefits and care, the papers were issued with a caveat stating “serious offense,” an indelible stain that, like Mr. Suttle’s, will follow her for the rest of her life.
 

Laws criminalize myths and misconceptions

HIV criminalization laws subject persons whose behaviors may expose others to HIV to felony or misdemeanor charges. Depending on the state, they can carry prison terms ranging from less than 10 years to life, according to the Centers for Disease Control and Prevention.

Originally enacted at the height of the AIDS epidemic in 1986, when fear was rampant and hundreds were dying, the laws were intended to reduce HIV transmission. But they’ve had unintended consequences: Amplifying stigmatization and discrimination and perpetuating HIV myths and misconceptions, including how HIV is transmitted.

Decades of scientific advances challenge the most basic reasoning behind laws (for example, that transmission is possible via biting or spitting or through a single sexual act, which studies have shown poses a risk as low as 0%-1.4%). In addition, few laws reflect one of the most important HIV research findings of the past decade: undetectable equals untransmittable, meaning that the virus cannot be sexually transmitted by people who are taking antiretroviral therapy and whose viral loads are undetectable.

In most of these cases, individuals who are positive for HIV are charged and punished for unintentional exposure, not deliberate intent to harm. Moreover, for the charge to stick, sexual partners don’t need to have acquired the virus or prove the transmission source if they do become HIV positive.

Ms. Howell noted that it was the Army that brought the charges against her, not her sexual partner at that time (who, incidentally, tested negative). He even testified on her behalf at the trial. “I’ll never forget it,” she said. “He said, ‘I don’t want anything to happen to Monique; even if you put her behind bars, she’s still HIV-positive and she’s still got those children. She told me to get a condom, and I chose not to.’ ”
 

Criminal vs. clinical fallout

In 2018, 20 scientists across the world issued a consensus statement underscoring the fact that HIV criminalization laws are based on fallacies and faulty science. The statement (which remains one of the most accessed in the Journal of the International AIDS Society) also points out that 33 countries (including the United States) use general criminal statutes such as attempted murder or reckless endangerment to lengthen sentences when people with HIV commit crimes.

When the laws were created, “many were the equivalent [to general criminal laws], because HIV was seen as a death sentence,” explained Chris Beyrer MD, MPH, professor of public health and human rights at Johns Hopkins Bloomberg School of Public Health, Baltimore. “So, failure to disclose your status, to wear a condom was seen as risking someone else’s life, which is no longer the case,” he added.

In fact, “from the perspective of the kinds of impact that these laws have had on transmission, or risk, or behavior, what you find is that they really have no public health benefit and they have real public harms,” said Dr. Beyrer.

Claire Farel, MD, assistant professor and medical director of the UNC Infectious Diseases Clinic at the University of North Carolina at Chapel Hill, concurs. “Because of the criminalization undercurrent, there are people who don’t get tested, meaning that they are at risk for worse health outcomes, such as cancer, vascular disease, and of course HIV-related poor outcomes, including progression to AIDS.”

Farel also points to the residual stigma associated with HIV. “Much of this is inextricable from that surrounding homophobia, especially among young men of color who have sex with men. It opens up a larger conversation that a lot of people don’t want to engage in,” she said.
 

Laws broaden existing disparities even further

The CDC released a study June 4 showing substantial declines in the overall incidence of HIV in the United States, with an important caveat: There’s been a worsening disparity in cases. Access to care and engagement with care remain poor among certain populations. For example, Black individuals accounted for 41% of new HIV infections in 2019, but they represent only 12% of the U.S. population; Hispanic/Latinx persons accounted for 29% of new infections, although they represent only 17% of the entire population.

The same is true for HIV criminalization: In 2020, more than 50% of defendants were people of color, according to U.S. case data collated by the HIV Justice Network.

Still, the momentum to change these antiquated laws is gaining speed. In May, the Illinois State Senate passed a bill repealing HIV criminalization, and this past March, Virginia’s Governor Ralph Northam signed a bill lowering HIV-related criminalization charges from a felony to a misdemeanor and changing the wording of its law to include both intent and transmission.** California, Colorado, Iowa, Michigan, Nevada, and North Carolina have also modernized or repealed their laws.
 

Ending the U.S. HIV epidemic: Patients first

Without true HIV criminalization reform, efforts to change the public and clinical mindset regarding HIV from its being a highly stigmatized disease to a preventable, treatable infection are likely to fall short. Dr. Beyrer emphasized that the onus lies with the scientific and activist communities working together. “I don’t know how you can end the epidemic if you are still stigmatizing the people who are actually acquiring these infections,” he said.

There are steps that patients can take while these forces push for change.

“As people first process their diagnosis, they need to learn as much about HIV and the science behind it as possible,” advised Mr. Suttle. He said that to protect oneself, it’s essential to learn about HIV criminalization and the laws in one’s state.

“Find someone you can trust, starting with your medical provider if possible, and if you have a significant other, bring that person to your appointments so they can see that you are in care and doing all that you can do to lower viral loads and protect others,” he added.

Ms. Howell said that although people should be in treatment and care, attitudes also need to change on the clinician side. “We’re just given these meds, told to take them, and are sent on our merry ways, but they don’t tell us how to live our lives properly; nobody grabs us and says, hey, these are the laws and you need to know this or that.”

When a person who is HIV positive does get caught up in the system, if possible, that person should consult an attorney who understands these laws. Mr. Suttle suggested reaching out to organizations in the movement to end HIV criminalization (e.g., the Sero Project, the Center for HIV Law and Policy, or the Positive Women’s Network) for further support, help with cases (including providing experts to testify), social services, and other resources. Mr. Suttle also encourages people who need help and direction to reach out to him directly at [email protected].

Forty years ago, the CDC published its first report of an illness in five healthy gay men living in Los Angeles. The first cases in women were reported shortly thereafter. Over the years, there have been many scientific advances in prevention and treatment. But as Dr. Beyrer aptly noted in an editorial published January 2021 in The Lancet HIV, “time has not lessened the sting of the early decades of AIDS.”

“We should not have to be afraid of who we are because we are HIV positive,” said Ms. Howell.

Dr. Farel, Mr. Suttle, and Ms. Howell report no relevant financial relationships. Dr. Beyrer has a consulting agreement with Merck.
 

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

*Correction, 6/14/2021: An earlier version of this story misstated Ms. Howell's age. She is 40.

**Correction, 6/14/2021: An earlier version of this story misspelled Gov. Northam's name.

For many people, being told that they are HIV positive is no longer a death sentence. But for Robert Suttle, a Black gay man and social justice educator, it is a life sentence.

Unexpectedly caught up in the HIV criminalization web at the age of 30, Mr. Suttle spent 6 months in a Louisiana state prison for a consensual sexual relationship with an adult partner. The crime? Not disclosing his HIV-positive status, a charge that Mr. Suttle says is untrue.

“I did disclose my status to my partner; however, I can’t really answer how they might have received it,” he said.

