Clinician Reviews

On June 14, 2017, just before noon, a doctor made an incision near a patient’s groin. Kari Kirk, a representative for the world’s largest medical device company, Medtronic, looked on and began texting her colleague a play-by-play.

“Fixing both legs from the ankles,” she wrote.

It was a fairly common procedure at the Robert J. Dole Veterans Affairs Medical Center in Wichita, Kansas, performed to treat blockages in the leg vessels.

Within reach were an array of Medtronic products: tubes with blades attached to shave hardened deposits off of artery walls; stents to widen blood vessels; balloons coated with therapeutic drugs.

Each time a doctor puts a foreign device in someone’s body, it carries a risk of complication, which can include clots or even require amputation. So medical experts, research and even Medtronic’s own device instructions urge doctors to use as few as are necessary.

But, as revealed in Kirk’s text messages, this doctor took an aggressive approach.

“Just used 12 [drug-coated balloons]!!” Kirk texted her colleague.

“Does that mean I owe u $$,” he responded.

“Thats what I’m thinking!!!” she said. “And now 14 balloons?!”

“but only one stent so far??”

“So far!”

As the texting continued, her colleague replied, “U are going to want to start going to the VA all the time.”

The messages, recently unsealed in an ongoing whistleblower lawsuit, give a window into the way money and medicine mingle in the booming business of peripheral artery disease, a condition that afflicts 6.5 million Americans over age 40 and is caused when fatty plaque builds up in arteries, blocking blood flow to the legs.

Representatives from companies are often present during vascular procedures to guide doctors on how to use their complex devices. This kind of access has the potential to influence treatment plans, as companies and their representatives profit when more of their product is used.

The suit, filed in 2017 by a sales representative for a competing medical device firm, alleges an illegal kickback scheme between Medtronic and hospital employees. According to the complaint and documents released in the suit, between 2011 and 2018, VA health care workers received steakhouse dinners, Apple electronics, and NASCAR tickets, and in turn, Medtronic secured a lucrative contract with the hospital. Meanwhile, the company’s representatives allegedly “groomed and trained” physicians at the facility, who then deployed the company’s devices even when it was not medically indicated.

Independently from the whistleblower suit, internal investigators at the Wichita facility have also examined the treatment patterns of its vascular patients in recent years and found numerous cases where medical devices were used excessively. While it’s not uncommon to deploy several devices, a medical expert on the investigation team found that the VA doctors sometimes used more than 15 at a time – one used 33 – deviating from the standard of care.

“It is unconscionable – there can be no valid medically acceptable basis to cram so many devices into a human being,” wrote attorneys representing the whistleblower in legal filings from January 2023. “This is not medical treatment. This is abuse.”

Dr. Kim Hodgson, former president of the Society for Vascular Surgery and an expert retained by the plaintiff, said the findings of the internal review of patient data raise “a high level of concern regarding necessity of treatment provided,” according to case documents.

Medtronic declined to respond to ProPublica’s questions, citing the ongoing litigation. “These allegations are false and Medtronic is defending against these claims in court,” said Boua Xiong, a spokesperson for the company. Medtronic representative Kirk declined to respond to ProPublica’s request for comment.

The hospital investigation found that amputations increased sixfold in the same time frame as the procedures in question, according to internal emails, but made no conclusion about whether those two things were connected. ProPublica reached out to the VA to ask whether any patients had been harmed.

The VA is “conducting an extensive review of patient care” at the Kansas hospital, “including the number of devices used on patients – to make sure that Veterans were not harmed by any procedures,” press secretary Terrence Hayes said in a statement. So far, the VA’s investigation has found no “quality of care issues,” he said, and the investigation will continue “until every Veteran’s case has been reviewed.” (Read the full statement here.) Neither the department nor the hospital has taken formal action against the medical providers, Hayes said.

The medical group that had a contract with the VA for vascular interventions, Wichita Radiological Group, did not respond to ProPublica’s requests for comment, nor did the doctors named in the suit: Dr. Shaun Gonda, Dr. Bret Winblad, and Dr. Kermit Rust. It is unclear from the case documents which doctors conducted which procedures. Eric Barth, an attorney for the medical group, denied the allegations in recent legal filings, calling the claims “baseless” and the lawsuit a “witch hunt.”

The lawsuit comes amid growing concern about one of these procedures – atherectomies – after researchers and doctors have uncovered patterns of excessive and inappropriate use. Recent research has found that this procedure, a common but costly treatment to shave or laser plaque from blood vessels, is not more effective than cheaper alternatives and may even be associated with a higher risk of complications including amputation. In recent years, several doctors and clinics have been investigated for allegedly taking advantage of Medicare’s reimbursement rates, and one study found that many doctors are resorting to atherectomies in the earliest stages of peripheral artery disease, against best practices that urge noninvasive treatment.

“Atherectomy is important in certain settings. But it’s being used in a way that is entirely inappropriate and it’s largely driven by the incentive structure,” said Dr. Caitlin Hicks, the lead author of the study and an associate professor of surgery at Johns Hopkins University School of Medicine.

Although different payment structures govern the care of veterans, the whistleblower lawsuit alleges that outside physicians, paid hourly by the Dole VA, were motivated to conduct longer and more complex procedures that would earn them higher payment.

Under different circumstances, the patient in the procedure room on that summer day could have been done after 2 hours.

But, 150 minutes in, those Medtronic representatives were still texting. At that point, more than 15 of their vascular devices had been used, including stents, balloons, and those for atherectomy.

“Long case!” Kirk’s colleague texted. “Is it looking ok??”

“It is,” she said. “Thought we were done a few times! Now he’s going back in to cut again!”

A little while later, she texted: “....17!”

He texted back [with laughing emoticons].

Hospital leaders had been scrutinizing the use of these procedures at the Dole VA for years.

In 2017, shortly after Rick Ament was hired to lead the facility, he noticed something was amiss. While the longtime hospital administrator was poring over the finances, he was alarmed to discover that the relatively small Dole VA had one of the most expensive cardiac programs in the country. As Ament dug deeper, he realized vascular interventions were the reason.

“It just did not make sense that the acuity level of our patients would generate such extreme cost variances from the norm,” he testified in December, in a deposition for the whistleblower case. “It was so significant, we needed to get to the bottom of it.”

Ament, a second generation Air Force veteran, quietly assembled a task force to investigate why the facility had purchased so many medical devices for these procedures. After they examined inventory records, calculating the total number of medical devices and the cost of devices per patient, they grew concerned.

“We were more expensive than, I believe it was, the top 10 hospitals in the VA combined,” he said. “My feeling was that we either had very, very bad providers or we had product walking out the door.”

Ament enlisted experts from other VA hospitals to help his team investigate, including an administrative officer who could understand finances and a respected interventional radiologist who could examine records. The task force gathered a list of patients from 2016 to 2018, according to internal emails, and analyzed their medical charts.

According to internal VA documents released through the whistleblower suit, the review found a number of clinical failings: Evidence-based medicine had not been followed in the majority of cases reviewed. Procedures were over-aggressive, treating lesions that should have been left alone. And there was a total disregard for established best practices for treating peripheral artery disease.

One of the experts on the investigative team explained to Ament that while it was not uncommon for doctors to use a couple of devices in one intervention, the total number of devices in many of the procedures at his facility went into the double digits, sometimes five times the expected amount.

In one encounter, a doctor deployed 33 devices in one procedure – 3 atherectomy devices, 9 stents, and 21 balloons.

This use of devices was exorbitant, Ament came to understand. “I want to say the term ‘egregious’ was used,” he testified. “It was kind of like validation, but I really wish I was wrong.”

“Did it make you concerned for patient care?” a lawyer asked during the deposition.

“It did,” Ament replied.

A member of his task force pulled data for veterans who had leg amputations due to vascular disease. Over 5 years, the number of veterans who had amputations increased, from about 6 in 2013 to 38 in 2018, according to internal emails released in the suit. The VA did not respond to ProPublica’s questions about the rise in amputations or whether it was due to complications from the procedures.

Even though Ament testified in December 2022 that he became aware of the excessive use of devices during his investigation that began about 5 years ago, neither he nor the VA have publicly acknowledged these findings outside of the lawsuit. It is unclear whether VA representatives informed the patients whose records were reviewed about their findings. ProPublica reached out to more than half a dozen veteran community groups in the Wichita area and none were aware of the investigation nor the allegations of overuse of vascular procedures at the facility.

The VA says that if its ongoing review finds instances of substandard care, it will reach out to affected patients and inform them about possible complications and benefits they may be entitled to. The press secretary said the review will take several months. Ament declined to respond to ProPublica’s questions, citing the ongoing case.

In 2018, Ament turned over his findings to the criminal division of the VA’s Office of Inspector General. He also shut down interventional radiology procedures at the facility’s catheter lab.

Federal agents separately opened an investigation into the same unit in the facility, looking into allegations of kickbacks.

More than 40 pages of expense reports from Medtronic, revealed in the whistleblower case, show sales representatives treating Dole health care workers to hundreds of meals over several years – lunches at Dempsey’s Biscuit Co.; business meals at the Scotch & Sirloin steakhouse; dinner at Chester’s Chophouse & Wine Bar, price per attendee: $122.39.

Federal agents obtained the receipts.

“Robert J. Dole VAMC employees may have received improper gratuities, in the forms of paid lunches, dinners, etc., from sales representatives from Medtronic,” Nathen Howard, a special agent in the VA OIG, wrote in an investigation memo from February 2019.

This kind of relationship could violate VA policy, which forbids federal employees from receiving any gifts, including meals, from people who do business or seek to do business with a federal institution. For health care workers, violating this policy could have serious implications for patients. Numerous studies have shown that even modest industry-sponsored gifts, including meals, may influence prescribing or treatment behavior of health care professionals.

The agents opened their investigation into kickbacks at the Wichita facility in response to the whistleblower lawsuit, which was filed by Thomas Schroeder in 2017. The VA OIG would not confirm or deny whether it was continuing to investigate kickbacks at the facility. The VA did not directly answer ProPublica’s questions about kickbacks at the Dole VA, but it said that every employee must complete an annual ethics training, which covers gift rules.

In recent years, Medtronic has settled a handful of other cases that have alleged kickbacks between company representatives and health care professionals.

In 2018, Medtronic’s subsidiary Covidien paid $13 million to settle claims with the U.S. Department of Justice that it paid kickbacks to health care institutions that used its mechanical blood clot devices. In 2019, the same subsidiary paid $17 million to resolve allegations that it provided in-kind marketing support to doctors using its vein products. And in 2020, Medtronic paid more than $8 million to settle claims that representatives had paid kickbacks to a neurosurgeon, including scores of lavish meals at a restaurant that the doctor owned, to induce him to purchase the company’s medication pumps.

Schroeder’s lawsuit is not the first time Medtronic’s vascular devices were named in an alleged kickback scheme. In early 2015, Medtronic acquired Covidien, and shortly after the merger, its subsidiary ev3 Inc. agreed to pay $1.25 million to resolve allegations that it had paid doctors who were “high volume users” of its atherectomy devices to act as evangelists for the company, and had provided physicians with company shares to participate in clinical trials for their tools.

The whistleblower in this earlier case, a former sales representative for the company, also alleged that the subsidiary was gaming Medicare’s payment system. Hospitals were often hesitant to conduct atherectomy procedures because of the low reimbursement rates. According to the suit, sales representatives encouraged doctors to admit patients for longer stays to reap greater reimbursements and make a profit, even though such stays were often not medically indicated.

“Medical device makers that try to boost their profits by causing patients to be admitted for unnecessary and expensive inpatient hospital stays will be held accountable,” special agent Thomas O’Donnell, from the Office of Inspector General at the U.S. Department of Health and Human Services, said in a press release for the settlement. “Both patients and taxpayers deserve to have medical decisions made based on what is medically appropriate.”

Medtronic spokesperson Xiong said that in each case, the company “cooperated fully with the DOJ to resolve its concerns and, where wrongdoing was found, took appropriate remedial action.”

Seton Hall Law School professor Jacob Elberg, a former assistant U.S. attorney for the District of New Jersey who led its health care and government fraud unit, is concerned by the frequency of such settlements in the last 2 decades. “There are, at this point, real questions as to whether the sanctions imposed by DOJ are sufficient to deter wrongdoing and to lead to meaningful change, especially within the medical device industry.”

Although the Department of Justice has declined to intervene in the lawsuit involving the Dole VA at this time, the case is ongoing and further depositions with Medtronic sales representatives and a former VA employee are scheduled for this month.

VA employees and doctors named in the suit declined to comment or did not respond to ProPublica’s questions about the alleged kickbacks and whether sales representatives may have influenced veterans’ treatment plans. In interviews with federal investigators, according to released transcripts, several of the employees who were questioned denied receiving frequent meals from sales representatives, contradicting Medtronic’s expense reports.

Their statements also stand in contrast to Medtronic representative Kari Kirk’s final text messages during that procedure in June 2017, which ultimately lasted more than 3 hours.

“Now u done??” her colleague asked.

“Just finished,” she texted. “Running to get them lunch!”

This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.

On June 14, 2017, just before noon, a doctor made an incision near a patient’s groin. Kari Kirk, a representative for the world’s largest medical device company, Medtronic, looked on and began texting her colleague a play-by-play.

“Fixing both legs from the ankles,” she wrote.

It was a fairly common procedure at the Robert J. Dole Veterans Affairs Medical Center in Wichita, Kansas, performed to treat blockages in the leg vessels.

Within reach were an array of Medtronic products: tubes with blades attached to shave hardened deposits off of artery walls; stents to widen blood vessels; balloons coated with therapeutic drugs.

Each time a doctor puts a foreign device in someone’s body, it carries a risk of complication, which can include clots or even require amputation. So medical experts, research and even Medtronic’s own device instructions urge doctors to use as few as are necessary.

But, as revealed in Kirk’s text messages, this doctor took an aggressive approach.

“Just used 12 [drug-coated balloons]!!” Kirk texted her colleague.

“Does that mean I owe u $$,” he responded.

“Thats what I’m thinking!!!” she said. “And now 14 balloons?!”

“but only one stent so far??”

“So far!”

As the texting continued, her colleague replied, “U are going to want to start going to the VA all the time.”

The messages, recently unsealed in an ongoing whistleblower lawsuit, give a window into the way money and medicine mingle in the booming business of peripheral artery disease, a condition that afflicts 6.5 million Americans over age 40 and is caused when fatty plaque builds up in arteries, blocking blood flow to the legs.

Representatives from companies are often present during vascular procedures to guide doctors on how to use their complex devices. This kind of access has the potential to influence treatment plans, as companies and their representatives profit when more of their product is used.

The suit, filed in 2017 by a sales representative for a competing medical device firm, alleges an illegal kickback scheme between Medtronic and hospital employees. According to the complaint and documents released in the suit, between 2011 and 2018, VA health care workers received steakhouse dinners, Apple electronics, and NASCAR tickets, and in turn, Medtronic secured a lucrative contract with the hospital. Meanwhile, the company’s representatives allegedly “groomed and trained” physicians at the facility, who then deployed the company’s devices even when it was not medically indicated.

Independently from the whistleblower suit, internal investigators at the Wichita facility have also examined the treatment patterns of its vascular patients in recent years and found numerous cases where medical devices were used excessively. While it’s not uncommon to deploy several devices, a medical expert on the investigation team found that the VA doctors sometimes used more than 15 at a time – one used 33 – deviating from the standard of care.