Today, at the age of 42, Mr. Suttle still carries the indelible stain of a conviction and of being a registered sex offender. “After their diagnosis, criminal charge, and/or conviction, many people think they’re done – either ‘I’ve gotten out of prison’ or ‘I’m still on probation’ – whatever the case may be,” he explained. “But we’re still living out these collateral consequences, be it with housing, moving to another state, or finding a job.”

The same is true for HIV-positive people who are charged and tried but manage to dodge prison for one reason or another. Monique Howell, a straight, 40-year-old former army soldier and single mother of five children, said that she was afraid to disclose her HIV status to a sexual partner but did advise him to wear a condom.* She points to her DD14 discharge papers (i.e., forms that verify that someone served in the military) that were issued when her military duty was rescinded following the dismissal of her court case.

“I was going to reenlist, but I got in trouble,” she said. She explained that although a DD14 separation helps to ensure that she can receive benefits and care, the papers were issued with a caveat stating “serious offense,” an indelible stain that, like Mr. Suttle’s, will follow her for the rest of her life.
 

Laws criminalize myths and misconceptions

HIV criminalization laws subject persons whose behaviors may expose others to HIV to felony or misdemeanor charges. Depending on the state, they can carry prison terms ranging from less than 10 years to life, according to the Centers for Disease Control and Prevention.

Originally enacted at the height of the AIDS epidemic in 1986, when fear was rampant and hundreds were dying, the laws were intended to reduce HIV transmission. But they’ve had unintended consequences: Amplifying stigmatization and discrimination and perpetuating HIV myths and misconceptions, including how HIV is transmitted.

Decades of scientific advances challenge the most basic reasoning behind laws (for example, that transmission is possible via biting or spitting or through a single sexual act, which studies have shown poses a risk as low as 0%-1.4%). In addition, few laws reflect one of the most important HIV research findings of the past decade: undetectable equals untransmittable, meaning that the virus cannot be sexually transmitted by people who are taking antiretroviral therapy and whose viral loads are undetectable.

In most of these cases, individuals who are positive for HIV are charged and punished for unintentional exposure, not deliberate intent to harm. Moreover, for the charge to stick, sexual partners don’t need to have acquired the virus or prove the transmission source if they do become HIV positive.

Ms. Howell noted that it was the Army that brought the charges against her, not her sexual partner at that time (who, incidentally, tested negative). He even testified on her behalf at the trial. “I’ll never forget it,” she said. “He said, ‘I don’t want anything to happen to Monique; even if you put her behind bars, she’s still HIV-positive and she’s still got those children. She told me to get a condom, and I chose not to.’ ”
 

Criminal vs. clinical fallout

In 2018, 20 scientists across the world issued a consensus statement underscoring the fact that HIV criminalization laws are based on fallacies and faulty science. The statement (which remains one of the most accessed in the Journal of the International AIDS Society) also points out that 33 countries (including the United States) use general criminal statutes such as attempted murder or reckless endangerment to lengthen sentences when people with HIV commit crimes.

When the laws were created, “many were the equivalent [to general criminal laws], because HIV was seen as a death sentence,” explained Chris Beyrer MD, MPH, professor of public health and human rights at Johns Hopkins Bloomberg School of Public Health, Baltimore. “So, failure to disclose your status, to wear a condom was seen as risking someone else’s life, which is no longer the case,” he added.

In fact, “from the perspective of the kinds of impact that these laws have had on transmission, or risk, or behavior, what you find is that they really have no public health benefit and they have real public harms,” said Dr. Beyrer.

Claire Farel, MD, assistant professor and medical director of the UNC Infectious Diseases Clinic at the University of North Carolina at Chapel Hill, concurs. “Because of the criminalization undercurrent, there are people who don’t get tested, meaning that they are at risk for worse health outcomes, such as cancer, vascular disease, and of course HIV-related poor outcomes, including progression to AIDS.”

Farel also points to the residual stigma associated with HIV. “Much of this is inextricable from that surrounding homophobia, especially among young men of color who have sex with men. It opens up a larger conversation that a lot of people don’t want to engage in,” she said.
 

Laws broaden existing disparities even further

The CDC released a study June 4 showing substantial declines in the overall incidence of HIV in the United States, with an important caveat: There’s been a worsening disparity in cases. Access to care and engagement with care remain poor among certain populations. For example, Black individuals accounted for 41% of new HIV infections in 2019, but they represent only 12% of the U.S. population; Hispanic/Latinx persons accounted for 29% of new infections, although they represent only 17% of the entire population.

The same is true for HIV criminalization: In 2020, more than 50% of defendants were people of color, according to U.S. case data collated by the HIV Justice Network.

Still, the momentum to change these antiquated laws is gaining speed. In May, the Illinois State Senate passed a bill repealing HIV criminalization, and this past March, Virginia’s Governor Ralph Northam signed a bill lowering HIV-related criminalization charges from a felony to a misdemeanor and changing the wording of its law to include both intent and transmission.** California, Colorado, Iowa, Michigan, Nevada, and North Carolina have also modernized or repealed their laws.
 

Ending the U.S. HIV epidemic: Patients first

Without true HIV criminalization reform, efforts to change the public and clinical mindset regarding HIV from its being a highly stigmatized disease to a preventable, treatable infection are likely to fall short. Dr. Beyrer emphasized that the onus lies with the scientific and activist communities working together. “I don’t know how you can end the epidemic if you are still stigmatizing the people who are actually acquiring these infections,” he said.

There are steps that patients can take while these forces push for change.

“As people first process their diagnosis, they need to learn as much about HIV and the science behind it as possible,” advised Mr. Suttle. He said that to protect oneself, it’s essential to learn about HIV criminalization and the laws in one’s state.

“Find someone you can trust, starting with your medical provider if possible, and if you have a significant other, bring that person to your appointments so they can see that you are in care and doing all that you can do to lower viral loads and protect others,” he added.

Ms. Howell said that although people should be in treatment and care, attitudes also need to change on the clinician side. “We’re just given these meds, told to take them, and are sent on our merry ways, but they don’t tell us how to live our lives properly; nobody grabs us and says, hey, these are the laws and you need to know this or that.”

When a person who is HIV positive does get caught up in the system, if possible, that person should consult an attorney who understands these laws. Mr. Suttle suggested reaching out to organizations in the movement to end HIV criminalization (e.g., the Sero Project, the Center for HIV Law and Policy, or the Positive Women’s Network) for further support, help with cases (including providing experts to testify), social services, and other resources. Mr. Suttle also encourages people who need help and direction to reach out to him directly at [email protected].

Forty years ago, the CDC published its first report of an illness in five healthy gay men living in Los Angeles. The first cases in women were reported shortly thereafter. Over the years, there have been many scientific advances in prevention and treatment. But as Dr. Beyrer aptly noted in an editorial published January 2021 in The Lancet HIV, “time has not lessened the sting of the early decades of AIDS.”

“We should not have to be afraid of who we are because we are HIV positive,” said Ms. Howell.

Dr. Farel, Mr. Suttle, and Ms. Howell report no relevant financial relationships. Dr. Beyrer has a consulting agreement with Merck.
 

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

*Correction, 6/14/2021: An earlier version of this story misstated Ms. Howell's age. She is 40.

**Correction, 6/14/2021: An earlier version of this story misspelled Gov. Northam's name.

A new clinical score has been developed, and externally validated, to identify patients at risk of bleeding after transcatheter aortic valve replacement (TAVR).

“Despite the TAVR iterations, we recognize that bleeding remains a very important and perhaps also neglected issue. Indeed, no specifically developed standard algorithm existed before this to assess bleeding risk post-TAVR,” lead author Eliano Pio Navarese, MD, PhD, said in an interview.

Although bleeding rates can be as high as 9% at 30 days and between 3% and 11% in the first year, only a few studies have applied existing scores to TAVR patients, he noted.

The PREDICT-TAVR score includes six common variables and can be calculated by hand using a simple nomogram or a web-based calculator, with a dedicated website in the works, said Dr. Navarese, Nicolaus Copernicus University and SIRO MEDICINE Network, Bydgoszcz, Poland, and the University of Alberta, Edmonton.

A strength of the score is that machine-learning methods were used and the choice of variables optimized through recursive feature elimination and cross validation to remove the weakest variables, he said. Artificial intelligence, including use of random forest, naïve Bayes, and logistic regression classifiers, was also applied to the algorithms and the results cross-checked with standard multivariate analysis.

“It was a tremendous effort in terms of the analytics conducted,” Dr. Navarese said. “This is not a simple score but the integration of the most sophisticated machine learning methods and algorithms.”

Details are published in the June 14 issue of JACC: Cardiovascular Interventions.

The six variables used to calculate 30-day bleeding risk after TAVR and the points assigned to each are:

• blood hemoglobin (0-10 points)
• serum iron concentration (0-5 points)
• common femoral artery diameter (0-3 points)
•  (0-3 points)
• dual antiplatelet therapy (DAPT; 0-2 points)
• oral anticoagulation therapy (0-2 points)

The six items were selected among 104 baseline variables from 5,185 consecutive patients undergoing transfemoral TAVR in the prospective RISPEVA (Registro Italiano GISE sull’Impianto di Valvola Aortica Percutanea) registry between March 2012 and December 2019, then validated in 5,043 patients in the prospective POL-TAVI (Polish Registry of Transcatheter Aortic Valve Implantation) between January 2013 and December 2019.

In the derivation cohort, 216 patients (4.2%) experienced bleeding events at 1 year, with 169 events (78%) occurring during the first 30 days.

PREDICT-TAVR exhibited high discriminatory power for bleeding events at 30 days, as reflected by an area under the curve (AUC) of 0.80 (95% confidence interval, 0.75-0.83). Internal validation by optimism bootstrap-corrected AUC was consistent at 0.79 (95% CI, 0.75-0.83).

PREDICT-TAVR also outperformed scores not developed for TAVR, such as the PARIS score for patients undergoing percutaneous coronary intervention (AUC, 0.69) and the well-validated HAS-BLED for patients receiving anticoagulation (AUC, 0.58; P < .001 for both).

In the validation cohort, the AUC for bleeding complications at 30 days was 0.78 (95% CI, 0.72-0.82) versus an AUC of 0.68 for PARIS and 0.66 for HAS-BLED.

A HAS-BLED score of 4 predicted a higher rate of severe bleeding and mortality in the year after transfemoral TAVR in the 2018 Japanese OCEAN-TAVI study.
 

Bleeding events by risk categories

Risk score quartiles identified as low risk were 8 points or less, as moderate risk were 8 to less than 10 points, as high risk were 10 to less than 12 points, and as very-high-risk score were above 12 points.

In the derivation cohort, 30-day bleeding events across quartiles were 0.8%, 1.1%, 2.5%, and 8.5%, respectively (overall P < .001).

Compared with the lowest quartile, bleeding risk was numerically higher for the second quartile (odds ratio, 1.75) and significantly higher in the third (OR, 2.0) and fourth (OR, 2.49) quartiles (P < .001 for both).

A landmark cumulative-event analysis showed a significantly greater risk of bleeding for the two highest quartiles up to 30 days; however, these differences were no longer significant from 30 days to 1 year, likely because of a limited number of events, the authors suggest. Similar results were seen in the validation cohort.

The number of patients in the high- and very-high-risk groups isn’t trivial, and bleeding rates reached as high as 12.6% in the highest quartile, Dr. Navarese observed. Guidelines recommend DAPT for 3 to 6 months after TAVR; however, emerging data, including a recent meta-analysis, suggest monotherapy may be a very good option.

“So, if you had a high bleeding risk and are considering postprocedural DAPT or anticoagulation, I would think twice rather than administering dual antiplatelet therapy or anticoagulation for a long time, or at least, I would consider the impact of this score on this choice,” he said.

Subgroup analyses showed AUCs ranging from 0.77 to 0.81 for subgroups such as age older than 80 years, diabetes, obesity, female sex, previous PCI, and New York Heart Association class III or IV.

Serum iron showed the highest AUC in the primary PREDICT-TAVR model; however, should iron levels be unavailable, a simplified score modeled without iron levels retained predictive power, yielding AUCs for 30-day bleeding of 0.78 in the derivation cohort and 0.75 in the validation cohort.

“PREDICT-TAVR score can impact clinical practice, not only selecting the optimal thrombotic regimen in certain high bleeding-risk populations but also to treat pre-TAVR anemia and iron deficiencies, which may affect outcomes,” Dr. Navarese said. “Of course, future prospective biological and clinical investigations are needed to elucidate the score and the role of the score’s treatable risk traits in reducing post-TAVR bleeding complications.”

Commenting for this news organization, Sunil Rao, MD, Duke University, Durham, N.C., said anemia is a covariant in many risk models for bleeding and vascular complications in PCI and acute coronary syndrome, but hemoglobin and iron levels are collinear.

“The problem I think is when you throw hemoglobin and iron in the same model, just by play of chance, one variable can knock out the other one,” he said. “So I don’t know necessarily if we need to start measuring iron on everyone. We certainly should be measuring hemoglobin, which I think most people will have, and if a patient has pre-existing anemia, that should be a red flag for us.”

Age and Society of Thoracic Surgeons (STS) risk score did not reach statistical significance in the model – likely reflecting the high-/extremely-high-risk patient population with an average STS score of 7.7 and average age of 82 years – but may become more important as TAVR is applied more widely, Dr. Rao and Zachary Wegermann, MD, Duke Clinical Research Institute, write in an accompanying editorial.

They also point out that the study was limited by a low rate of bleeding events, and, importantly, the score can’t distinguish between minor or major bleeding.

“It’s worth trying to repeat the analyses in lower-risk patients because we may find other covariates that are important,” Dr. Rao said in an interview. “The other thing we need to get to is probably being a little bit more sophisticated. The variables included in these models are the ones that are measured; they’re also the ones that are clinically apparent.”

“But there’s a whole area of genomic medicine, proteomic medicine, metabolomic medicine that, as it starts developing and becomes more and more sophisticated, my suspicion is that we’re going to get even more precise and accurate about patients’ risk, and it’s going to become more individualized, rather than just measuring variables like age and lab values,” he said.