“It is unconscionable – there can be no valid medically acceptable basis to cram so many devices into a human being,” wrote attorneys representing the whistleblower in legal filings from January 2023. “This is not medical treatment. This is abuse.”

Dr. Kim Hodgson, former president of the Society for Vascular Surgery and an expert retained by the plaintiff, said the findings of the internal review of patient data raise “a high level of concern regarding necessity of treatment provided,” according to case documents.

Medtronic declined to respond to ProPublica’s questions, citing the ongoing litigation. “These allegations are false and Medtronic is defending against these claims in court,” said Boua Xiong, a spokesperson for the company. Medtronic representative Kirk declined to respond to ProPublica’s request for comment.

The hospital investigation found that amputations increased sixfold in the same time frame as the procedures in question, according to internal emails, but made no conclusion about whether those two things were connected. ProPublica reached out to the VA to ask whether any patients had been harmed.

The VA is “conducting an extensive review of patient care” at the Kansas hospital, “including the number of devices used on patients – to make sure that Veterans were not harmed by any procedures,” press secretary Terrence Hayes said in a statement. So far, the VA’s investigation has found no “quality of care issues,” he said, and the investigation will continue “until every Veteran’s case has been reviewed.” (Read the full statement here.) Neither the department nor the hospital has taken formal action against the medical providers, Hayes said.

The medical group that had a contract with the VA for vascular interventions, Wichita Radiological Group, did not respond to ProPublica’s requests for comment, nor did the doctors named in the suit: Dr. Shaun Gonda, Dr. Bret Winblad, and Dr. Kermit Rust. It is unclear from the case documents which doctors conducted which procedures. Eric Barth, an attorney for the medical group, denied the allegations in recent legal filings, calling the claims “baseless” and the lawsuit a “witch hunt.”

The lawsuit comes amid growing concern about one of these procedures – atherectomies – after researchers and doctors have uncovered patterns of excessive and inappropriate use. Recent research has found that this procedure, a common but costly treatment to shave or laser plaque from blood vessels, is not more effective than cheaper alternatives and may even be associated with a higher risk of complications including amputation. In recent years, several doctors and clinics have been investigated for allegedly taking advantage of Medicare’s reimbursement rates, and one study found that many doctors are resorting to atherectomies in the earliest stages of peripheral artery disease, against best practices that urge noninvasive treatment.

“Atherectomy is important in certain settings. But it’s being used in a way that is entirely inappropriate and it’s largely driven by the incentive structure,” said Dr. Caitlin Hicks, the lead author of the study and an associate professor of surgery at Johns Hopkins University School of Medicine.

Although different payment structures govern the care of veterans, the whistleblower lawsuit alleges that outside physicians, paid hourly by the Dole VA, were motivated to conduct longer and more complex procedures that would earn them higher payment.

Under different circumstances, the patient in the procedure room on that summer day could have been done after 2 hours.

But, 150 minutes in, those Medtronic representatives were still texting. At that point, more than 15 of their vascular devices had been used, including stents, balloons, and those for atherectomy.

“Long case!” Kirk’s colleague texted. “Is it looking ok??”

“It is,” she said. “Thought we were done a few times! Now he’s going back in to cut again!”

A little while later, she texted: “....17!”

He texted back [with laughing emoticons].

Hospital leaders had been scrutinizing the use of these procedures at the Dole VA for years.

In 2017, shortly after Rick Ament was hired to lead the facility, he noticed something was amiss. While the longtime hospital administrator was poring over the finances, he was alarmed to discover that the relatively small Dole VA had one of the most expensive cardiac programs in the country. As Ament dug deeper, he realized vascular interventions were the reason.

“It just did not make sense that the acuity level of our patients would generate such extreme cost variances from the norm,” he testified in December, in a deposition for the whistleblower case. “It was so significant, we needed to get to the bottom of it.”

Ament, a second generation Air Force veteran, quietly assembled a task force to investigate why the facility had purchased so many medical devices for these procedures. After they examined inventory records, calculating the total number of medical devices and the cost of devices per patient, they grew concerned.

“We were more expensive than, I believe it was, the top 10 hospitals in the VA combined,” he said. “My feeling was that we either had very, very bad providers or we had product walking out the door.”

Ament enlisted experts from other VA hospitals to help his team investigate, including an administrative officer who could understand finances and a respected interventional radiologist who could examine records. The task force gathered a list of patients from 2016 to 2018, according to internal emails, and analyzed their medical charts.

According to internal VA documents released through the whistleblower suit, the review found a number of clinical failings: Evidence-based medicine had not been followed in the majority of cases reviewed. Procedures were over-aggressive, treating lesions that should have been left alone. And there was a total disregard for established best practices for treating peripheral artery disease.

One of the experts on the investigative team explained to Ament that while it was not uncommon for doctors to use a couple of devices in one intervention, the total number of devices in many of the procedures at his facility went into the double digits, sometimes five times the expected amount.

In one encounter, a doctor deployed 33 devices in one procedure – 3 atherectomy devices, 9 stents, and 21 balloons.

This use of devices was exorbitant, Ament came to understand. “I want to say the term ‘egregious’ was used,” he testified. “It was kind of like validation, but I really wish I was wrong.”

“Did it make you concerned for patient care?” a lawyer asked during the deposition.

“It did,” Ament replied.

A member of his task force pulled data for veterans who had leg amputations due to vascular disease. Over 5 years, the number of veterans who had amputations increased, from about 6 in 2013 to 38 in 2018, according to internal emails released in the suit. The VA did not respond to ProPublica’s questions about the rise in amputations or whether it was due to complications from the procedures.

Even though Ament testified in December 2022 that he became aware of the excessive use of devices during his investigation that began about 5 years ago, neither he nor the VA have publicly acknowledged these findings outside of the lawsuit. It is unclear whether VA representatives informed the patients whose records were reviewed about their findings. ProPublica reached out to more than half a dozen veteran community groups in the Wichita area and none were aware of the investigation nor the allegations of overuse of vascular procedures at the facility.

The VA says that if its ongoing review finds instances of substandard care, it will reach out to affected patients and inform them about possible complications and benefits they may be entitled to. The press secretary said the review will take several months. Ament declined to respond to ProPublica’s questions, citing the ongoing case.

In 2018, Ament turned over his findings to the criminal division of the VA’s Office of Inspector General. He also shut down interventional radiology procedures at the facility’s catheter lab.

Federal agents separately opened an investigation into the same unit in the facility, looking into allegations of kickbacks.

More than 40 pages of expense reports from Medtronic, revealed in the whistleblower case, show sales representatives treating Dole health care workers to hundreds of meals over several years – lunches at Dempsey’s Biscuit Co.; business meals at the Scotch & Sirloin steakhouse; dinner at Chester’s Chophouse & Wine Bar, price per attendee: $122.39.

Federal agents obtained the receipts.

“Robert J. Dole VAMC employees may have received improper gratuities, in the forms of paid lunches, dinners, etc., from sales representatives from Medtronic,” Nathen Howard, a special agent in the VA OIG, wrote in an investigation memo from February 2019.

This kind of relationship could violate VA policy, which forbids federal employees from receiving any gifts, including meals, from people who do business or seek to do business with a federal institution. For health care workers, violating this policy could have serious implications for patients. Numerous studies have shown that even modest industry-sponsored gifts, including meals, may influence prescribing or treatment behavior of health care professionals.

The agents opened their investigation into kickbacks at the Wichita facility in response to the whistleblower lawsuit, which was filed by Thomas Schroeder in 2017. The VA OIG would not confirm or deny whether it was continuing to investigate kickbacks at the facility. The VA did not directly answer ProPublica’s questions about kickbacks at the Dole VA, but it said that every employee must complete an annual ethics training, which covers gift rules.

In recent years, Medtronic has settled a handful of other cases that have alleged kickbacks between company representatives and health care professionals.

In 2018, Medtronic’s subsidiary Covidien paid $13 million to settle claims with the U.S. Department of Justice that it paid kickbacks to health care institutions that used its mechanical blood clot devices. In 2019, the same subsidiary paid $17 million to resolve allegations that it provided in-kind marketing support to doctors using its vein products. And in 2020, Medtronic paid more than $8 million to settle claims that representatives had paid kickbacks to a neurosurgeon, including scores of lavish meals at a restaurant that the doctor owned, to induce him to purchase the company’s medication pumps.

Schroeder’s lawsuit is not the first time Medtronic’s vascular devices were named in an alleged kickback scheme. In early 2015, Medtronic acquired Covidien, and shortly after the merger, its subsidiary ev3 Inc. agreed to pay $1.25 million to resolve allegations that it had paid doctors who were “high volume users” of its atherectomy devices to act as evangelists for the company, and had provided physicians with company shares to participate in clinical trials for their tools.

The whistleblower in this earlier case, a former sales representative for the company, also alleged that the subsidiary was gaming Medicare’s payment system. Hospitals were often hesitant to conduct atherectomy procedures because of the low reimbursement rates. According to the suit, sales representatives encouraged doctors to admit patients for longer stays to reap greater reimbursements and make a profit, even though such stays were often not medically indicated.

“Medical device makers that try to boost their profits by causing patients to be admitted for unnecessary and expensive inpatient hospital stays will be held accountable,” special agent Thomas O’Donnell, from the Office of Inspector General at the U.S. Department of Health and Human Services, said in a press release for the settlement. “Both patients and taxpayers deserve to have medical decisions made based on what is medically appropriate.”

Medtronic spokesperson Xiong said that in each case, the company “cooperated fully with the DOJ to resolve its concerns and, where wrongdoing was found, took appropriate remedial action.”

Seton Hall Law School professor Jacob Elberg, a former assistant U.S. attorney for the District of New Jersey who led its health care and government fraud unit, is concerned by the frequency of such settlements in the last 2 decades. “There are, at this point, real questions as to whether the sanctions imposed by DOJ are sufficient to deter wrongdoing and to lead to meaningful change, especially within the medical device industry.”

Although the Department of Justice has declined to intervene in the lawsuit involving the Dole VA at this time, the case is ongoing and further depositions with Medtronic sales representatives and a former VA employee are scheduled for this month.

VA employees and doctors named in the suit declined to comment or did not respond to ProPublica’s questions about the alleged kickbacks and whether sales representatives may have influenced veterans’ treatment plans. In interviews with federal investigators, according to released transcripts, several of the employees who were questioned denied receiving frequent meals from sales representatives, contradicting Medtronic’s expense reports.

Their statements also stand in contrast to Medtronic representative Kari Kirk’s final text messages during that procedure in June 2017, which ultimately lasted more than 3 hours.

“Now u done??” her colleague asked.

“Just finished,” she texted. “Running to get them lunch!”

This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.

On June 14, 2017, just before noon, a doctor made an incision near a patient’s groin. Kari Kirk, a representative for the world’s largest medical device company, Medtronic, looked on and began texting her colleague a play-by-play.

“Fixing both legs from the ankles,” she wrote.

It was a fairly common procedure at the Robert J. Dole Veterans Affairs Medical Center in Wichita, Kansas, performed to treat blockages in the leg vessels.

Within reach were an array of Medtronic products: tubes with blades attached to shave hardened deposits off of artery walls; stents to widen blood vessels; balloons coated with therapeutic drugs.

Each time a doctor puts a foreign device in someone’s body, it carries a risk of complication, which can include clots or even require amputation. So medical experts, research and even Medtronic’s own device instructions urge doctors to use as few as are necessary.

But, as revealed in Kirk’s text messages, this doctor took an aggressive approach.

“Just used 12 [drug-coated balloons]!!” Kirk texted her colleague.

“Does that mean I owe u $$,” he responded.

“Thats what I’m thinking!!!” she said. “And now 14 balloons?!”

“but only one stent so far??”

“So far!”

As the texting continued, her colleague replied, “U are going to want to start going to the VA all the time.”

The messages, recently unsealed in an ongoing whistleblower lawsuit, give a window into the way money and medicine mingle in the booming business of peripheral artery disease, a condition that afflicts 6.5 million Americans over age 40 and is caused when fatty plaque builds up in arteries, blocking blood flow to the legs.

Representatives from companies are often present during vascular procedures to guide doctors on how to use their complex devices. This kind of access has the potential to influence treatment plans, as companies and their representatives profit when more of their product is used.

The suit, filed in 2017 by a sales representative for a competing medical device firm, alleges an illegal kickback scheme between Medtronic and hospital employees. According to the complaint and documents released in the suit, between 2011 and 2018, VA health care workers received steakhouse dinners, Apple electronics, and NASCAR tickets, and in turn, Medtronic secured a lucrative contract with the hospital. Meanwhile, the company’s representatives allegedly “groomed and trained” physicians at the facility, who then deployed the company’s devices even when it was not medically indicated.

Independently from the whistleblower suit, internal investigators at the Wichita facility have also examined the treatment patterns of its vascular patients in recent years and found numerous cases where medical devices were used excessively. While it’s not uncommon to deploy several devices, a medical expert on the investigation team found that the VA doctors sometimes used more than 15 at a time – one used 33 – deviating from the standard of care.

“It is unconscionable – there can be no valid medically acceptable basis to cram so many devices into a human being,” wrote attorneys representing the whistleblower in legal filings from January 2023. “This is not medical treatment. This is abuse.”

Dr. Kim Hodgson, former president of the Society for Vascular Surgery and an expert retained by the plaintiff, said the findings of the internal review of patient data raise “a high level of concern regarding necessity of treatment provided,” according to case documents.

Medtronic declined to respond to ProPublica’s questions, citing the ongoing litigation. “These allegations are false and Medtronic is defending against these claims in court,” said Boua Xiong, a spokesperson for the company. Medtronic representative Kirk declined to respond to ProPublica’s request for comment.

The hospital investigation found that amputations increased sixfold in the same time frame as the procedures in question, according to internal emails, but made no conclusion about whether those two things were connected. ProPublica reached out to the VA to ask whether any patients had been harmed.

The VA is “conducting an extensive review of patient care” at the Kansas hospital, “including the number of devices used on patients – to make sure that Veterans were not harmed by any procedures,” press secretary Terrence Hayes said in a statement. So far, the VA’s investigation has found no “quality of care issues,” he said, and the investigation will continue “until every Veteran’s case has been reviewed.” (Read the full statement here.) Neither the department nor the hospital has taken formal action against the medical providers, Hayes said.

The medical group that had a contract with the VA for vascular interventions, Wichita Radiological Group, did not respond to ProPublica’s requests for comment, nor did the doctors named in the suit: Dr. Shaun Gonda, Dr. Bret Winblad, and Dr. Kermit Rust. It is unclear from the case documents which doctors conducted which procedures. Eric Barth, an attorney for the medical group, denied the allegations in recent legal filings, calling the claims “baseless” and the lawsuit a “witch hunt.”

The lawsuit comes amid growing concern about one of these procedures – atherectomies – after researchers and doctors have uncovered patterns of excessive and inappropriate use. Recent research has found that this procedure, a common but costly treatment to shave or laser plaque from blood vessels, is not more effective than cheaper alternatives and may even be associated with a higher risk of complications including amputation. In recent years, several doctors and clinics have been investigated for allegedly taking advantage of Medicare’s reimbursement rates, and one study found that many doctors are resorting to atherectomies in the earliest stages of peripheral artery disease, against best practices that urge noninvasive treatment.

“Atherectomy is important in certain settings. But it’s being used in a way that is entirely inappropriate and it’s largely driven by the incentive structure,” said Dr. Caitlin Hicks, the lead author of the study and an associate professor of surgery at Johns Hopkins University School of Medicine.

Although different payment structures govern the care of veterans, the whistleblower lawsuit alleges that outside physicians, paid hourly by the Dole VA, were motivated to conduct longer and more complex procedures that would earn them higher payment.

Under different circumstances, the patient in the procedure room on that summer day could have been done after 2 hours.

But, 150 minutes in, those Medtronic representatives were still texting. At that point, more than 15 of their vascular devices had been used, including stents, balloons, and those for atherectomy.

“Long case!” Kirk’s colleague texted. “Is it looking ok??”

“It is,” she said. “Thought we were done a few times! Now he’s going back in to cut again!”

A little while later, she texted: “....17!”

He texted back [with laughing emoticons].

Hospital leaders had been scrutinizing the use of these procedures at the Dole VA for years.

In 2017, shortly after Rick Ament was hired to lead the facility, he noticed something was amiss. While the longtime hospital administrator was poring over the finances, he was alarmed to discover that the relatively small Dole VA had one of the most expensive cardiac programs in the country. As Ament dug deeper, he realized vascular interventions were the reason.

“It just did not make sense that the acuity level of our patients would generate such extreme cost variances from the norm,” he testified in December, in a deposition for the whistleblower case. “It was so significant, we needed to get to the bottom of it.”

Ament, a second generation Air Force veteran, quietly assembled a task force to investigate why the facility had purchased so many medical devices for these procedures. After they examined inventory records, calculating the total number of medical devices and the cost of devices per patient, they grew concerned.

“We were more expensive than, I believe it was, the top 10 hospitals in the VA combined,” he said. “My feeling was that we either had very, very bad providers or we had product walking out the door.”

Ament enlisted experts from other VA hospitals to help his team investigate, including an administrative officer who could understand finances and a respected interventional radiologist who could examine records. The task force gathered a list of patients from 2016 to 2018, according to internal emails, and analyzed their medical charts.

According to internal VA documents released through the whistleblower suit, the review found a number of clinical failings: Evidence-based medicine had not been followed in the majority of cases reviewed. Procedures were over-aggressive, treating lesions that should have been left alone. And there was a total disregard for established best practices for treating peripheral artery disease.

One of the experts on the investigative team explained to Ament that while it was not uncommon for doctors to use a couple of devices in one intervention, the total number of devices in many of the procedures at his facility went into the double digits, sometimes five times the expected amount.

In one encounter, a doctor deployed 33 devices in one procedure – 3 atherectomy devices, 9 stents, and 21 balloons.

This use of devices was exorbitant, Ament came to understand. “I want to say the term ‘egregious’ was used,” he testified. “It was kind of like validation, but I really wish I was wrong.”

“Did it make you concerned for patient care?” a lawyer asked during the deposition.

“It did,” Ament replied.

A member of his task force pulled data for veterans who had leg amputations due to vascular disease. Over 5 years, the number of veterans who had amputations increased, from about 6 in 2013 to 38 in 2018, according to internal emails released in the suit. The VA did not respond to ProPublica’s questions about the rise in amputations or whether it was due to complications from the procedures.

Even though Ament testified in December 2022 that he became aware of the excessive use of devices during his investigation that began about 5 years ago, neither he nor the VA have publicly acknowledged these findings outside of the lawsuit. It is unclear whether VA representatives informed the patients whose records were reviewed about their findings. ProPublica reached out to more than half a dozen veteran community groups in the Wichita area and none were aware of the investigation nor the allegations of overuse of vascular procedures at the facility.

The VA says that if its ongoing review finds instances of substandard care, it will reach out to affected patients and inform them about possible complications and benefits they may be entitled to. The press secretary said the review will take several months. Ament declined to respond to ProPublica’s questions, citing the ongoing case.

In 2018, Ament turned over his findings to the criminal division of the VA’s Office of Inspector General. He also shut down interventional radiology procedures at the facility’s catheter lab.

Federal agents separately opened an investigation into the same unit in the facility, looking into allegations of kickbacks.

More than 40 pages of expense reports from Medtronic, revealed in the whistleblower case, show sales representatives treating Dole health care workers to hundreds of meals over several years – lunches at Dempsey’s Biscuit Co.; business meals at the Scotch & Sirloin steakhouse; dinner at Chester’s Chophouse & Wine Bar, price per attendee: $122.39.

Federal agents obtained the receipts.

“Robert J. Dole VAMC employees may have received improper gratuities, in the forms of paid lunches, dinners, etc., from sales representatives from Medtronic,” Nathen Howard, a special agent in the VA OIG, wrote in an investigation memo from February 2019.

This kind of relationship could violate VA policy, which forbids federal employees from receiving any gifts, including meals, from people who do business or seek to do business with a federal institution. For health care workers, violating this policy could have serious implications for patients. Numerous studies have shown that even modest industry-sponsored gifts, including meals, may influence prescribing or treatment behavior of health care professionals.

The agents opened their investigation into kickbacks at the Wichita facility in response to the whistleblower lawsuit, which was filed by Thomas Schroeder in 2017. The VA OIG would not confirm or deny whether it was continuing to investigate kickbacks at the facility. The VA did not directly answer ProPublica’s questions about kickbacks at the Dole VA, but it said that every employee must complete an annual ethics training, which covers gift rules.

In recent years, Medtronic has settled a handful of other cases that have alleged kickbacks between company representatives and health care professionals.

In 2018, Medtronic’s subsidiary Covidien paid $13 million to settle claims with the U.S. Department of Justice that it paid kickbacks to health care institutions that used its mechanical blood clot devices. In 2019, the same subsidiary paid $17 million to resolve allegations that it provided in-kind marketing support to doctors using its vein products. And in 2020, Medtronic paid more than $8 million to settle claims that representatives had paid kickbacks to a neurosurgeon, including scores of lavish meals at a restaurant that the doctor owned, to induce him to purchase the company’s medication pumps.

Schroeder’s lawsuit is not the first time Medtronic’s vascular devices were named in an alleged kickback scheme. In early 2015, Medtronic acquired Covidien, and shortly after the merger, its subsidiary ev3 Inc. agreed to pay $1.25 million to resolve allegations that it had paid doctors who were “high volume users” of its atherectomy devices to act as evangelists for the company, and had provided physicians with company shares to participate in clinical trials for their tools.

The whistleblower in this earlier case, a former sales representative for the company, also alleged that the subsidiary was gaming Medicare’s payment system. Hospitals were often hesitant to conduct atherectomy procedures because of the low reimbursement rates. According to the suit, sales representatives encouraged doctors to admit patients for longer stays to reap greater reimbursements and make a profit, even though such stays were often not medically indicated.

“Medical device makers that try to boost their profits by causing patients to be admitted for unnecessary and expensive inpatient hospital stays will be held accountable,” special agent Thomas O’Donnell, from the Office of Inspector General at the U.S. Department of Health and Human Services, said in a press release for the settlement. “Both patients and taxpayers deserve to have medical decisions made based on what is medically appropriate.”

Medtronic spokesperson Xiong said that in each case, the company “cooperated fully with the DOJ to resolve its concerns and, where wrongdoing was found, took appropriate remedial action.”

Seton Hall Law School professor Jacob Elberg, a former assistant U.S. attorney for the District of New Jersey who led its health care and government fraud unit, is concerned by the frequency of such settlements in the last 2 decades. “There are, at this point, real questions as to whether the sanctions imposed by DOJ are sufficient to deter wrongdoing and to lead to meaningful change, especially within the medical device industry.”

Although the Department of Justice has declined to intervene in the lawsuit involving the Dole VA at this time, the case is ongoing and further depositions with Medtronic sales representatives and a former VA employee are scheduled for this month.

VA employees and doctors named in the suit declined to comment or did not respond to ProPublica’s questions about the alleged kickbacks and whether sales representatives may have influenced veterans’ treatment plans. In interviews with federal investigators, according to released transcripts, several of the employees who were questioned denied receiving frequent meals from sales representatives, contradicting Medtronic’s expense reports.

Their statements also stand in contrast to Medtronic representative Kari Kirk’s final text messages during that procedure in June 2017, which ultimately lasted more than 3 hours.

“Now u done??” her colleague asked.

“Just finished,” she texted. “Running to get them lunch!”

This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.

A strategy for the treatment of tuberculosis involving just an 8-week treatment regimen – along with close posttreatment monitoring and treatment extension if needed – shows potential as an effective alternative to the standard 24-week regimen.

“We found that if we use the strategy of a bedaquiline-linezolid five-drug regimen for 8 weeks and then followed patients for 96 weeks, [the regimen] was noninferior, clinically, to the standard regimen in terms of the number of people alive, free of TB disease, and not on treatment,” said lead author Nicholas Paton, MD, of the National University of Singapore, in a press conference held during the Conference on Retroviruses & Opportunistic Infections.

“The total time on treatment was reduced by half – instead of 160 days, it was 85 days for the total duration.”

Commenting on the study, which was published concurrently in the New England Journal of Medicine, Richard E. Chaisson, MD, noted that, although more needs to be understood, the high number of responses is nevertheless encouraging.

“Clinicians will not feel comfortable with the short regimens at this point, but it is remarkable that so many patients did well with shorter treatments,” Dr. Chaisson, who is a professor of medicine, epidemiology, and international health and director of the Johns Hopkins University Center for Tuberculosis Research, Baltimore, said in an interview.

Importantly, the study should help push forward “future studies [that] will stratify patients according to their likelihood of responding to shorter treatments,” he said.

The current global standard for TB treatment, practiced for 4 decades, has been a 6-month rifampin-based regimen. Although the regimen performs well, curing more than 95% of cases in clinical trials, in real-world practice, the prolonged duration can be problematic, with issues of nonadherence and loss of patients to follow-up.

Previous research has shown that shorter regimens have potential, with some studies showing as many as 85% of patients cured with 3- and 4-month regimens, and some promising 2-month regimens showing efficacy specifically for those with smear-negative TB.

These efforts suggest that “the current 6-month regimen may lead to overtreatment in the majority of persons in order to prevent relapse in a minority of persons,” the authors asserted.
 

TRUNCATE-TB

To investigate a suitable shorter-term alternative, the authors conducted the phase 2-3, prospective, open-label TRUNCATE-TB trial, in which 674 patients with rifampin-susceptible pulmonary TB were enrolled at 18 sites in Asia and Africa.

The patients were randomly assigned to receive either the standard treatment regimen (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks; n = 181), or one of four novel five-drug regimens to be administered over 8 weeks, along with extended treatment for persistent clinical disease of up to 12 weeks, if needed, and a plan for retreatment in the case of relapse (n = 493).

Two of the regimens were dropped because of logistic criteria; the two remaining shorter-course groups included in the study involved either high-dose rifampin plus linezolid or bedaquiline plus linezolid, each combined with isoniazid, pyrazinamide, and ethambutol.

Of the patients, 62% were male, and four withdrew or were lost to follow-up by the end of the study at a final follow-up at week 96.

Among patients assigned to the 8-week regimens, 80% stopped at exactly 8 weeks, while 9% wound up having extended treatment to 10 weeks and 3% were extended to 12 weeks.

For the primary endpoint, a composite of death, ongoing treatment, or active disease at week 96, the rate was lowest in the standard 24-week therapy group, occurring in 7 of 181 patients (3.9%), compared with 21 of 184 patients (11.4%) in the rifampin plus linezolid group (adjusted difference, 7.4 percentage points, which did not meet noninferiority criterion), and 11 of 189 (5.8%) in the group in the bedaquiline plus linezolid group (adjusted difference, 0.8 percentage points, meeting noninferiority criterion).

The mean total duration of treatment through week 96 in the standard treatment group was 180 days versus 106 days in the rifampin–linezolid group, and 85 days in the bedaquiline-linezolid group.

The results were consistent across multiple subgroups defined according to baseline characteristics, including some that could be linked to severe disease and a high risk for relapse.

In terms of safety, there were no significant differences between the groups in terms of grade 3 or 4 adverse events.

Of note, only two patients (1.1%) in the bedaquiline plus linezolid group acquired a resistance, which Dr. Paton said was “encouraging,” because of concerns about resistance to that drug.
 

‘Unfavorable’ composite also evaluated

In an updated analysis of the study that Dr. Paton presented at the meeting, the authors looked at a revised “unfavorable” primary outcome – a composite including treatment failure, relapse, death, or nonattendance at week 96 without evidence of prior disease clearance.

The rate remained lowest in the standard 24-week therapy group (3.9%) versus 25% in the rifampin plus linezolid group, and 13.8% in the bedaquiline plus linezolid group.

Though the lower rate with the standard treatment was expected, Dr. Paton said the results nevertheless hold promise, at least for some patients, for successful treatment with the 8-week bedaquiline plus linezolid strategy.

“What the trial has told us is that even with that 13.8% relapse rate, we can manage patients within this strategy and people can do fine at the end, because with some simple clinical biomarkers, we can pick the people who may have a high chance of achieving a cure.”

Dr. Chaisson expressed concern over the higher unfavorable rates, but said the results help pave the way for refining a workable-shorter term strategy.

“TRUNCATE-TB did find that most patients could be successfully treated in 2 months with the novel regimen of bedaquiline plus linezolid, but the failure rate was still unacceptably high,” he said. 

“This regimen will not be widely adapted at this point, but additional analyses may identify subsets of patients who will do well with shorter regimens, and future studies will stratify patients according to their likelihood of responding to shorter treatments.”

The authors of an accompanying editorial further commented that the benefits of a shorter treatment strategy could very well outweigh possible shortcomings.

“Treatment algorithms such as that used in the TRUNCATE-TB trial are fundamental to tuberculosis control,” wrote Véronique Dartois, PhD, Center for Discovery and Innovation, Nutley, N.J., and Eric J. Rubin, MD, PhD, the editor-in-chief of NEJM. “Although implementing them could be a challenge, any added burden might be offset by reduced costs, better adherence, and increased patient satisfaction. Thus, for tuberculosis, a strategy might be more than just a regimen.”

The good news, as summed up by CROI vice-chair Landon Myer, MD, PhD, in the press conference, is that “we’re moving closer and closer to the holy grail of a short, efficacious regimen for TB treatment. We’re getting there slowly, but we’re getting there.”

The study received grant funding from the Singapore National Medical Research Council; a grant from the Department of Health and Social Care; the Foreign, Commonwealth, and Development Office; the Medical Research Council; and Wellcome Trust; as well as a grant from the UK Research and Innovation Medical Research Council. Dr. Dartois reported no relevant financial relationships. Dr. Chaisson had no disclosures to report.

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

A strategy for the treatment of tuberculosis involving just an 8-week treatment regimen – along with close posttreatment monitoring and treatment extension if needed – shows potential as an effective alternative to the standard 24-week regimen.

“We found that if we use the strategy of a bedaquiline-linezolid five-drug regimen for 8 weeks and then followed patients for 96 weeks, [the regimen] was noninferior, clinically, to the standard regimen in terms of the number of people alive, free of TB disease, and not on treatment,” said lead author Nicholas Paton, MD, of the National University of Singapore, in a press conference held during the Conference on Retroviruses & Opportunistic Infections.

“The total time on treatment was reduced by half – instead of 160 days, it was 85 days for the total duration.”