In the meantime, having variables documented in the electronic health record, with hard stops deployed if variables aren’t measured, is “a step in the right direction,” he added.

Dr. Navarese has received research grants from Abbott, Amgen, and Medtronic and received lecture fees and honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work. Dr. Rao and Dr. Wegermann report no relevant financial disclosures.

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

A new clinical score has been developed, and externally validated, to identify patients at risk of bleeding after transcatheter aortic valve replacement (TAVR).

“Despite the TAVR iterations, we recognize that bleeding remains a very important and perhaps also neglected issue. Indeed, no specifically developed standard algorithm existed before this to assess bleeding risk post-TAVR,” lead author Eliano Pio Navarese, MD, PhD, said in an interview.

Although bleeding rates can be as high as 9% at 30 days and between 3% and 11% in the first year, only a few studies have applied existing scores to TAVR patients, he noted.

The PREDICT-TAVR score includes six common variables and can be calculated by hand using a simple nomogram or a web-based calculator, with a dedicated website in the works, said Dr. Navarese, Nicolaus Copernicus University and SIRO MEDICINE Network, Bydgoszcz, Poland, and the University of Alberta, Edmonton.

A strength of the score is that machine-learning methods were used and the choice of variables optimized through recursive feature elimination and cross validation to remove the weakest variables, he said. Artificial intelligence, including use of random forest, naïve Bayes, and logistic regression classifiers, was also applied to the algorithms and the results cross-checked with standard multivariate analysis.

“It was a tremendous effort in terms of the analytics conducted,” Dr. Navarese said. “This is not a simple score but the integration of the most sophisticated machine learning methods and algorithms.”

Details are published in the June 14 issue of JACC: Cardiovascular Interventions.

The six variables used to calculate 30-day bleeding risk after TAVR and the points assigned to each are:

• blood hemoglobin (0-10 points)
• serum iron concentration (0-5 points)
• common femoral artery diameter (0-3 points)
•  (0-3 points)
• dual antiplatelet therapy (DAPT; 0-2 points)
• oral anticoagulation therapy (0-2 points)

The six items were selected among 104 baseline variables from 5,185 consecutive patients undergoing transfemoral TAVR in the prospective RISPEVA (Registro Italiano GISE sull’Impianto di Valvola Aortica Percutanea) registry between March 2012 and December 2019, then validated in 5,043 patients in the prospective POL-TAVI (Polish Registry of Transcatheter Aortic Valve Implantation) between January 2013 and December 2019.

In the derivation cohort, 216 patients (4.2%) experienced bleeding events at 1 year, with 169 events (78%) occurring during the first 30 days.

PREDICT-TAVR exhibited high discriminatory power for bleeding events at 30 days, as reflected by an area under the curve (AUC) of 0.80 (95% confidence interval, 0.75-0.83). Internal validation by optimism bootstrap-corrected AUC was consistent at 0.79 (95% CI, 0.75-0.83).

PREDICT-TAVR also outperformed scores not developed for TAVR, such as the PARIS score for patients undergoing percutaneous coronary intervention (AUC, 0.69) and the well-validated HAS-BLED for patients receiving anticoagulation (AUC, 0.58; P < .001 for both).

In the validation cohort, the AUC for bleeding complications at 30 days was 0.78 (95% CI, 0.72-0.82) versus an AUC of 0.68 for PARIS and 0.66 for HAS-BLED.

A HAS-BLED score of 4 predicted a higher rate of severe bleeding and mortality in the year after transfemoral TAVR in the 2018 Japanese OCEAN-TAVI study.
 

Bleeding events by risk categories

Risk score quartiles identified as low risk were 8 points or less, as moderate risk were 8 to less than 10 points, as high risk were 10 to less than 12 points, and as very-high-risk score were above 12 points.

In the derivation cohort, 30-day bleeding events across quartiles were 0.8%, 1.1%, 2.5%, and 8.5%, respectively (overall P < .001).

Compared with the lowest quartile, bleeding risk was numerically higher for the second quartile (odds ratio, 1.75) and significantly higher in the third (OR, 2.0) and fourth (OR, 2.49) quartiles (P < .001 for both).

A landmark cumulative-event analysis showed a significantly greater risk of bleeding for the two highest quartiles up to 30 days; however, these differences were no longer significant from 30 days to 1 year, likely because of a limited number of events, the authors suggest. Similar results were seen in the validation cohort.

The number of patients in the high- and very-high-risk groups isn’t trivial, and bleeding rates reached as high as 12.6% in the highest quartile, Dr. Navarese observed. Guidelines recommend DAPT for 3 to 6 months after TAVR; however, emerging data, including a recent meta-analysis, suggest monotherapy may be a very good option.

“So, if you had a high bleeding risk and are considering postprocedural DAPT or anticoagulation, I would think twice rather than administering dual antiplatelet therapy or anticoagulation for a long time, or at least, I would consider the impact of this score on this choice,” he said.

Subgroup analyses showed AUCs ranging from 0.77 to 0.81 for subgroups such as age older than 80 years, diabetes, obesity, female sex, previous PCI, and New York Heart Association class III or IV.

Serum iron showed the highest AUC in the primary PREDICT-TAVR model; however, should iron levels be unavailable, a simplified score modeled without iron levels retained predictive power, yielding AUCs for 30-day bleeding of 0.78 in the derivation cohort and 0.75 in the validation cohort.

“PREDICT-TAVR score can impact clinical practice, not only selecting the optimal thrombotic regimen in certain high bleeding-risk populations but also to treat pre-TAVR anemia and iron deficiencies, which may affect outcomes,” Dr. Navarese said. “Of course, future prospective biological and clinical investigations are needed to elucidate the score and the role of the score’s treatable risk traits in reducing post-TAVR bleeding complications.”

Commenting for this news organization, Sunil Rao, MD, Duke University, Durham, N.C., said anemia is a covariant in many risk models for bleeding and vascular complications in PCI and acute coronary syndrome, but hemoglobin and iron levels are collinear.

“The problem I think is when you throw hemoglobin and iron in the same model, just by play of chance, one variable can knock out the other one,” he said. “So I don’t know necessarily if we need to start measuring iron on everyone. We certainly should be measuring hemoglobin, which I think most people will have, and if a patient has pre-existing anemia, that should be a red flag for us.”

Age and Society of Thoracic Surgeons (STS) risk score did not reach statistical significance in the model – likely reflecting the high-/extremely-high-risk patient population with an average STS score of 7.7 and average age of 82 years – but may become more important as TAVR is applied more widely, Dr. Rao and Zachary Wegermann, MD, Duke Clinical Research Institute, write in an accompanying editorial.

They also point out that the study was limited by a low rate of bleeding events, and, importantly, the score can’t distinguish between minor or major bleeding.

“It’s worth trying to repeat the analyses in lower-risk patients because we may find other covariates that are important,” Dr. Rao said in an interview. “The other thing we need to get to is probably being a little bit more sophisticated. The variables included in these models are the ones that are measured; they’re also the ones that are clinically apparent.”