Commenting on the study, which was published concurrently in the New England Journal of Medicine, Richard E. Chaisson, MD, noted that, although more needs to be understood, the high number of responses is nevertheless encouraging.

“Clinicians will not feel comfortable with the short regimens at this point, but it is remarkable that so many patients did well with shorter treatments,” Dr. Chaisson, who is a professor of medicine, epidemiology, and international health and director of the Johns Hopkins University Center for Tuberculosis Research, Baltimore, said in an interview.

Importantly, the study should help push forward “future studies [that] will stratify patients according to their likelihood of responding to shorter treatments,” he said.

The current global standard for TB treatment, practiced for 4 decades, has been a 6-month rifampin-based regimen. Although the regimen performs well, curing more than 95% of cases in clinical trials, in real-world practice, the prolonged duration can be problematic, with issues of nonadherence and loss of patients to follow-up.

Previous research has shown that shorter regimens have potential, with some studies showing as many as 85% of patients cured with 3- and 4-month regimens, and some promising 2-month regimens showing efficacy specifically for those with smear-negative TB.

These efforts suggest that “the current 6-month regimen may lead to overtreatment in the majority of persons in order to prevent relapse in a minority of persons,” the authors asserted.
 

TRUNCATE-TB

To investigate a suitable shorter-term alternative, the authors conducted the phase 2-3, prospective, open-label TRUNCATE-TB trial, in which 674 patients with rifampin-susceptible pulmonary TB were enrolled at 18 sites in Asia and Africa.

The patients were randomly assigned to receive either the standard treatment regimen (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks; n = 181), or one of four novel five-drug regimens to be administered over 8 weeks, along with extended treatment for persistent clinical disease of up to 12 weeks, if needed, and a plan for retreatment in the case of relapse (n = 493).

Two of the regimens were dropped because of logistic criteria; the two remaining shorter-course groups included in the study involved either high-dose rifampin plus linezolid or bedaquiline plus linezolid, each combined with isoniazid, pyrazinamide, and ethambutol.

Of the patients, 62% were male, and four withdrew or were lost to follow-up by the end of the study at a final follow-up at week 96.

Among patients assigned to the 8-week regimens, 80% stopped at exactly 8 weeks, while 9% wound up having extended treatment to 10 weeks and 3% were extended to 12 weeks.

For the primary endpoint, a composite of death, ongoing treatment, or active disease at week 96, the rate was lowest in the standard 24-week therapy group, occurring in 7 of 181 patients (3.9%), compared with 21 of 184 patients (11.4%) in the rifampin plus linezolid group (adjusted difference, 7.4 percentage points, which did not meet noninferiority criterion), and 11 of 189 (5.8%) in the group in the bedaquiline plus linezolid group (adjusted difference, 0.8 percentage points, meeting noninferiority criterion).

The mean total duration of treatment through week 96 in the standard treatment group was 180 days versus 106 days in the rifampin–linezolid group, and 85 days in the bedaquiline-linezolid group.

The results were consistent across multiple subgroups defined according to baseline characteristics, including some that could be linked to severe disease and a high risk for relapse.

In terms of safety, there were no significant differences between the groups in terms of grade 3 or 4 adverse events.

Of note, only two patients (1.1%) in the bedaquiline plus linezolid group acquired a resistance, which Dr. Paton said was “encouraging,” because of concerns about resistance to that drug.
 

‘Unfavorable’ composite also evaluated

In an updated analysis of the study that Dr. Paton presented at the meeting, the authors looked at a revised “unfavorable” primary outcome – a composite including treatment failure, relapse, death, or nonattendance at week 96 without evidence of prior disease clearance.

The rate remained lowest in the standard 24-week therapy group (3.9%) versus 25% in the rifampin plus linezolid group, and 13.8% in the bedaquiline plus linezolid group.

Though the lower rate with the standard treatment was expected, Dr. Paton said the results nevertheless hold promise, at least for some patients, for successful treatment with the 8-week bedaquiline plus linezolid strategy.

“What the trial has told us is that even with that 13.8% relapse rate, we can manage patients within this strategy and people can do fine at the end, because with some simple clinical biomarkers, we can pick the people who may have a high chance of achieving a cure.”

Dr. Chaisson expressed concern over the higher unfavorable rates, but said the results help pave the way for refining a workable-shorter term strategy.

“TRUNCATE-TB did find that most patients could be successfully treated in 2 months with the novel regimen of bedaquiline plus linezolid, but the failure rate was still unacceptably high,” he said. 

“This regimen will not be widely adapted at this point, but additional analyses may identify subsets of patients who will do well with shorter regimens, and future studies will stratify patients according to their likelihood of responding to shorter treatments.”

The authors of an accompanying editorial further commented that the benefits of a shorter treatment strategy could very well outweigh possible shortcomings.

“Treatment algorithms such as that used in the TRUNCATE-TB trial are fundamental to tuberculosis control,” wrote Véronique Dartois, PhD, Center for Discovery and Innovation, Nutley, N.J., and Eric J. Rubin, MD, PhD, the editor-in-chief of NEJM. “Although implementing them could be a challenge, any added burden might be offset by reduced costs, better adherence, and increased patient satisfaction. Thus, for tuberculosis, a strategy might be more than just a regimen.”

The good news, as summed up by CROI vice-chair Landon Myer, MD, PhD, in the press conference, is that “we’re moving closer and closer to the holy grail of a short, efficacious regimen for TB treatment. We’re getting there slowly, but we’re getting there.”

The study received grant funding from the Singapore National Medical Research Council; a grant from the Department of Health and Social Care; the Foreign, Commonwealth, and Development Office; the Medical Research Council; and Wellcome Trust; as well as a grant from the UK Research and Innovation Medical Research Council. Dr. Dartois reported no relevant financial relationships. Dr. Chaisson had no disclosures to report.

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

A strategy for the treatment of tuberculosis involving just an 8-week treatment regimen – along with close posttreatment monitoring and treatment extension if needed – shows potential as an effective alternative to the standard 24-week regimen.

“We found that if we use the strategy of a bedaquiline-linezolid five-drug regimen for 8 weeks and then followed patients for 96 weeks, [the regimen] was noninferior, clinically, to the standard regimen in terms of the number of people alive, free of TB disease, and not on treatment,” said lead author Nicholas Paton, MD, of the National University of Singapore, in a press conference held during the Conference on Retroviruses & Opportunistic Infections.

“The total time on treatment was reduced by half – instead of 160 days, it was 85 days for the total duration.”

Commenting on the study, which was published concurrently in the New England Journal of Medicine, Richard E. Chaisson, MD, noted that, although more needs to be understood, the high number of responses is nevertheless encouraging.

“Clinicians will not feel comfortable with the short regimens at this point, but it is remarkable that so many patients did well with shorter treatments,” Dr. Chaisson, who is a professor of medicine, epidemiology, and international health and director of the Johns Hopkins University Center for Tuberculosis Research, Baltimore, said in an interview.

Importantly, the study should help push forward “future studies [that] will stratify patients according to their likelihood of responding to shorter treatments,” he said.

The current global standard for TB treatment, practiced for 4 decades, has been a 6-month rifampin-based regimen. Although the regimen performs well, curing more than 95% of cases in clinical trials, in real-world practice, the prolonged duration can be problematic, with issues of nonadherence and loss of patients to follow-up.

Previous research has shown that shorter regimens have potential, with some studies showing as many as 85% of patients cured with 3- and 4-month regimens, and some promising 2-month regimens showing efficacy specifically for those with smear-negative TB.

These efforts suggest that “the current 6-month regimen may lead to overtreatment in the majority of persons in order to prevent relapse in a minority of persons,” the authors asserted.
 

TRUNCATE-TB

To investigate a suitable shorter-term alternative, the authors conducted the phase 2-3, prospective, open-label TRUNCATE-TB trial, in which 674 patients with rifampin-susceptible pulmonary TB were enrolled at 18 sites in Asia and Africa.

The patients were randomly assigned to receive either the standard treatment regimen (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks; n = 181), or one of four novel five-drug regimens to be administered over 8 weeks, along with extended treatment for persistent clinical disease of up to 12 weeks, if needed, and a plan for retreatment in the case of relapse (n = 493).

Two of the regimens were dropped because of logistic criteria; the two remaining shorter-course groups included in the study involved either high-dose rifampin plus linezolid or bedaquiline plus linezolid, each combined with isoniazid, pyrazinamide, and ethambutol.

Of the patients, 62% were male, and four withdrew or were lost to follow-up by the end of the study at a final follow-up at week 96.

Among patients assigned to the 8-week regimens, 80% stopped at exactly 8 weeks, while 9% wound up having extended treatment to 10 weeks and 3% were extended to 12 weeks.

For the primary endpoint, a composite of death, ongoing treatment, or active disease at week 96, the rate was lowest in the standard 24-week therapy group, occurring in 7 of 181 patients (3.9%), compared with 21 of 184 patients (11.4%) in the rifampin plus linezolid group (adjusted difference, 7.4 percentage points, which did not meet noninferiority criterion), and 11 of 189 (5.8%) in the group in the bedaquiline plus linezolid group (adjusted difference, 0.8 percentage points, meeting noninferiority criterion).

The mean total duration of treatment through week 96 in the standard treatment group was 180 days versus 106 days in the rifampin–linezolid group, and 85 days in the bedaquiline-linezolid group.

The results were consistent across multiple subgroups defined according to baseline characteristics, including some that could be linked to severe disease and a high risk for relapse.

In terms of safety, there were no significant differences between the groups in terms of grade 3 or 4 adverse events.

Of note, only two patients (1.1%) in the bedaquiline plus linezolid group acquired a resistance, which Dr. Paton said was “encouraging,” because of concerns about resistance to that drug.
 

‘Unfavorable’ composite also evaluated

In an updated analysis of the study that Dr. Paton presented at the meeting, the authors looked at a revised “unfavorable” primary outcome – a composite including treatment failure, relapse, death, or nonattendance at week 96 without evidence of prior disease clearance.

The rate remained lowest in the standard 24-week therapy group (3.9%) versus 25% in the rifampin plus linezolid group, and 13.8% in the bedaquiline plus linezolid group.

Though the lower rate with the standard treatment was expected, Dr. Paton said the results nevertheless hold promise, at least for some patients, for successful treatment with the 8-week bedaquiline plus linezolid strategy.

“What the trial has told us is that even with that 13.8% relapse rate, we can manage patients within this strategy and people can do fine at the end, because with some simple clinical biomarkers, we can pick the people who may have a high chance of achieving a cure.”

Dr. Chaisson expressed concern over the higher unfavorable rates, but said the results help pave the way for refining a workable-shorter term strategy.

“TRUNCATE-TB did find that most patients could be successfully treated in 2 months with the novel regimen of bedaquiline plus linezolid, but the failure rate was still unacceptably high,” he said. 

“This regimen will not be widely adapted at this point, but additional analyses may identify subsets of patients who will do well with shorter regimens, and future studies will stratify patients according to their likelihood of responding to shorter treatments.”

The authors of an accompanying editorial further commented that the benefits of a shorter treatment strategy could very well outweigh possible shortcomings.

“Treatment algorithms such as that used in the TRUNCATE-TB trial are fundamental to tuberculosis control,” wrote Véronique Dartois, PhD, Center for Discovery and Innovation, Nutley, N.J., and Eric J. Rubin, MD, PhD, the editor-in-chief of NEJM. “Although implementing them could be a challenge, any added burden might be offset by reduced costs, better adherence, and increased patient satisfaction. Thus, for tuberculosis, a strategy might be more than just a regimen.”

The good news, as summed up by CROI vice-chair Landon Myer, MD, PhD, in the press conference, is that “we’re moving closer and closer to the holy grail of a short, efficacious regimen for TB treatment. We’re getting there slowly, but we’re getting there.”

The study received grant funding from the Singapore National Medical Research Council; a grant from the Department of Health and Social Care; the Foreign, Commonwealth, and Development Office; the Medical Research Council; and Wellcome Trust; as well as a grant from the UK Research and Innovation Medical Research Council. Dr. Dartois reported no relevant financial relationships. Dr. Chaisson had no disclosures to report.

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

IgG4 fights viruses and bacteria. However, sometimes it targets the body itself. “This then leads to inflammation, the healing of which the body is unable to keep under control,” explained Ulf Müller-Ladner, MD, PhD, chairperson of the German Society of Internal Medicine.

At the DGIM annual press conference, Dr. Müller-Ladner, who is also director of the department of rheumatology and clinical immunology at the Kerckhoff Clinic in Bad Nauheim, Germany, explained how IgG4 inflammation is triggered throughout the body and what therapeutic options are available.
 

Many manifestations

IgG4-associated inflammation can affect one or more organs or the surrounding connective tissue and cause fibrosis. As a result of fibrosis, the organ gradually loses function and is eventually transformed completely into scarred connective tissue.

“In the case of IgG4-associated inflammation, these fibroses have a histological structure, but extracting a sample is not possible from every affected organ,” said Dr. Müller-Ladner. Liver, bile ducts, blood vessels, skin, eyes, or even the central nervous system – practically every organ system can be affected by these inflammatory reactions.

IgG4-associated diseases have likely been around for some time, but it is only in the past 10 years that awareness has grown that, despite various manifestations, “they are all one and the same disease,” said Dr. Müller-Ladner.

IgG4-associated chronic, inflammatory, fibrosing diseases were only classified together as a single entity in the past few years. In terms of pathophysiology, B lymphocytes, IgG4-positive plasma cells, follicular T-helper cells, cytotoxic CD4-positive T cells, and macrophages work together and trigger an inflammatory reaction, which then encourages fibroblasts to overproduce connective tissue.
 

Beware inexplicable inflammation

It is estimated that 1 in 100,000 people suffer from the disease, but the number of incorrectly categorized patients may be significantly higher.

The diagnostic challenge lies in the fact that IgG4-associated inflammation occurs in almost every organ. It can cause different symptoms, depending on the organ affected.

Dr. Müller-Ladner provided the following take-home message: “Every inexplicable inflammation event and every organ dysfunction, especially if associated with an increase in connective tissue, could be an IgG4-associated disease. Keeping this in mind is the key to recovery.”

With most people, the inflammation persists for many years before any symptoms of the disease develop. Highly acute courses of progression are also possible.

Classic symptoms, such as fever, are not so characteristic of the latent inflammatory reaction, and according to classification criteria published by specialist rheumatology societies, they are an exclusion criterion. This is true with respect to the differential diagnosis for vasculitis, which also occurs throughout the body.
 

Histology is key

Blood levels of IgG4 and imaging are not always enough to confirm the diagnosis. In such cases, the histology is often a crucial factor in making a definitive diagnosis. Dominant organs in IgG4-associated diseases are the pancreas, the liver, the gallbladder, the intestines, the retroperitoneum, large blood vessels, the kidneys, the heart, the brain, saliva, tear ducts, as well all of the body’s connective tissue.

The kidneys play host to inflammation in the connective tissue and space-occupying masses in particular. “If the pancreas is affected, the signs can vary from diffuse swelling to the onset of diabetes mellitus. In contrast, if the aorta is affected, then the inflammation is characterized through a thickening of the vessel walls, aneurysms, and the corresponding circulation disorders,” said Dr. Müller-Ladner.

Because of the long period before the diagnosis is made, more than 50% of patients exhibit irreversible organ damage at the time of diagnosis, he added.
 

Glucocorticoids and immunosuppressants

Despite therapeutic intervention, the disease can have a fatal outcome, even if the patient is young, said Dr. Müller-Ladner. Glucocorticoids are the current therapy of choice. The dose is more than 0.5 mg of prednisolone equivalent per kg of body weight. “This usually leads to a rapid improvement in the inflammation. Subsequently, every organ is thoroughly diagnosed to assess the severity of the disease and to plan further treatment steps.”

In the long term, proven immunosuppressants, such as azathioprine, mycophenolate, leflunomide, and methotrexate, can be used, just as for many other chronic inflammatory diseases. Cyclophosphamide or cyclosporine is used more rarely, owing to their side effect profiles.

Because of the B-cell dominance, B-cell–depleting therapy with rituximab is currently a highly effective therapeutic option but one that must be applied for, because such use is off label. “If the body responds well to the medication, organ function often recovers,” said Dr. Müller-Ladner.

This article was translated from the Medscape German edition. A version appeared on Medscape.com.

IgG4 fights viruses and bacteria. However, sometimes it targets the body itself. “This then leads to inflammation, the healing of which the body is unable to keep under control,” explained Ulf Müller-Ladner, MD, PhD, chairperson of the German Society of Internal Medicine.

At the DGIM annual press conference, Dr. Müller-Ladner, who is also director of the department of rheumatology and clinical immunology at the Kerckhoff Clinic in Bad Nauheim, Germany, explained how IgG4 inflammation is triggered throughout the body and what therapeutic options are available.
 

Many manifestations

IgG4-associated inflammation can affect one or more organs or the surrounding connective tissue and cause fibrosis. As a result of fibrosis, the organ gradually loses function and is eventually transformed completely into scarred connective tissue.

“In the case of IgG4-associated inflammation, these fibroses have a histological structure, but extracting a sample is not possible from every affected organ,” said Dr. Müller-Ladner. Liver, bile ducts, blood vessels, skin, eyes, or even the central nervous system – practically every organ system can be affected by these inflammatory reactions.

IgG4-associated diseases have likely been around for some time, but it is only in the past 10 years that awareness has grown that, despite various manifestations, “they are all one and the same disease,” said Dr. Müller-Ladner.

IgG4-associated chronic, inflammatory, fibrosing diseases were only classified together as a single entity in the past few years. In terms of pathophysiology, B lymphocytes, IgG4-positive plasma cells, follicular T-helper cells, cytotoxic CD4-positive T cells, and macrophages work together and trigger an inflammatory reaction, which then encourages fibroblasts to overproduce connective tissue.
 

Beware inexplicable inflammation

It is estimated that 1 in 100,000 people suffer from the disease, but the number of incorrectly categorized patients may be significantly higher.

The diagnostic challenge lies in the fact that IgG4-associated inflammation occurs in almost every organ. It can cause different symptoms, depending on the organ affected.

Dr. Müller-Ladner provided the following take-home message: “Every inexplicable inflammation event and every organ dysfunction, especially if associated with an increase in connective tissue, could be an IgG4-associated disease. Keeping this in mind is the key to recovery.”

With most people, the inflammation persists for many years before any symptoms of the disease develop. Highly acute courses of progression are also possible.

Classic symptoms, such as fever, are not so characteristic of the latent inflammatory reaction, and according to classification criteria published by specialist rheumatology societies, they are an exclusion criterion. This is true with respect to the differential diagnosis for vasculitis, which also occurs throughout the body.
 

Histology is key

Blood levels of IgG4 and imaging are not always enough to confirm the diagnosis. In such cases, the histology is often a crucial factor in making a definitive diagnosis. Dominant organs in IgG4-associated diseases are the pancreas, the liver, the gallbladder, the intestines, the retroperitoneum, large blood vessels, the kidneys, the heart, the brain, saliva, tear ducts, as well all of the body’s connective tissue.

The kidneys play host to inflammation in the connective tissue and space-occupying masses in particular. “If the pancreas is affected, the signs can vary from diffuse swelling to the onset of diabetes mellitus. In contrast, if the aorta is affected, then the inflammation is characterized through a thickening of the vessel walls, aneurysms, and the corresponding circulation disorders,” said Dr. Müller-Ladner.

Because of the long period before the diagnosis is made, more than 50% of patients exhibit irreversible organ damage at the time of diagnosis, he added.
 

Glucocorticoids and immunosuppressants

Despite therapeutic intervention, the disease can have a fatal outcome, even if the patient is young, said Dr. Müller-Ladner. Glucocorticoids are the current therapy of choice. The dose is more than 0.5 mg of prednisolone equivalent per kg of body weight. “This usually leads to a rapid improvement in the inflammation. Subsequently, every organ is thoroughly diagnosed to assess the severity of the disease and to plan further treatment steps.”

In the long term, proven immunosuppressants, such as azathioprine, mycophenolate, leflunomide, and methotrexate, can be used, just as for many other chronic inflammatory diseases. Cyclophosphamide or cyclosporine is used more rarely, owing to their side effect profiles.

Because of the B-cell dominance, B-cell–depleting therapy with rituximab is currently a highly effective therapeutic option but one that must be applied for, because such use is off label. “If the body responds well to the medication, organ function often recovers,” said Dr. Müller-Ladner.

This article was translated from the Medscape German edition. A version appeared on Medscape.com.

IgG4 fights viruses and bacteria. However, sometimes it targets the body itself. “This then leads to inflammation, the healing of which the body is unable to keep under control,” explained Ulf Müller-Ladner, MD, PhD, chairperson of the German Society of Internal Medicine.

At the DGIM annual press conference, Dr. Müller-Ladner, who is also director of the department of rheumatology and clinical immunology at the Kerckhoff Clinic in Bad Nauheim, Germany, explained how IgG4 inflammation is triggered throughout the body and what therapeutic options are available.
 

Many manifestations

IgG4-associated inflammation can affect one or more organs or the surrounding connective tissue and cause fibrosis. As a result of fibrosis, the organ gradually loses function and is eventually transformed completely into scarred connective tissue.

“In the case of IgG4-associated inflammation, these fibroses have a histological structure, but extracting a sample is not possible from every affected organ,” said Dr. Müller-Ladner. Liver, bile ducts, blood vessels, skin, eyes, or even the central nervous system – practically every organ system can be affected by these inflammatory reactions.

IgG4-associated diseases have likely been around for some time, but it is only in the past 10 years that awareness has grown that, despite various manifestations, “they are all one and the same disease,” said Dr. Müller-Ladner.

IgG4-associated chronic, inflammatory, fibrosing diseases were only classified together as a single entity in the past few years. In terms of pathophysiology, B lymphocytes, IgG4-positive plasma cells, follicular T-helper cells, cytotoxic CD4-positive T cells, and macrophages work together and trigger an inflammatory reaction, which then encourages fibroblasts to overproduce connective tissue.
 

Beware inexplicable inflammation

It is estimated that 1 in 100,000 people suffer from the disease, but the number of incorrectly categorized patients may be significantly higher.

The diagnostic challenge lies in the fact that IgG4-associated inflammation occurs in almost every organ. It can cause different symptoms, depending on the organ affected.

Dr. Müller-Ladner provided the following take-home message: “Every inexplicable inflammation event and every organ dysfunction, especially if associated with an increase in connective tissue, could be an IgG4-associated disease. Keeping this in mind is the key to recovery.”

With most people, the inflammation persists for many years before any symptoms of the disease develop. Highly acute courses of progression are also possible.

Classic symptoms, such as fever, are not so characteristic of the latent inflammatory reaction, and according to classification criteria published by specialist rheumatology societies, they are an exclusion criterion. This is true with respect to the differential diagnosis for vasculitis, which also occurs throughout the body.
 

Histology is key

Blood levels of IgG4 and imaging are not always enough to confirm the diagnosis. In such cases, the histology is often a crucial factor in making a definitive diagnosis. Dominant organs in IgG4-associated diseases are the pancreas, the liver, the gallbladder, the intestines, the retroperitoneum, large blood vessels, the kidneys, the heart, the brain, saliva, tear ducts, as well all of the body’s connective tissue.

The kidneys play host to inflammation in the connective tissue and space-occupying masses in particular. “If the pancreas is affected, the signs can vary from diffuse swelling to the onset of diabetes mellitus. In contrast, if the aorta is affected, then the inflammation is characterized through a thickening of the vessel walls, aneurysms, and the corresponding circulation disorders,” said Dr. Müller-Ladner.

Because of the long period before the diagnosis is made, more than 50% of patients exhibit irreversible organ damage at the time of diagnosis, he added.
 

Glucocorticoids and immunosuppressants

Despite therapeutic intervention, the disease can have a fatal outcome, even if the patient is young, said Dr. Müller-Ladner. Glucocorticoids are the current therapy of choice. The dose is more than 0.5 mg of prednisolone equivalent per kg of body weight. “This usually leads to a rapid improvement in the inflammation. Subsequently, every organ is thoroughly diagnosed to assess the severity of the disease and to plan further treatment steps.”

In the long term, proven immunosuppressants, such as azathioprine, mycophenolate, leflunomide, and methotrexate, can be used, just as for many other chronic inflammatory diseases. Cyclophosphamide or cyclosporine is used more rarely, owing to their side effect profiles.

Because of the B-cell dominance, B-cell–depleting therapy with rituximab is currently a highly effective therapeutic option but one that must be applied for, because such use is off label. “If the body responds well to the medication, organ function often recovers,” said Dr. Müller-Ladner.

This article was translated from the Medscape German edition. A version appeared on Medscape.com.

The natural immunity provided by a COVID infection protects a person against severe illness on a par with two doses of mRNA vaccine, a new study says. 

People who’ve been infected with COVID reduced their chances of hospitalization and death by 88% over 10 months compared to somebody who hasn’t been infected, according to the study, published in The Lancet. 

The natural immunity provided by infection was “at least as high, if not higher” than the immunity provided by two doses of Moderna or Pfizer mRNA vaccines against the ancestral, Alpha, Delta, and Omicron BA.1 variants, the researchers reported. 

But protection against the BA.1 subvariant of Omicron was not as high – 36% at 10 months after infection, wrote the research team from the Institute for Health Metrics and Evaluation at the University of Washington.

They examined 65 studies from 19 countries through Sept. 31, 2022. They did not study data about infection from Omicron XBB and its sub-lineages. People who had immunity from both infection and vaccination, known as hybrid immunity, were not studied. 

The findings don’t mean people should skip the vaccines and get COVID on purpose, one of the researchers told NBC News. 

“The problem of saying ‘I’m gonna get infected to get immunity’ is you might be one of those people that end up in the hospital or die,” said Christopher Murray, MD, DPhil, director of the IHME. “Why would you take the risk when you can get immunity through vaccination quite safely?”

The findings could help people figure out the most effective time to get vaccinated or boosted and guide officials in setting policies on workplace vaccine mandates and rules for high-occupancy indoor settings, the researchers concluded.

This was the largest meta-analysis of immunity following infection to date, NBC News reports.

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

The natural immunity provided by a COVID infection protects a person against severe illness on a par with two doses of mRNA vaccine, a new study says. 

People who’ve been infected with COVID reduced their chances of hospitalization and death by 88% over 10 months compared to somebody who hasn’t been infected, according to the study, published in The Lancet. 

The natural immunity provided by infection was “at least as high, if not higher” than the immunity provided by two doses of Moderna or Pfizer mRNA vaccines against the ancestral, Alpha, Delta, and Omicron BA.1 variants, the researchers reported. 

But protection against the BA.1 subvariant of Omicron was not as high – 36% at 10 months after infection, wrote the research team from the Institute for Health Metrics and Evaluation at the University of Washington.

They examined 65 studies from 19 countries through Sept. 31, 2022. They did not study data about infection from Omicron XBB and its sub-lineages. People who had immunity from both infection and vaccination, known as hybrid immunity, were not studied. 

The findings don’t mean people should skip the vaccines and get COVID on purpose, one of the researchers told NBC News. 

“The problem of saying ‘I’m gonna get infected to get immunity’ is you might be one of those people that end up in the hospital or die,” said Christopher Murray, MD, DPhil, director of the IHME. “Why would you take the risk when you can get immunity through vaccination quite safely?”

The findings could help people figure out the most effective time to get vaccinated or boosted and guide officials in setting policies on workplace vaccine mandates and rules for high-occupancy indoor settings, the researchers concluded.

This was the largest meta-analysis of immunity following infection to date, NBC News reports.

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

The natural immunity provided by a COVID infection protects a person against severe illness on a par with two doses of mRNA vaccine, a new study says. 

People who’ve been infected with COVID reduced their chances of hospitalization and death by 88% over 10 months compared to somebody who hasn’t been infected, according to the study, published in The Lancet. 

The natural immunity provided by infection was “at least as high, if not higher” than the immunity provided by two doses of Moderna or Pfizer mRNA vaccines against the ancestral, Alpha, Delta, and Omicron BA.1 variants, the researchers reported. 

But protection against the BA.1 subvariant of Omicron was not as high – 36% at 10 months after infection, wrote the research team from the Institute for Health Metrics and Evaluation at the University of Washington.

They examined 65 studies from 19 countries through Sept. 31, 2022. They did not study data about infection from Omicron XBB and its sub-lineages. People who had immunity from both infection and vaccination, known as hybrid immunity, were not studied. 

The findings don’t mean people should skip the vaccines and get COVID on purpose, one of the researchers told NBC News. 

“The problem of saying ‘I’m gonna get infected to get immunity’ is you might be one of those people that end up in the hospital or die,” said Christopher Murray, MD, DPhil, director of the IHME. “Why would you take the risk when you can get immunity through vaccination quite safely?”

The findings could help people figure out the most effective time to get vaccinated or boosted and guide officials in setting policies on workplace vaccine mandates and rules for high-occupancy indoor settings, the researchers concluded.

This was the largest meta-analysis of immunity following infection to date, NBC News reports.

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

HONOLULU – In the clinical experience of John S. Barbieri, MD, MBA, cheilitis occurs in nearly all patients taking any dose of isotretinoin.

“If they don’t have dry lips, you have to wonder if they’re even absorbing isotretinoin,” Dr. Barbieri, director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “Everyone is going to get dry lips.”

According to a retrospective review of 1,743 patients started on isotretinoin, other common mucocutaneous side effects include eczema, nose bleeds, and eye problems. Emerging research suggests that there may be a role for oral omega-3 in decreasing such side effects of the drug. In a case control study, 118 patients were randomized to isotretinoin alone or isotretinoin plus 1 g/day of oral omega-3 for 16 weeks. At week 16, the rate of dry lips was 26% in the isoretinoin only group compared with 14% in the combination group; similar trends were seen with dry nose (11% vs. 0 %, respectively) and dry skin (11% vs. 2%).

“Omega-3 is a simple thing that we can think about recommending for patients,” Dr. Barbieri said. “It’s very safe, inexpensive, and it may help us manage these common sides effect we run into.”

Another potential side effect of isotretinoin that he characterized as underappreciated is chronic dry eye and other ocular changes. One retrospective cohort study of 14,682 adolescents and young adults in Israel found that use of the drug resulted in reduced tear production and reduced tear quality. In another study, a review and meta-analysis of 21 publications involving 1,105 eyes of 842 patients, isotretinoin use was associated with increased conjunctival fluorescein staining, decreased corneal thickness, and worse patient-reported ocular surface disease index scores.