“But there’s a whole area of genomic medicine, proteomic medicine, metabolomic medicine that, as it starts developing and becomes more and more sophisticated, my suspicion is that we’re going to get even more precise and accurate about patients’ risk, and it’s going to become more individualized, rather than just measuring variables like age and lab values,” he said.

In the meantime, having variables documented in the electronic health record, with hard stops deployed if variables aren’t measured, is “a step in the right direction,” he added.

Dr. Navarese has received research grants from Abbott, Amgen, and Medtronic and received lecture fees and honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work. Dr. Rao and Dr. Wegermann report no relevant financial disclosures.

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

A new clinical score has been developed, and externally validated, to identify patients at risk of bleeding after transcatheter aortic valve replacement (TAVR).

“Despite the TAVR iterations, we recognize that bleeding remains a very important and perhaps also neglected issue. Indeed, no specifically developed standard algorithm existed before this to assess bleeding risk post-TAVR,” lead author Eliano Pio Navarese, MD, PhD, said in an interview.

Although bleeding rates can be as high as 9% at 30 days and between 3% and 11% in the first year, only a few studies have applied existing scores to TAVR patients, he noted.

The PREDICT-TAVR score includes six common variables and can be calculated by hand using a simple nomogram or a web-based calculator, with a dedicated website in the works, said Dr. Navarese, Nicolaus Copernicus University and SIRO MEDICINE Network, Bydgoszcz, Poland, and the University of Alberta, Edmonton.

A strength of the score is that machine-learning methods were used and the choice of variables optimized through recursive feature elimination and cross validation to remove the weakest variables, he said. Artificial intelligence, including use of random forest, naïve Bayes, and logistic regression classifiers, was also applied to the algorithms and the results cross-checked with standard multivariate analysis.

“It was a tremendous effort in terms of the analytics conducted,” Dr. Navarese said. “This is not a simple score but the integration of the most sophisticated machine learning methods and algorithms.”

Details are published in the June 14 issue of JACC: Cardiovascular Interventions.

The six variables used to calculate 30-day bleeding risk after TAVR and the points assigned to each are:

• blood hemoglobin (0-10 points)
• serum iron concentration (0-5 points)
• common femoral artery diameter (0-3 points)
•  (0-3 points)
• dual antiplatelet therapy (DAPT; 0-2 points)
• oral anticoagulation therapy (0-2 points)

The six items were selected among 104 baseline variables from 5,185 consecutive patients undergoing transfemoral TAVR in the prospective RISPEVA (Registro Italiano GISE sull’Impianto di Valvola Aortica Percutanea) registry between March 2012 and December 2019, then validated in 5,043 patients in the prospective POL-TAVI (Polish Registry of Transcatheter Aortic Valve Implantation) between January 2013 and December 2019.

In the derivation cohort, 216 patients (4.2%) experienced bleeding events at 1 year, with 169 events (78%) occurring during the first 30 days.

PREDICT-TAVR exhibited high discriminatory power for bleeding events at 30 days, as reflected by an area under the curve (AUC) of 0.80 (95% confidence interval, 0.75-0.83). Internal validation by optimism bootstrap-corrected AUC was consistent at 0.79 (95% CI, 0.75-0.83).

PREDICT-TAVR also outperformed scores not developed for TAVR, such as the PARIS score for patients undergoing percutaneous coronary intervention (AUC, 0.69) and the well-validated HAS-BLED for patients receiving anticoagulation (AUC, 0.58; P < .001 for both).

In the validation cohort, the AUC for bleeding complications at 30 days was 0.78 (95% CI, 0.72-0.82) versus an AUC of 0.68 for PARIS and 0.66 for HAS-BLED.

A HAS-BLED score of 4 predicted a higher rate of severe bleeding and mortality in the year after transfemoral TAVR in the 2018 Japanese OCEAN-TAVI study.
 

Bleeding events by risk categories

Risk score quartiles identified as low risk were 8 points or less, as moderate risk were 8 to less than 10 points, as high risk were 10 to less than 12 points, and as very-high-risk score were above 12 points.

In the derivation cohort, 30-day bleeding events across quartiles were 0.8%, 1.1%, 2.5%, and 8.5%, respectively (overall P < .001).

Compared with the lowest quartile, bleeding risk was numerically higher for the second quartile (odds ratio, 1.75) and significantly higher in the third (OR, 2.0) and fourth (OR, 2.49) quartiles (P < .001 for both).

A landmark cumulative-event analysis showed a significantly greater risk of bleeding for the two highest quartiles up to 30 days; however, these differences were no longer significant from 30 days to 1 year, likely because of a limited number of events, the authors suggest. Similar results were seen in the validation cohort.

The number of patients in the high- and very-high-risk groups isn’t trivial, and bleeding rates reached as high as 12.6% in the highest quartile, Dr. Navarese observed. Guidelines recommend DAPT for 3 to 6 months after TAVR; however, emerging data, including a recent meta-analysis, suggest monotherapy may be a very good option.

“So, if you had a high bleeding risk and are considering postprocedural DAPT or anticoagulation, I would think twice rather than administering dual antiplatelet therapy or anticoagulation for a long time, or at least, I would consider the impact of this score on this choice,” he said.

Subgroup analyses showed AUCs ranging from 0.77 to 0.81 for subgroups such as age older than 80 years, diabetes, obesity, female sex, previous PCI, and New York Heart Association class III or IV.

Serum iron showed the highest AUC in the primary PREDICT-TAVR model; however, should iron levels be unavailable, a simplified score modeled without iron levels retained predictive power, yielding AUCs for 30-day bleeding of 0.78 in the derivation cohort and 0.75 in the validation cohort.

“PREDICT-TAVR score can impact clinical practice, not only selecting the optimal thrombotic regimen in certain high bleeding-risk populations but also to treat pre-TAVR anemia and iron deficiencies, which may affect outcomes,” Dr. Navarese said. “Of course, future prospective biological and clinical investigations are needed to elucidate the score and the role of the score’s treatable risk traits in reducing post-TAVR bleeding complications.”

Commenting for this news organization, Sunil Rao, MD, Duke University, Durham, N.C., said anemia is a covariant in many risk models for bleeding and vascular complications in PCI and acute coronary syndrome, but hemoglobin and iron levels are collinear.

“The problem I think is when you throw hemoglobin and iron in the same model, just by play of chance, one variable can knock out the other one,” he said. “So I don’t know necessarily if we need to start measuring iron on everyone. We certainly should be measuring hemoglobin, which I think most people will have, and if a patient has pre-existing anemia, that should be a red flag for us.”

Age and Society of Thoracic Surgeons (STS) risk score did not reach statistical significance in the model – likely reflecting the high-/extremely-high-risk patient population with an average STS score of 7.7 and average age of 82 years – but may become more important as TAVR is applied more widely, Dr. Rao and Zachary Wegermann, MD, Duke Clinical Research Institute, write in an accompanying editorial.