“These changes may be mediated by meibomian gland dysfunction and atrophy,” Dr. Barbieri said. “Fortunately, many of these tear film changes appear to resolve after treatment. Those changes in corneal thickness do seem to get better. That’s reassuring.”

In a study of 54 patients treated with isotretinoin, tear production and quality returned to baseline within 6 months of treatment completion. “But some changes in the meibomian gland may be persistent,” Dr. Barbieri said. “At 6 and 12 months after the end of treatment, you can still see changes in the meibomian glands of patients who were treated with a standard course of 120 to 150 mg/kg isotretinoin,” he said, referring to the results of a study of 88 patients .

One study investigated the effects of omega-3 fatty acids and punctal plugs on tear film and ocular surface parameters in 90 patients receiving systemic isotretinoin therapy. They were divided into three groups: Those who received a soft preloaded silicone plug that was inserted in the inferior punctum of both eyes and received oral omega-3 fatty acid capsules twice daily for a total dose of 1,040 mg/day for 6 months; those who received a soft preloaded silicone plug and oral placebo, and those who received isotretinoin alone. At 6 months’ follow-up, those who were treated with omega-3 combined with the preloaded silicone plug had better meibomian gland function than did those who received isotretinoin alone or isotretinoin with the preloaded silicone plug.

Dr. Barbieri also noted that antihistamines may play a role in enhancing the effect of isotretinoin. In one study, 20 patients were treated with isotretinoin 0.4 mg/kg per day and 20 patients were also treated with an antihistamine, desloratadine 5 mg/day for 12 weeks. At week 12, patients in the group treated with isotretinoin and the antihistamine showed a more statistically significant decrease in acne lesion counts, compared with the isotretinoin-only group (reductions of 44.8% vs. 17.8%, respectively, in noninflammatory lesions; 55.8% vs. 22.9% in inflammatory lesions, and 45.6% vs. 18.7% in total lesions (P < .05 for all associations).

A subsequent larger study yielded similar findings. There were also lower rates of initial flaring and higher rates of patient satisfaction in the antihistamine groups in both studies.

In an interview at the meeting, Lawrence F. Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego, described Dr. Barbieri as “a leader in taking a comprehensive view on what the history and latest information is on isotretinoin. His fresh approach is something everyone should consider and figure out what they can use in their practice.”

Dr. Barbieri disclosed that he receives consulting fees from Dexcel for work unrelated to his presentation. Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Galderma, and Ortho Dermatologics. Medscape and this news organization are owned by the same parent company.

HONOLULU – In the clinical experience of John S. Barbieri, MD, MBA, cheilitis occurs in nearly all patients taking any dose of isotretinoin.

“If they don’t have dry lips, you have to wonder if they’re even absorbing isotretinoin,” Dr. Barbieri, director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “Everyone is going to get dry lips.”

According to a retrospective review of 1,743 patients started on isotretinoin, other common mucocutaneous side effects include eczema, nose bleeds, and eye problems. Emerging research suggests that there may be a role for oral omega-3 in decreasing such side effects of the drug. In a case control study, 118 patients were randomized to isotretinoin alone or isotretinoin plus 1 g/day of oral omega-3 for 16 weeks. At week 16, the rate of dry lips was 26% in the isoretinoin only group compared with 14% in the combination group; similar trends were seen with dry nose (11% vs. 0 %, respectively) and dry skin (11% vs. 2%).

“Omega-3 is a simple thing that we can think about recommending for patients,” Dr. Barbieri said. “It’s very safe, inexpensive, and it may help us manage these common sides effect we run into.”

Another potential side effect of isotretinoin that he characterized as underappreciated is chronic dry eye and other ocular changes. One retrospective cohort study of 14,682 adolescents and young adults in Israel found that use of the drug resulted in reduced tear production and reduced tear quality. In another study, a review and meta-analysis of 21 publications involving 1,105 eyes of 842 patients, isotretinoin use was associated with increased conjunctival fluorescein staining, decreased corneal thickness, and worse patient-reported ocular surface disease index scores.

“These changes may be mediated by meibomian gland dysfunction and atrophy,” Dr. Barbieri said. “Fortunately, many of these tear film changes appear to resolve after treatment. Those changes in corneal thickness do seem to get better. That’s reassuring.”

In a study of 54 patients treated with isotretinoin, tear production and quality returned to baseline within 6 months of treatment completion. “But some changes in the meibomian gland may be persistent,” Dr. Barbieri said. “At 6 and 12 months after the end of treatment, you can still see changes in the meibomian glands of patients who were treated with a standard course of 120 to 150 mg/kg isotretinoin,” he said, referring to the results of a study of 88 patients .

One study investigated the effects of omega-3 fatty acids and punctal plugs on tear film and ocular surface parameters in 90 patients receiving systemic isotretinoin therapy. They were divided into three groups: Those who received a soft preloaded silicone plug that was inserted in the inferior punctum of both eyes and received oral omega-3 fatty acid capsules twice daily for a total dose of 1,040 mg/day for 6 months; those who received a soft preloaded silicone plug and oral placebo, and those who received isotretinoin alone. At 6 months’ follow-up, those who were treated with omega-3 combined with the preloaded silicone plug had better meibomian gland function than did those who received isotretinoin alone or isotretinoin with the preloaded silicone plug.

Dr. Barbieri also noted that antihistamines may play a role in enhancing the effect of isotretinoin. In one study, 20 patients were treated with isotretinoin 0.4 mg/kg per day and 20 patients were also treated with an antihistamine, desloratadine 5 mg/day for 12 weeks. At week 12, patients in the group treated with isotretinoin and the antihistamine showed a more statistically significant decrease in acne lesion counts, compared with the isotretinoin-only group (reductions of 44.8% vs. 17.8%, respectively, in noninflammatory lesions; 55.8% vs. 22.9% in inflammatory lesions, and 45.6% vs. 18.7% in total lesions (P < .05 for all associations).

A subsequent larger study yielded similar findings. There were also lower rates of initial flaring and higher rates of patient satisfaction in the antihistamine groups in both studies.

In an interview at the meeting, Lawrence F. Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego, described Dr. Barbieri as “a leader in taking a comprehensive view on what the history and latest information is on isotretinoin. His fresh approach is something everyone should consider and figure out what they can use in their practice.”

Dr. Barbieri disclosed that he receives consulting fees from Dexcel for work unrelated to his presentation. Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Galderma, and Ortho Dermatologics. Medscape and this news organization are owned by the same parent company.

HONOLULU – In the clinical experience of John S. Barbieri, MD, MBA, cheilitis occurs in nearly all patients taking any dose of isotretinoin.

“If they don’t have dry lips, you have to wonder if they’re even absorbing isotretinoin,” Dr. Barbieri, director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said at the Hawaii Dermatology Seminar provided by MedscapeLIVE! “Everyone is going to get dry lips.”

According to a retrospective review of 1,743 patients started on isotretinoin, other common mucocutaneous side effects include eczema, nose bleeds, and eye problems. Emerging research suggests that there may be a role for oral omega-3 in decreasing such side effects of the drug. In a case control study, 118 patients were randomized to isotretinoin alone or isotretinoin plus 1 g/day of oral omega-3 for 16 weeks. At week 16, the rate of dry lips was 26% in the isoretinoin only group compared with 14% in the combination group; similar trends were seen with dry nose (11% vs. 0 %, respectively) and dry skin (11% vs. 2%).

“Omega-3 is a simple thing that we can think about recommending for patients,” Dr. Barbieri said. “It’s very safe, inexpensive, and it may help us manage these common sides effect we run into.”

Another potential side effect of isotretinoin that he characterized as underappreciated is chronic dry eye and other ocular changes. One retrospective cohort study of 14,682 adolescents and young adults in Israel found that use of the drug resulted in reduced tear production and reduced tear quality. In another study, a review and meta-analysis of 21 publications involving 1,105 eyes of 842 patients, isotretinoin use was associated with increased conjunctival fluorescein staining, decreased corneal thickness, and worse patient-reported ocular surface disease index scores.

“These changes may be mediated by meibomian gland dysfunction and atrophy,” Dr. Barbieri said. “Fortunately, many of these tear film changes appear to resolve after treatment. Those changes in corneal thickness do seem to get better. That’s reassuring.”

In a study of 54 patients treated with isotretinoin, tear production and quality returned to baseline within 6 months of treatment completion. “But some changes in the meibomian gland may be persistent,” Dr. Barbieri said. “At 6 and 12 months after the end of treatment, you can still see changes in the meibomian glands of patients who were treated with a standard course of 120 to 150 mg/kg isotretinoin,” he said, referring to the results of a study of 88 patients .

One study investigated the effects of omega-3 fatty acids and punctal plugs on tear film and ocular surface parameters in 90 patients receiving systemic isotretinoin therapy. They were divided into three groups: Those who received a soft preloaded silicone plug that was inserted in the inferior punctum of both eyes and received oral omega-3 fatty acid capsules twice daily for a total dose of 1,040 mg/day for 6 months; those who received a soft preloaded silicone plug and oral placebo, and those who received isotretinoin alone. At 6 months’ follow-up, those who were treated with omega-3 combined with the preloaded silicone plug had better meibomian gland function than did those who received isotretinoin alone or isotretinoin with the preloaded silicone plug.

Dr. Barbieri also noted that antihistamines may play a role in enhancing the effect of isotretinoin. In one study, 20 patients were treated with isotretinoin 0.4 mg/kg per day and 20 patients were also treated with an antihistamine, desloratadine 5 mg/day for 12 weeks. At week 12, patients in the group treated with isotretinoin and the antihistamine showed a more statistically significant decrease in acne lesion counts, compared with the isotretinoin-only group (reductions of 44.8% vs. 17.8%, respectively, in noninflammatory lesions; 55.8% vs. 22.9% in inflammatory lesions, and 45.6% vs. 18.7% in total lesions (P < .05 for all associations).

A subsequent larger study yielded similar findings. There were also lower rates of initial flaring and higher rates of patient satisfaction in the antihistamine groups in both studies.

In an interview at the meeting, Lawrence F. Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego, described Dr. Barbieri as “a leader in taking a comprehensive view on what the history and latest information is on isotretinoin. His fresh approach is something everyone should consider and figure out what they can use in their practice.”

Dr. Barbieri disclosed that he receives consulting fees from Dexcel for work unrelated to his presentation. Dr. Eichenfield disclosed that he has been an investigator and/or consultant for Almirall, Cassiopea, Dermata, Galderma, and Ortho Dermatologics. Medscape and this news organization are owned by the same parent company.

Approximately one in four patients with untreated COVID-19 experience symptom relapse, while almost one in three exhibits relapse of viral load, a recent study finds.

These findings offer a natural history of COVID-19 that will inform discussions and research concerning antiviral therapy, lead author Jonathan Z. Li, MD, associate professor of infectious disease at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues reported in Annals of Internal Medicine.

“There are increasing reports that high-risk patients are avoiding nirmatrelvir-ritonavir due to concerns about post-Paxlovid rebound, but there remains a gap in our knowledge of the frequency of symptom and viral relapse during untreated natural infection,” Dr. Li said in a written comment.

To address this gap, Dr. Li and colleagues analyzed data from 563 participants from the placebo group of the Adaptive Platform Treatment Trial for Outpatients with COVID-19 (ACTIV-2/A5401).

From days 0-28, patients recorded severity of 13 symptoms, with scores ranging from absent to severe (absent = 0, mild = 1, moderate = 2, severe = 3). RNA testing was performed on samples from nasal swabs on days 0–14, 21, and 28.

“The symptom rebound definition was determined by consensus of the study team, which comprises more than 10 infectious disease, pulmonary, and critical care physicians, as likely representing a clinically meaningful change in symptoms,” Dr. Li said.

Symptom scores needed to increase by at least 4 points to reach the threshold. For instance, a patient would qualify for relapse if they had worsening of four symptoms from mild to moderate, emergence of two new moderate symptoms, or emergence of one new moderate and two new mild symptoms.

The threshold for viral relapse was defined by an increase of at least 0.5 log10 RNA copies/mL from one nasal swab to the next, while high-level viral relapse was defined by an increase of at least 5.0 log10 RNA copies/mL. The former threshold was chosen based on previous analysis of viral rebound after nirmatrelvir treatment in the EPIC-HR phase 3 trial, whereas the high-level relapse point was based on Dr. Li and colleagues’ previous work linking this cutoff with the presence of infectious virus.

Their present analysis revealed that 26% of patients had symptom relapse at a median of 11 days after first symptom onset. Viral relapse occurred in 31% of patients, while high-level viral relapse occurred in 13% of participants. In about 9 out 10 cases, these relapses were detected at only one time point, suggesting they were transient. Of note, symptom relapse and high-level viral relapse occurred simultaneously in only 3% of patients.

This lack of correlation was “surprising” and “highlights that recovery from any infection is not always a linear process,” Dr. Li said.

This finding also suggests that untreated patients with recurring symptoms probably pose a low risk of contagion, according to David Wohl, MD, coauthor of the paper and professor of medicine in the division of infectious diseases at the University of North Carolina at Chapel Hill.
 

Paxlovid may not be to blame for COVID-19 rebound

“These results provide important context for the reports of Paxlovid rebound and show that baseline rates of symptom and viral relapse should be accounted for when studying the risk of rebound after antiviral therapy,” Dr. Li said.

Dr. Wohl suggested that these data can also play a role in conversations with patients who experience rebound after taking antiviral therapy.

“Many who have a return of their symptoms after taking Paxlovid blame the drug, and that may be justified, but this study suggests it happens in untreated people too,” Dr. Wohl said in a written comment.
 

Longer antiviral therapy deserves investigation

This is a “very important study” because it offers a baseline for comparing the natural history of COVID-19 with clinical course after antiviral therapy, said Timothy Henrich, MD, associate professor in the division of experimental medicine at University of California, San Francisco.

“Unlike this natural history, where it’s kind of sputtering up and down as it goes down, [after antiviral therapy,] it goes away for several days, and then it comes back up; and when it comes up, people have symptoms again,” Dr. Henrich said in an interview.

This suggests that each type of rebound is a unique phenomenon and, from a clinical perspective, that antiviral therapy may need to be extended.

“We treat for too short a period of time,” Dr. Henrich said. “We’re able to suppress [SARS-CoV-2] to the point where we’re not detecting it in the nasal pharynx, but it’s clearly still there. And it’s clearly still in a place that can replicate without the drug.”

That said, treating for longer may not be a sure-fire solution, especially if antiviral therapy is started early in the clinical course, as this could delay SARS-CoV-2-specific immune responses that are necessary for resolution, Dr. Henrich added,

“We need further study of longer-term therapies,” he said.

An array of research questions need to be addressed, according to Aditya Shah, MBBS, an infectious disease specialist at Mayo Clinic, Rochester, Minn. In a written comment, he probed the significance of rebound in various clinical scenarios.

“What [type of] rebound matters and what doesn’t?” Dr. Shah asked. “Does symptom rebound matter? How many untreated and treated ‘symptom rebounders’ need additional treatment or health care? If rebound does not really matter, but if Paxlovid helps in certain unvaccinated and high-risk patients, then does rebound matter? Future research should also focus on Paxlovid utility in vaccinated but high-risk patients. Is it as beneficial in them as it is in unvaccinated high-risk patients?”

While potentially regimen-altering questions like these remain unanswered, Dr. Henrich advised providers to keep patients focused on what we do know about the benefits of antiviral therapy given the current 5-day course, which is that it reduces the risk of severe disease and hospitalization.

The investigators disclosed relationships with Merck, Gilead, ViiV, and others. Dr. Henrich disclosed grant support from Merck and a consulting role with Roche. Dr. Shah disclosed no conflicts of interest.

Approximately one in four patients with untreated COVID-19 experience symptom relapse, while almost one in three exhibits relapse of viral load, a recent study finds.

These findings offer a natural history of COVID-19 that will inform discussions and research concerning antiviral therapy, lead author Jonathan Z. Li, MD, associate professor of infectious disease at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues reported in Annals of Internal Medicine.

“There are increasing reports that high-risk patients are avoiding nirmatrelvir-ritonavir due to concerns about post-Paxlovid rebound, but there remains a gap in our knowledge of the frequency of symptom and viral relapse during untreated natural infection,” Dr. Li said in a written comment.

To address this gap, Dr. Li and colleagues analyzed data from 563 participants from the placebo group of the Adaptive Platform Treatment Trial for Outpatients with COVID-19 (ACTIV-2/A5401).

From days 0-28, patients recorded severity of 13 symptoms, with scores ranging from absent to severe (absent = 0, mild = 1, moderate = 2, severe = 3). RNA testing was performed on samples from nasal swabs on days 0–14, 21, and 28.

“The symptom rebound definition was determined by consensus of the study team, which comprises more than 10 infectious disease, pulmonary, and critical care physicians, as likely representing a clinically meaningful change in symptoms,” Dr. Li said.

Symptom scores needed to increase by at least 4 points to reach the threshold. For instance, a patient would qualify for relapse if they had worsening of four symptoms from mild to moderate, emergence of two new moderate symptoms, or emergence of one new moderate and two new mild symptoms.

The threshold for viral relapse was defined by an increase of at least 0.5 log10 RNA copies/mL from one nasal swab to the next, while high-level viral relapse was defined by an increase of at least 5.0 log10 RNA copies/mL. The former threshold was chosen based on previous analysis of viral rebound after nirmatrelvir treatment in the EPIC-HR phase 3 trial, whereas the high-level relapse point was based on Dr. Li and colleagues’ previous work linking this cutoff with the presence of infectious virus.

Their present analysis revealed that 26% of patients had symptom relapse at a median of 11 days after first symptom onset. Viral relapse occurred in 31% of patients, while high-level viral relapse occurred in 13% of participants. In about 9 out 10 cases, these relapses were detected at only one time point, suggesting they were transient. Of note, symptom relapse and high-level viral relapse occurred simultaneously in only 3% of patients.

This lack of correlation was “surprising” and “highlights that recovery from any infection is not always a linear process,” Dr. Li said.

This finding also suggests that untreated patients with recurring symptoms probably pose a low risk of contagion, according to David Wohl, MD, coauthor of the paper and professor of medicine in the division of infectious diseases at the University of North Carolina at Chapel Hill.
 

Paxlovid may not be to blame for COVID-19 rebound

“These results provide important context for the reports of Paxlovid rebound and show that baseline rates of symptom and viral relapse should be accounted for when studying the risk of rebound after antiviral therapy,” Dr. Li said.

Dr. Wohl suggested that these data can also play a role in conversations with patients who experience rebound after taking antiviral therapy.

“Many who have a return of their symptoms after taking Paxlovid blame the drug, and that may be justified, but this study suggests it happens in untreated people too,” Dr. Wohl said in a written comment.
 

Longer antiviral therapy deserves investigation

This is a “very important study” because it offers a baseline for comparing the natural history of COVID-19 with clinical course after antiviral therapy, said Timothy Henrich, MD, associate professor in the division of experimental medicine at University of California, San Francisco.

“Unlike this natural history, where it’s kind of sputtering up and down as it goes down, [after antiviral therapy,] it goes away for several days, and then it comes back up; and when it comes up, people have symptoms again,” Dr. Henrich said in an interview.

This suggests that each type of rebound is a unique phenomenon and, from a clinical perspective, that antiviral therapy may need to be extended.

“We treat for too short a period of time,” Dr. Henrich said. “We’re able to suppress [SARS-CoV-2] to the point where we’re not detecting it in the nasal pharynx, but it’s clearly still there. And it’s clearly still in a place that can replicate without the drug.”

That said, treating for longer may not be a sure-fire solution, especially if antiviral therapy is started early in the clinical course, as this could delay SARS-CoV-2-specific immune responses that are necessary for resolution, Dr. Henrich added,

“We need further study of longer-term therapies,” he said.

An array of research questions need to be addressed, according to Aditya Shah, MBBS, an infectious disease specialist at Mayo Clinic, Rochester, Minn. In a written comment, he probed the significance of rebound in various clinical scenarios.

“What [type of] rebound matters and what doesn’t?” Dr. Shah asked. “Does symptom rebound matter? How many untreated and treated ‘symptom rebounders’ need additional treatment or health care? If rebound does not really matter, but if Paxlovid helps in certain unvaccinated and high-risk patients, then does rebound matter? Future research should also focus on Paxlovid utility in vaccinated but high-risk patients. Is it as beneficial in them as it is in unvaccinated high-risk patients?”

While potentially regimen-altering questions like these remain unanswered, Dr. Henrich advised providers to keep patients focused on what we do know about the benefits of antiviral therapy given the current 5-day course, which is that it reduces the risk of severe disease and hospitalization.

The investigators disclosed relationships with Merck, Gilead, ViiV, and others. Dr. Henrich disclosed grant support from Merck and a consulting role with Roche. Dr. Shah disclosed no conflicts of interest.

Approximately one in four patients with untreated COVID-19 experience symptom relapse, while almost one in three exhibits relapse of viral load, a recent study finds.

These findings offer a natural history of COVID-19 that will inform discussions and research concerning antiviral therapy, lead author Jonathan Z. Li, MD, associate professor of infectious disease at Brigham and Women’s Hospital and Harvard Medical School, both in Boston, and colleagues reported in Annals of Internal Medicine.

“There are increasing reports that high-risk patients are avoiding nirmatrelvir-ritonavir due to concerns about post-Paxlovid rebound, but there remains a gap in our knowledge of the frequency of symptom and viral relapse during untreated natural infection,” Dr. Li said in a written comment.

To address this gap, Dr. Li and colleagues analyzed data from 563 participants from the placebo group of the Adaptive Platform Treatment Trial for Outpatients with COVID-19 (ACTIV-2/A5401).

From days 0-28, patients recorded severity of 13 symptoms, with scores ranging from absent to severe (absent = 0, mild = 1, moderate = 2, severe = 3). RNA testing was performed on samples from nasal swabs on days 0–14, 21, and 28.

“The symptom rebound definition was determined by consensus of the study team, which comprises more than 10 infectious disease, pulmonary, and critical care physicians, as likely representing a clinically meaningful change in symptoms,” Dr. Li said.

Symptom scores needed to increase by at least 4 points to reach the threshold. For instance, a patient would qualify for relapse if they had worsening of four symptoms from mild to moderate, emergence of two new moderate symptoms, or emergence of one new moderate and two new mild symptoms.

The threshold for viral relapse was defined by an increase of at least 0.5 log10 RNA copies/mL from one nasal swab to the next, while high-level viral relapse was defined by an increase of at least 5.0 log10 RNA copies/mL. The former threshold was chosen based on previous analysis of viral rebound after nirmatrelvir treatment in the EPIC-HR phase 3 trial, whereas the high-level relapse point was based on Dr. Li and colleagues’ previous work linking this cutoff with the presence of infectious virus.

Their present analysis revealed that 26% of patients had symptom relapse at a median of 11 days after first symptom onset. Viral relapse occurred in 31% of patients, while high-level viral relapse occurred in 13% of participants. In about 9 out 10 cases, these relapses were detected at only one time point, suggesting they were transient. Of note, symptom relapse and high-level viral relapse occurred simultaneously in only 3% of patients.

This lack of correlation was “surprising” and “highlights that recovery from any infection is not always a linear process,” Dr. Li said.

This finding also suggests that untreated patients with recurring symptoms probably pose a low risk of contagion, according to David Wohl, MD, coauthor of the paper and professor of medicine in the division of infectious diseases at the University of North Carolina at Chapel Hill.
 

Paxlovid may not be to blame for COVID-19 rebound

“These results provide important context for the reports of Paxlovid rebound and show that baseline rates of symptom and viral relapse should be accounted for when studying the risk of rebound after antiviral therapy,” Dr. Li said.

Dr. Wohl suggested that these data can also play a role in conversations with patients who experience rebound after taking antiviral therapy.

“Many who have a return of their symptoms after taking Paxlovid blame the drug, and that may be justified, but this study suggests it happens in untreated people too,” Dr. Wohl said in a written comment.
 

Longer antiviral therapy deserves investigation

This is a “very important study” because it offers a baseline for comparing the natural history of COVID-19 with clinical course after antiviral therapy, said Timothy Henrich, MD, associate professor in the division of experimental medicine at University of California, San Francisco.

“Unlike this natural history, where it’s kind of sputtering up and down as it goes down, [after antiviral therapy,] it goes away for several days, and then it comes back up; and when it comes up, people have symptoms again,” Dr. Henrich said in an interview.

This suggests that each type of rebound is a unique phenomenon and, from a clinical perspective, that antiviral therapy may need to be extended.

“We treat for too short a period of time,” Dr. Henrich said. “We’re able to suppress [SARS-CoV-2] to the point where we’re not detecting it in the nasal pharynx, but it’s clearly still there. And it’s clearly still in a place that can replicate without the drug.”

That said, treating for longer may not be a sure-fire solution, especially if antiviral therapy is started early in the clinical course, as this could delay SARS-CoV-2-specific immune responses that are necessary for resolution, Dr. Henrich added,

“We need further study of longer-term therapies,” he said.

An array of research questions need to be addressed, according to Aditya Shah, MBBS, an infectious disease specialist at Mayo Clinic, Rochester, Minn. In a written comment, he probed the significance of rebound in various clinical scenarios.

“What [type of] rebound matters and what doesn’t?” Dr. Shah asked. “Does symptom rebound matter? How many untreated and treated ‘symptom rebounders’ need additional treatment or health care? If rebound does not really matter, but if Paxlovid helps in certain unvaccinated and high-risk patients, then does rebound matter? Future research should also focus on Paxlovid utility in vaccinated but high-risk patients. Is it as beneficial in them as it is in unvaccinated high-risk patients?”

While potentially regimen-altering questions like these remain unanswered, Dr. Henrich advised providers to keep patients focused on what we do know about the benefits of antiviral therapy given the current 5-day course, which is that it reduces the risk of severe disease and hospitalization.

The investigators disclosed relationships with Merck, Gilead, ViiV, and others. Dr. Henrich disclosed grant support from Merck and a consulting role with Roche. Dr. Shah disclosed no conflicts of interest.

Patients with a large cerebral infarction have better functional recovery when they receive endovascular therapy early on in addition to usual medical management, a new study shows.

The trial was stopped early because a planned interim analysis showed efficacy of endovascular therapy in this patient population.

Among patients in China with acute ischemic stroke and a large cerebral infarction, treatment with endovascular therapy within 24 hours after stroke onset “resulted in a better functional outcome at 3 months than medical management alone,” lead author Xiaochuan Huo, MD, PhD, associate chief physician, interventional neurology department, Beijing Tiantan Hospital, Capital Medical University, told this news organization.

“This trial added important evidence for the benefits of endovascular therapy,” Dr. Huo added.

The findings were presented at the International Stroke Conference and were published online in The New England Journal of Medicine. The conference was presented by the American Stroke Association, a division of the American Heart Association.

Will change practice

Commenting on the results, Tudor G. Jovin, MD, professor and chair, department of neurology, Cooper Medical School of Rowan University, Camden, N.J., said he has “little doubt” this study will change practice.

Despite previous studies showing signals of benefit from thrombectomy for patients with large-core infarcts, and some even finding a large treatment effect, “somehow the world didn’t register this,” said Dr. Jovin.

“The stroke community was perhaps reluctant to accept these signals that were there in plain sight because we have been primed for such a long time that reperfusing large infarcts was, if not detrimental, not beneficial.”

But this study, along with another study showing similar results, SELECT 2, which was also presented at this meeting and was published in the same issue of NEJM, provide “overwhelming proof” and “have finally made the community aware,” said Dr. Jovin. “This is sort of a wake-up call to say, ‘Hey, this is real; patients with large infarcts also benefit from thrombectomy.’ “

This new research suggests it’s not necessary to learn the infarct size, at least in the early time window, and doing so just wastes precious time, added Dr. Jovin.

The impact of thrombectomy on patients with “super large infarcts” is still not clear, although these are “extremely rare” in the early time window, perhaps representing only about 1% of patients, said Dr. Jovin.

The increased rate of hemorrhages in study patients receiving thrombectomy “is the price you pay” for the benefits, he said. He noted that this is not any different from the situation with tissue plasminogen activator (tPA), which is routinely used because the benefits far outweigh the risks.
 

ANGEL-ASPECT

As patients with large infarctions are generally excluded from studies of thrombectomy, it’s been unclear whether they benefit from this therapy, the researchers noted.

The multicenter Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core (ANGEL-ASPECT) trial included 455 adult patients (median age, 68 years; 38.7% women) who had a large infarct core caused by acute large-vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score [ASPECTS] 3-5 without core volume limitations or ASPECTS 0–2 with core volume between 70 and 100 mL).

Study participants had to have a score of 6-30 on the National Institutes of Health Stroke Scale (NIHSS) and a retrospectively determined prestroke score of 0 or 1 on the Modified Rankin Scale (mRS).

The median baseline NIHSS score of study patients was 16, the median ASPECTS was 3, and the median infarct-core volume was 62 mL.

Researchers randomly assigned patients to undergo either medical management alone or medical management as well as endovascular therapy. Medical management included intravenous (IV) thrombolysis for those who were eligible.

IV thrombolysis was administered before thrombectomy for about 28% of patients in each group. Some 78.7% of all patients arrived at the hospital outside the typical 4.5-hour window and were ineligible for thrombolysis.

A greater percentage of patients in the endovascular therapy group was receiving antihypertensive medications (83.0%) than in the medical management alone group (54.0%). About 20% of patients in each group were taking an anticoagulant medication.

When the trial was halted, outcome data were available for 336 patients. An additional 120 patients had undergone randomization, and 455 had completed 90 days of follow-up.
 

Better functional outcome

The primary outcome was the score on the mRS at 90 days. Results showed a shift in the distribution of scores on the mRS at 90 days toward better outcomes favoring endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval [CI], 1.11-1.69; P = .004).

The efficacy of endovascular therapy with respect to the primary outcome was similar across predefined subgroups and across all trial sites. However, the trial was not powered to allow definite conclusions based on the results of subgroup analyses.

Although patients with an ASPECT score of 0-2 (indicating very large infarct cores) are considered unlikely to benefit from endovascular treatment, the researchers did find some signals of gain for these patients.

“Although no conclusions can be drawn because the trial was not powered for this analysis and the confidence interval for the odds ratio between the trial groups included 1, there may have been a benefit with endovascular therapy in this subgroup,” the authors wrote. “More trials are warranted to determine if this benefit is valid.”

As for secondary outcomes, the percentage of patients with a score of 0-2 on the mRS at 90 days was 30.0% in the endovascular therapy group and 11.6% in the medical management group (relative risk [RR], 2.62; 95% CI, 1.69-4.06).