They also point out that the study was limited by a low rate of bleeding events, and, importantly, the score can’t distinguish between minor or major bleeding.

“It’s worth trying to repeat the analyses in lower-risk patients because we may find other covariates that are important,” Dr. Rao said in an interview. “The other thing we need to get to is probably being a little bit more sophisticated. The variables included in these models are the ones that are measured; they’re also the ones that are clinically apparent.”

“But there’s a whole area of genomic medicine, proteomic medicine, metabolomic medicine that, as it starts developing and becomes more and more sophisticated, my suspicion is that we’re going to get even more precise and accurate about patients’ risk, and it’s going to become more individualized, rather than just measuring variables like age and lab values,” he said.

In the meantime, having variables documented in the electronic health record, with hard stops deployed if variables aren’t measured, is “a step in the right direction,” he added.

Dr. Navarese has received research grants from Abbott, Amgen, and Medtronic and received lecture fees and honoraria from Amgen, AstraZeneca, Bayer, Pfizer, and Sanofi-Regeneron, outside the submitted work. Dr. Rao and Dr. Wegermann report no relevant financial disclosures.

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

Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.

The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.

“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.

“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”

Background immunosuppressants contribute to unprecedented placebo responses

The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.

A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.

Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.

The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.

The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.

In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.

Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.

Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
 

Changes in secondary endpoints followed same pattern as CRISS

The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.

However, the researchers again found that duration of background therapy affected FVC.

“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.

Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.

Is there a subgroup for whom lenabasum would be efficacious?

Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.

“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”

Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.

Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.

“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”

Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”

Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.

“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.

He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.

“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”

Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.

“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”

The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.

The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.

“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.

“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”

Background immunosuppressants contribute to unprecedented placebo responses

The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.

A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.

Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.

The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.

The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.

In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.

Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.

Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
 

Changes in secondary endpoints followed same pattern as CRISS

The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.

However, the researchers again found that duration of background therapy affected FVC.

“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.

Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.

Is there a subgroup for whom lenabasum would be efficacious?

Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.

“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”

Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.

Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.

“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”

Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”

Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.

“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.

He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.

“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”

Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.

“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”

The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.

The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.

“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.

“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”

Background immunosuppressants contribute to unprecedented placebo responses

The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.

A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.

Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.

The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.

The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.

In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.

Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.

Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
 

Changes in secondary endpoints followed same pattern as CRISS

The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.

However, the researchers again found that duration of background therapy affected FVC.

“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.

Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.

Is there a subgroup for whom lenabasum would be efficacious?

Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.

“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”

Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.

Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.

“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”

Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”

Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.

“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.

He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.

“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”

Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.

“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”

The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

A dermal-wounding strategy involving fractionated laser resurfacing not only treated actinic keratoses, but it prevented the development of nonmelanoma skin cancer on treated areas, according to the results of a small, randomized trial.

“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”

Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.

To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.

Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m² with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.

At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001^{, Dr. Wargo reported}. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”

Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.

“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.

He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.

Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.

The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.

[email protected]

A dermal-wounding strategy involving fractionated laser resurfacing not only treated actinic keratoses, but it prevented the development of nonmelanoma skin cancer on treated areas, according to the results of a small, randomized trial.

“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”

Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.

To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.

Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m² with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.

At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001^{, Dr. Wargo reported}. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”

Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.

“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.

He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.

Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.

The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.

[email protected]

A dermal-wounding strategy involving fractionated laser resurfacing not only treated actinic keratoses, but it prevented the development of nonmelanoma skin cancer on treated areas, according to the results of a small, randomized trial.

“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”

Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.

To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.

Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m² with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.

At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001^{, Dr. Wargo reported}. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”

Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.

“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.

He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.

Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.

The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.

[email protected]

A HER3-targeted therapy has demonstrated clinically meaningful and durable efficacy in heavily pretreated patients with EGFR-mutant non–small cell lung cancer, according to results of a phase 1 study.

Patritumab deruxtecan, an antibody-drug conjugate targeting HER3, had an overall response rate (ORR) of 39% and median progression-free survival (PFS) of 8.2 months in a phase 1 study that included patients previously treated with tyrosine kinase inhibitors (TKIs) and chemotherapy, the results show.

The efficacy was seen across EGFR TKI resistance mechanisms in this very difficult-to-treat patient population, according to investigator Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute, Boston.

“There is not one category of individuals that are having a response, or not having a response,” Dr. Jänne said in a presentation at the annual meeting of the American Society of Clinical Oncology (Abstract 9007).

“Responses are observed in patients with identifiable resistance mechanisms, and in patients that do not have an identifiable resistance mechanism, but have progressed on prior EGFR TKI therapy,” he added.

More than 80% of non–small cell lung cancer (NSCLC) tumors express HER3, and of note, HER3 alterations do not appear to confer resistance to EGFR TKIs in patients with EGFR-mutant NSCLC, according to Dr. Jänne.
 

Study details

Also known as HER3-DXd, patritumab deruxtecan consists of a fully human anti-HER3 monoclonal antibody linked to a topoisomerase inhibitor payload by a tetrapeptide-based cleavable linker.

The antibody-drug conjugate is also being evaluated in metastatic breast cancer and colorectal cancer, Dr. Jänne said.

In the present phase 1 dose escalation and dose expansion study, a total of 57 patients were treated with patritumab deruxtecan at 5.6 mg/kg, the recommended dose for the expansion phase.

The median age of these patients was 65 years, and the majority (63%) were women, Dr. Jänne reported. About half had a history of central nervous system metastases.

The median number of prior lines of systemic therapy was four, making this a heavily pretreated patient population, Dr. Jänne said. All patients had received prior EGFR TKI therapy, and 86% specifically had prior osimertinib. Ninety-one percent had prior platinum-based chemotherapy, and 40% had received immunotherapy.
 

Spectrum of responses

The confirmed ORR of 39% included 1 complete response (2%) and 21 partial responses (37%), Dr. Jänne reported. The disease control rate was 72%, and median duration of response was 6.9 months at a median follow-up of 10.2 months.

The median PFS was 8.2 months in 57 patients overall and in a subset of 44 patients who had received prior osimertinib and platinum-based chemotherapy, according to the report.

Activity of patritumab deruxtecan was seen not only across patients with diverse mechanisms of EGFR TKI resistance, but also regardless of prior number of treatments, and regardless of history of brain metastases, the investigator said.

In addition, clinical responses were seen across a spectrum of baseline HER3 expression by immunohistochemistry, the investigator added.

Safety was assessed in 81 patients treated at a range of doses in the phase 1 trial. The most common grade 3 or greater treatment-emergent adverse events, observed in 5% or more of patients, included thrombocytopenia, neutropenia, and anemia, while other side effects such as fatigue and dyspnea were observed, Dr. Jänne said. About 9% of the adverse events led to treatment discontinuation in the safety cohort.

Interstitial lung disease was observed in four patients, or 5% of the safety cohort. Three of these were grade 1-2 and one was grade 3, according to the report.
 

Questions to explore

The efficacy of patritumab deruxtecan was “high” in this phase 1 study, based on the reported response rate and median PFS, said discussant Nicolas Girard, MD, PhD, of Institut Curie in Paris.

However, the most striking finding of the study was the efficacy of the antibody-drug conjugate across all reported resistance mechanisms, Dr. Girard said in his remarks.

Questions that remains to be explored, according to Dr. Girard, include the impact of previous treatment sequencing with TKIs and chemotherapy on patient outcomes with patritumab deruxtecan, as well as the assessment of intracranial response and PFS for patients treated with the agent.

In addition, antitumor activity was seen across a wide range of baseline HER3 expression levels in this study, suggesting that a predictive biomarker remains to be identified, according to Dr. Girard.

“HER3 immunohistochemistry does not seem to be the candidate in this setting,” he said.

The study was sponsored by Daiichi Sankyo. Dr. Jänne reported disclosures related to Daiichi Sankyo, as well as Araxes Pharma, Astellas Pharma, AstraZeneca, and multiple other pharmaceutical companies. Dr. Jänne is also coinventor on a Dana Farber Cancer Institute–owned patent on EGFR mutations licensed to Labcorp and receives postmarketing royalties from this invention.

Dr. Girard reported disclosures related to AbbVie, AstraZeneca, Boehringer Ingelheim, and multiple other pharmaceutical companies.

A HER3-targeted therapy has demonstrated clinically meaningful and durable efficacy in heavily pretreated patients with EGFR-mutant non–small cell lung cancer, according to results of a phase 1 study.

Patritumab deruxtecan, an antibody-drug conjugate targeting HER3, had an overall response rate (ORR) of 39% and median progression-free survival (PFS) of 8.2 months in a phase 1 study that included patients previously treated with tyrosine kinase inhibitors (TKIs) and chemotherapy, the results show.

The efficacy was seen across EGFR TKI resistance mechanisms in this very difficult-to-treat patient population, according to investigator Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute, Boston.

“There is not one category of individuals that are having a response, or not having a response,” Dr. Jänne said in a presentation at the annual meeting of the American Society of Clinical Oncology (Abstract 9007).

“Responses are observed in patients with identifiable resistance mechanisms, and in patients that do not have an identifiable resistance mechanism, but have progressed on prior EGFR TKI therapy,” he added.

More than 80% of non–small cell lung cancer (NSCLC) tumors express HER3, and of note, HER3 alterations do not appear to confer resistance to EGFR TKIs in patients with EGFR-mutant NSCLC, according to Dr. Jänne.
 

Study details

Also known as HER3-DXd, patritumab deruxtecan consists of a fully human anti-HER3 monoclonal antibody linked to a topoisomerase inhibitor payload by a tetrapeptide-based cleavable linker.

The antibody-drug conjugate is also being evaluated in metastatic breast cancer and colorectal cancer, Dr. Jänne said.

In the present phase 1 dose escalation and dose expansion study, a total of 57 patients were treated with patritumab deruxtecan at 5.6 mg/kg, the recommended dose for the expansion phase.

The median age of these patients was 65 years, and the majority (63%) were women, Dr. Jänne reported. About half had a history of central nervous system metastases.

The median number of prior lines of systemic therapy was four, making this a heavily pretreated patient population, Dr. Jänne said. All patients had received prior EGFR TKI therapy, and 86% specifically had prior osimertinib. Ninety-one percent had prior platinum-based chemotherapy, and 40% had received immunotherapy.
 

Spectrum of responses

The confirmed ORR of 39% included 1 complete response (2%) and 21 partial responses (37%), Dr. Jänne reported. The disease control rate was 72%, and median duration of response was 6.9 months at a median follow-up of 10.2 months.

The median PFS was 8.2 months in 57 patients overall and in a subset of 44 patients who had received prior osimertinib and platinum-based chemotherapy, according to the report.

Activity of patritumab deruxtecan was seen not only across patients with diverse mechanisms of EGFR TKI resistance, but also regardless of prior number of treatments, and regardless of history of brain metastases, the investigator said.

In addition, clinical responses were seen across a spectrum of baseline HER3 expression by immunohistochemistry, the investigator added.

Safety was assessed in 81 patients treated at a range of doses in the phase 1 trial. The most common grade 3 or greater treatment-emergent adverse events, observed in 5% or more of patients, included thrombocytopenia, neutropenia, and anemia, while other side effects such as fatigue and dyspnea were observed, Dr. Jänne said. About 9% of the adverse events led to treatment discontinuation in the safety cohort.

Interstitial lung disease was observed in four patients, or 5% of the safety cohort. Three of these were grade 1-2 and one was grade 3, according to the report.
 

Questions to explore

The efficacy of patritumab deruxtecan was “high” in this phase 1 study, based on the reported response rate and median PFS, said discussant Nicolas Girard, MD, PhD, of Institut Curie in Paris.

However, the most striking finding of the study was the efficacy of the antibody-drug conjugate across all reported resistance mechanisms, Dr. Girard said in his remarks.

Questions that remains to be explored, according to Dr. Girard, include the impact of previous treatment sequencing with TKIs and chemotherapy on patient outcomes with patritumab deruxtecan, as well as the assessment of intracranial response and PFS for patients treated with the agent.

In addition, antitumor activity was seen across a wide range of baseline HER3 expression levels in this study, suggesting that a predictive biomarker remains to be identified, according to Dr. Girard.

“HER3 immunohistochemistry does not seem to be the candidate in this setting,” he said.

The study was sponsored by Daiichi Sankyo. Dr. Jänne reported disclosures related to Daiichi Sankyo, as well as Araxes Pharma, Astellas Pharma, AstraZeneca, and multiple other pharmaceutical companies. Dr. Jänne is also coinventor on a Dana Farber Cancer Institute–owned patent on EGFR mutations licensed to Labcorp and receives postmarketing royalties from this invention.

Dr. Girard reported disclosures related to AbbVie, AstraZeneca, Boehringer Ingelheim, and multiple other pharmaceutical companies.

A HER3-targeted therapy has demonstrated clinically meaningful and durable efficacy in heavily pretreated patients with EGFR-mutant non–small cell lung cancer, according to results of a phase 1 study.

Patritumab deruxtecan, an antibody-drug conjugate targeting HER3, had an overall response rate (ORR) of 39% and median progression-free survival (PFS) of 8.2 months in a phase 1 study that included patients previously treated with tyrosine kinase inhibitors (TKIs) and chemotherapy, the results show.

The efficacy was seen across EGFR TKI resistance mechanisms in this very difficult-to-treat patient population, according to investigator Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute, Boston.

“There is not one category of individuals that are having a response, or not having a response,” Dr. Jänne said in a presentation at the annual meeting of the American Society of Clinical Oncology (Abstract 9007).

“Responses are observed in patients with identifiable resistance mechanisms, and in patients that do not have an identifiable resistance mechanism, but have progressed on prior EGFR TKI therapy,” he added.

More than 80% of non–small cell lung cancer (NSCLC) tumors express HER3, and of note, HER3 alterations do not appear to confer resistance to EGFR TKIs in patients with EGFR-mutant NSCLC, according to Dr. Jänne.
 

Study details

Also known as HER3-DXd, patritumab deruxtecan consists of a fully human anti-HER3 monoclonal antibody linked to a topoisomerase inhibitor payload by a tetrapeptide-based cleavable linker.

The antibody-drug conjugate is also being evaluated in metastatic breast cancer and colorectal cancer, Dr. Jänne said.

In the present phase 1 dose escalation and dose expansion study, a total of 57 patients were treated with patritumab deruxtecan at 5.6 mg/kg, the recommended dose for the expansion phase.

The median age of these patients was 65 years, and the majority (63%) were women, Dr. Jänne reported. About half had a history of central nervous system metastases.

The median number of prior lines of systemic therapy was four, making this a heavily pretreated patient population, Dr. Jänne said. All patients had received prior EGFR TKI therapy, and 86% specifically had prior osimertinib. Ninety-one percent had prior platinum-based chemotherapy, and 40% had received immunotherapy.
 

Spectrum of responses

The confirmed ORR of 39% included 1 complete response (2%) and 21 partial responses (37%), Dr. Jänne reported. The disease control rate was 72%, and median duration of response was 6.9 months at a median follow-up of 10.2 months.

The median PFS was 8.2 months in 57 patients overall and in a subset of 44 patients who had received prior osimertinib and platinum-based chemotherapy, according to the report.

Activity of patritumab deruxtecan was seen not only across patients with diverse mechanisms of EGFR TKI resistance, but also regardless of prior number of treatments, and regardless of history of brain metastases, the investigator said.

In addition, clinical responses were seen across a spectrum of baseline HER3 expression by immunohistochemistry, the investigator added.

Safety was assessed in 81 patients treated at a range of doses in the phase 1 trial. The most common grade 3 or greater treatment-emergent adverse events, observed in 5% or more of patients, included thrombocytopenia, neutropenia, and anemia, while other side effects such as fatigue and dyspnea were observed, Dr. Jänne said. About 9% of the adverse events led to treatment discontinuation in the safety cohort.

Interstitial lung disease was observed in four patients, or 5% of the safety cohort. Three of these were grade 1-2 and one was grade 3, according to the report.
 

Questions to explore

The efficacy of patritumab deruxtecan was “high” in this phase 1 study, based on the reported response rate and median PFS, said discussant Nicolas Girard, MD, PhD, of Institut Curie in Paris.

However, the most striking finding of the study was the efficacy of the antibody-drug conjugate across all reported resistance mechanisms, Dr. Girard said in his remarks.

Questions that remains to be explored, according to Dr. Girard, include the impact of previous treatment sequencing with TKIs and chemotherapy on patient outcomes with patritumab deruxtecan, as well as the assessment of intracranial response and PFS for patients treated with the agent.

In addition, antitumor activity was seen across a wide range of baseline HER3 expression levels in this study, suggesting that a predictive biomarker remains to be identified, according to Dr. Girard.

“HER3 immunohistochemistry does not seem to be the candidate in this setting,” he said.

The study was sponsored by Daiichi Sankyo. Dr. Jänne reported disclosures related to Daiichi Sankyo, as well as Araxes Pharma, Astellas Pharma, AstraZeneca, and multiple other pharmaceutical companies. Dr. Jänne is also coinventor on a Dana Farber Cancer Institute–owned patent on EGFR mutations licensed to Labcorp and receives postmarketing royalties from this invention.

Dr. Girard reported disclosures related to AbbVie, AstraZeneca, Boehringer Ingelheim, and multiple other pharmaceutical companies.

Background: Critically ill patients are often vitamin D deficient, but no large randomized trials have investigated whether early vitamin D supplementation can affect clinical outcomes.

Study design: Multicenter, randomized, double-blind, placebo-controlled phase 3 trial.Setting: 44 U.S. hospitals, during April 2017–July 2018.

Synopsis: The study enrolled 1,078 patients with 25-hydroxyvitamin D levels < 20 ng/mL who were critically ill (defined as patients being admitted to the ICU with one or more risk factor for lung injury or death). Participants were randomized to early administration of a single dose of 540,000 IUs of enteral vitamin D₃ or placebo. The authors did not identify a statistically significant difference in the 90-day all-cause mortality between the two groups. Additionally, there were no significant differences in length of stay, ventilator-free days or serious adverse outcomes between the two groups.

Bottom line: Early administration of high-dose enteral vitamin D₃ did not decrease 90-day all-cause mortality in critically ill, vitamin D–deficient patients.

Citation: Ginde A et al. Early high-dose vitamin D₃ for critically ill, vitamin D–deficient patients. N Engl J Med. 2019 Dec 26; 281:2529-40.

Dr. Persaud is a hospitalist, Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, both in Boston.

Background: Critically ill patients are often vitamin D deficient, but no large randomized trials have investigated whether early vitamin D supplementation can affect clinical outcomes.

Study design: Multicenter, randomized, double-blind, placebo-controlled phase 3 trial.Setting: 44 U.S. hospitals, during April 2017–July 2018.

Synopsis: The study enrolled 1,078 patients with 25-hydroxyvitamin D levels < 20 ng/mL who were critically ill (defined as patients being admitted to the ICU with one or more risk factor for lung injury or death). Participants were randomized to early administration of a single dose of 540,000 IUs of enteral vitamin D₃ or placebo. The authors did not identify a statistically significant difference in the 90-day all-cause mortality between the two groups. Additionally, there were no significant differences in length of stay, ventilator-free days or serious adverse outcomes between the two groups.

Bottom line: Early administration of high-dose enteral vitamin D₃ did not decrease 90-day all-cause mortality in critically ill, vitamin D–deficient patients.

Citation: Ginde A et al. Early high-dose vitamin D₃ for critically ill, vitamin D–deficient patients. N Engl J Med. 2019 Dec 26; 281:2529-40.

Dr. Persaud is a hospitalist, Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, both in Boston.

Background: Critically ill patients are often vitamin D deficient, but no large randomized trials have investigated whether early vitamin D supplementation can affect clinical outcomes.

Study design: Multicenter, randomized, double-blind, placebo-controlled phase 3 trial.Setting: 44 U.S. hospitals, during April 2017–July 2018.

Synopsis: The study enrolled 1,078 patients with 25-hydroxyvitamin D levels < 20 ng/mL who were critically ill (defined as patients being admitted to the ICU with one or more risk factor for lung injury or death). Participants were randomized to early administration of a single dose of 540,000 IUs of enteral vitamin D₃ or placebo. The authors did not identify a statistically significant difference in the 90-day all-cause mortality between the two groups. Additionally, there were no significant differences in length of stay, ventilator-free days or serious adverse outcomes between the two groups.

Bottom line: Early administration of high-dose enteral vitamin D₃ did not decrease 90-day all-cause mortality in critically ill, vitamin D–deficient patients.

Citation: Ginde A et al. Early high-dose vitamin D₃ for critically ill, vitamin D–deficient patients. N Engl J Med. 2019 Dec 26; 281:2529-40.

Dr. Persaud is a hospitalist, Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, both in Boston.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.