The percentage of patients with a score of 0-3 on the mRS at 90 days was 47.0% in the endovascular therapy group and 33.3% in the medical management group (RR, 1.50; 95% CI, 1.17-1.91).

The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours, which occurred in 6.1% of the endovascular therapy group, compared to 2.7% in the medical management group (RR, 2.07; 95% CI, 0.79-5.41; P = .12)

Mortality within 90 days was 21.7% in the endovascular therapy group and 20.0% in the medical management group. Other serious adverse events occurred in 40.0% in the endovascular therapy group and 38.2% in the medical management group (P = .70).

The percentage of patients receiving IV thrombolysis was relatively low, which may have affected outcomes in the medical management group. Another potential limitation was that urokinase rather than alteplase, which is probably more effective, was used for thrombolysis in a small percentage of patients.

Further, the study did not include patients older than 80 years or those with an ASPECT value greater than 5 and infarct core volume of 70-100 mL, and it included only Chinese patients, so the results may not be generalizable, the researchers noted.

These findings will likely change clinical practice, said Dr. Huo, who noted that the current guideline doesn’t provide “a high-level recommendation” for [endovascular therapy] in patients with a low ASPECT score.

“These new results will change the guideline” to suggest endovascular therapy for large-core patients, he said.
 

Welcome news

An accompanying editorial by Pierre Fayad, MD, department of neurological sciences, division of vascular neurology and stroke, University of Nebraska Medical Center, Omaha, welcomed results from this and other recent related studies.

From these new results, “it is reasonable to suggest that endovascular thrombectomy be offered to patients with large strokes” if they arrive in a timely fashion at a center capable of performing the procedure and have an ASPECT value of 3-5 or an ischemic-core volume of 50 mL or greater, he wrote.

“The improved chance of independent walking and the ability to perform other daily activities in patients with the most severe strokes is welcome news for patients and for the field of stroke treatment.”

The study received funding from Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology. Dr. Huo and Dr. Jovin report no relevant financial relationships.

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

Patients with a large cerebral infarction have better functional recovery when they receive endovascular therapy early on in addition to usual medical management, a new study shows.

The trial was stopped early because a planned interim analysis showed efficacy of endovascular therapy in this patient population.

Among patients in China with acute ischemic stroke and a large cerebral infarction, treatment with endovascular therapy within 24 hours after stroke onset “resulted in a better functional outcome at 3 months than medical management alone,” lead author Xiaochuan Huo, MD, PhD, associate chief physician, interventional neurology department, Beijing Tiantan Hospital, Capital Medical University, told this news organization.

“This trial added important evidence for the benefits of endovascular therapy,” Dr. Huo added.

The findings were presented at the International Stroke Conference and were published online in The New England Journal of Medicine. The conference was presented by the American Stroke Association, a division of the American Heart Association.

Will change practice

Commenting on the results, Tudor G. Jovin, MD, professor and chair, department of neurology, Cooper Medical School of Rowan University, Camden, N.J., said he has “little doubt” this study will change practice.

Despite previous studies showing signals of benefit from thrombectomy for patients with large-core infarcts, and some even finding a large treatment effect, “somehow the world didn’t register this,” said Dr. Jovin.

“The stroke community was perhaps reluctant to accept these signals that were there in plain sight because we have been primed for such a long time that reperfusing large infarcts was, if not detrimental, not beneficial.”

But this study, along with another study showing similar results, SELECT 2, which was also presented at this meeting and was published in the same issue of NEJM, provide “overwhelming proof” and “have finally made the community aware,” said Dr. Jovin. “This is sort of a wake-up call to say, ‘Hey, this is real; patients with large infarcts also benefit from thrombectomy.’ “

This new research suggests it’s not necessary to learn the infarct size, at least in the early time window, and doing so just wastes precious time, added Dr. Jovin.

The impact of thrombectomy on patients with “super large infarcts” is still not clear, although these are “extremely rare” in the early time window, perhaps representing only about 1% of patients, said Dr. Jovin.

The increased rate of hemorrhages in study patients receiving thrombectomy “is the price you pay” for the benefits, he said. He noted that this is not any different from the situation with tissue plasminogen activator (tPA), which is routinely used because the benefits far outweigh the risks.
 

ANGEL-ASPECT

As patients with large infarctions are generally excluded from studies of thrombectomy, it’s been unclear whether they benefit from this therapy, the researchers noted.

The multicenter Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core (ANGEL-ASPECT) trial included 455 adult patients (median age, 68 years; 38.7% women) who had a large infarct core caused by acute large-vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score [ASPECTS] 3-5 without core volume limitations or ASPECTS 0–2 with core volume between 70 and 100 mL).

Study participants had to have a score of 6-30 on the National Institutes of Health Stroke Scale (NIHSS) and a retrospectively determined prestroke score of 0 or 1 on the Modified Rankin Scale (mRS).

The median baseline NIHSS score of study patients was 16, the median ASPECTS was 3, and the median infarct-core volume was 62 mL.

Researchers randomly assigned patients to undergo either medical management alone or medical management as well as endovascular therapy. Medical management included intravenous (IV) thrombolysis for those who were eligible.

IV thrombolysis was administered before thrombectomy for about 28% of patients in each group. Some 78.7% of all patients arrived at the hospital outside the typical 4.5-hour window and were ineligible for thrombolysis.

A greater percentage of patients in the endovascular therapy group was receiving antihypertensive medications (83.0%) than in the medical management alone group (54.0%). About 20% of patients in each group were taking an anticoagulant medication.

When the trial was halted, outcome data were available for 336 patients. An additional 120 patients had undergone randomization, and 455 had completed 90 days of follow-up.
 

Better functional outcome

The primary outcome was the score on the mRS at 90 days. Results showed a shift in the distribution of scores on the mRS at 90 days toward better outcomes favoring endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval [CI], 1.11-1.69; P = .004).

The efficacy of endovascular therapy with respect to the primary outcome was similar across predefined subgroups and across all trial sites. However, the trial was not powered to allow definite conclusions based on the results of subgroup analyses.

Although patients with an ASPECT score of 0-2 (indicating very large infarct cores) are considered unlikely to benefit from endovascular treatment, the researchers did find some signals of gain for these patients.

“Although no conclusions can be drawn because the trial was not powered for this analysis and the confidence interval for the odds ratio between the trial groups included 1, there may have been a benefit with endovascular therapy in this subgroup,” the authors wrote. “More trials are warranted to determine if this benefit is valid.”

As for secondary outcomes, the percentage of patients with a score of 0-2 on the mRS at 90 days was 30.0% in the endovascular therapy group and 11.6% in the medical management group (relative risk [RR], 2.62; 95% CI, 1.69-4.06).

The percentage of patients with a score of 0-3 on the mRS at 90 days was 47.0% in the endovascular therapy group and 33.3% in the medical management group (RR, 1.50; 95% CI, 1.17-1.91).

The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours, which occurred in 6.1% of the endovascular therapy group, compared to 2.7% in the medical management group (RR, 2.07; 95% CI, 0.79-5.41; P = .12)

Mortality within 90 days was 21.7% in the endovascular therapy group and 20.0% in the medical management group. Other serious adverse events occurred in 40.0% in the endovascular therapy group and 38.2% in the medical management group (P = .70).

The percentage of patients receiving IV thrombolysis was relatively low, which may have affected outcomes in the medical management group. Another potential limitation was that urokinase rather than alteplase, which is probably more effective, was used for thrombolysis in a small percentage of patients.

Further, the study did not include patients older than 80 years or those with an ASPECT value greater than 5 and infarct core volume of 70-100 mL, and it included only Chinese patients, so the results may not be generalizable, the researchers noted.

These findings will likely change clinical practice, said Dr. Huo, who noted that the current guideline doesn’t provide “a high-level recommendation” for [endovascular therapy] in patients with a low ASPECT score.

“These new results will change the guideline” to suggest endovascular therapy for large-core patients, he said.
 

Welcome news

An accompanying editorial by Pierre Fayad, MD, department of neurological sciences, division of vascular neurology and stroke, University of Nebraska Medical Center, Omaha, welcomed results from this and other recent related studies.

From these new results, “it is reasonable to suggest that endovascular thrombectomy be offered to patients with large strokes” if they arrive in a timely fashion at a center capable of performing the procedure and have an ASPECT value of 3-5 or an ischemic-core volume of 50 mL or greater, he wrote.

“The improved chance of independent walking and the ability to perform other daily activities in patients with the most severe strokes is welcome news for patients and for the field of stroke treatment.”

The study received funding from Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology. Dr. Huo and Dr. Jovin report no relevant financial relationships.

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

Patients with a large cerebral infarction have better functional recovery when they receive endovascular therapy early on in addition to usual medical management, a new study shows.

The trial was stopped early because a planned interim analysis showed efficacy of endovascular therapy in this patient population.

Among patients in China with acute ischemic stroke and a large cerebral infarction, treatment with endovascular therapy within 24 hours after stroke onset “resulted in a better functional outcome at 3 months than medical management alone,” lead author Xiaochuan Huo, MD, PhD, associate chief physician, interventional neurology department, Beijing Tiantan Hospital, Capital Medical University, told this news organization.

“This trial added important evidence for the benefits of endovascular therapy,” Dr. Huo added.

The findings were presented at the International Stroke Conference and were published online in The New England Journal of Medicine. The conference was presented by the American Stroke Association, a division of the American Heart Association.

Will change practice

Commenting on the results, Tudor G. Jovin, MD, professor and chair, department of neurology, Cooper Medical School of Rowan University, Camden, N.J., said he has “little doubt” this study will change practice.

Despite previous studies showing signals of benefit from thrombectomy for patients with large-core infarcts, and some even finding a large treatment effect, “somehow the world didn’t register this,” said Dr. Jovin.

“The stroke community was perhaps reluctant to accept these signals that were there in plain sight because we have been primed for such a long time that reperfusing large infarcts was, if not detrimental, not beneficial.”

But this study, along with another study showing similar results, SELECT 2, which was also presented at this meeting and was published in the same issue of NEJM, provide “overwhelming proof” and “have finally made the community aware,” said Dr. Jovin. “This is sort of a wake-up call to say, ‘Hey, this is real; patients with large infarcts also benefit from thrombectomy.’ “

This new research suggests it’s not necessary to learn the infarct size, at least in the early time window, and doing so just wastes precious time, added Dr. Jovin.

The impact of thrombectomy on patients with “super large infarcts” is still not clear, although these are “extremely rare” in the early time window, perhaps representing only about 1% of patients, said Dr. Jovin.

The increased rate of hemorrhages in study patients receiving thrombectomy “is the price you pay” for the benefits, he said. He noted that this is not any different from the situation with tissue plasminogen activator (tPA), which is routinely used because the benefits far outweigh the risks.
 

ANGEL-ASPECT

As patients with large infarctions are generally excluded from studies of thrombectomy, it’s been unclear whether they benefit from this therapy, the researchers noted.

The multicenter Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients With a Large Infarct Core (ANGEL-ASPECT) trial included 455 adult patients (median age, 68 years; 38.7% women) who had a large infarct core caused by acute large-vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score [ASPECTS] 3-5 without core volume limitations or ASPECTS 0–2 with core volume between 70 and 100 mL).

Study participants had to have a score of 6-30 on the National Institutes of Health Stroke Scale (NIHSS) and a retrospectively determined prestroke score of 0 or 1 on the Modified Rankin Scale (mRS).

The median baseline NIHSS score of study patients was 16, the median ASPECTS was 3, and the median infarct-core volume was 62 mL.

Researchers randomly assigned patients to undergo either medical management alone or medical management as well as endovascular therapy. Medical management included intravenous (IV) thrombolysis for those who were eligible.

IV thrombolysis was administered before thrombectomy for about 28% of patients in each group. Some 78.7% of all patients arrived at the hospital outside the typical 4.5-hour window and were ineligible for thrombolysis.

A greater percentage of patients in the endovascular therapy group was receiving antihypertensive medications (83.0%) than in the medical management alone group (54.0%). About 20% of patients in each group were taking an anticoagulant medication.

When the trial was halted, outcome data were available for 336 patients. An additional 120 patients had undergone randomization, and 455 had completed 90 days of follow-up.
 

Better functional outcome

The primary outcome was the score on the mRS at 90 days. Results showed a shift in the distribution of scores on the mRS at 90 days toward better outcomes favoring endovascular therapy over medical management alone (generalized odds ratio, 1.37; 95% confidence interval [CI], 1.11-1.69; P = .004).

The efficacy of endovascular therapy with respect to the primary outcome was similar across predefined subgroups and across all trial sites. However, the trial was not powered to allow definite conclusions based on the results of subgroup analyses.

Although patients with an ASPECT score of 0-2 (indicating very large infarct cores) are considered unlikely to benefit from endovascular treatment, the researchers did find some signals of gain for these patients.

“Although no conclusions can be drawn because the trial was not powered for this analysis and the confidence interval for the odds ratio between the trial groups included 1, there may have been a benefit with endovascular therapy in this subgroup,” the authors wrote. “More trials are warranted to determine if this benefit is valid.”

As for secondary outcomes, the percentage of patients with a score of 0-2 on the mRS at 90 days was 30.0% in the endovascular therapy group and 11.6% in the medical management group (relative risk [RR], 2.62; 95% CI, 1.69-4.06).

The percentage of patients with a score of 0-3 on the mRS at 90 days was 47.0% in the endovascular therapy group and 33.3% in the medical management group (RR, 1.50; 95% CI, 1.17-1.91).

The primary safety outcome was symptomatic intracranial hemorrhage within 48 hours, which occurred in 6.1% of the endovascular therapy group, compared to 2.7% in the medical management group (RR, 2.07; 95% CI, 0.79-5.41; P = .12)

Mortality within 90 days was 21.7% in the endovascular therapy group and 20.0% in the medical management group. Other serious adverse events occurred in 40.0% in the endovascular therapy group and 38.2% in the medical management group (P = .70).

The percentage of patients receiving IV thrombolysis was relatively low, which may have affected outcomes in the medical management group. Another potential limitation was that urokinase rather than alteplase, which is probably more effective, was used for thrombolysis in a small percentage of patients.

Further, the study did not include patients older than 80 years or those with an ASPECT value greater than 5 and infarct core volume of 70-100 mL, and it included only Chinese patients, so the results may not be generalizable, the researchers noted.

These findings will likely change clinical practice, said Dr. Huo, who noted that the current guideline doesn’t provide “a high-level recommendation” for [endovascular therapy] in patients with a low ASPECT score.

“These new results will change the guideline” to suggest endovascular therapy for large-core patients, he said.
 

Welcome news

An accompanying editorial by Pierre Fayad, MD, department of neurological sciences, division of vascular neurology and stroke, University of Nebraska Medical Center, Omaha, welcomed results from this and other recent related studies.

From these new results, “it is reasonable to suggest that endovascular thrombectomy be offered to patients with large strokes” if they arrive in a timely fashion at a center capable of performing the procedure and have an ASPECT value of 3-5 or an ischemic-core volume of 50 mL or greater, he wrote.

“The improved chance of independent walking and the ability to perform other daily activities in patients with the most severe strokes is welcome news for patients and for the field of stroke treatment.”

The study received funding from Covidien Healthcare International Trading (Shanghai), Johnson & Johnson MedTech, Genesis MedTech (Shanghai), and Shanghai HeartCare Medical Technology. Dr. Huo and Dr. Jovin report no relevant financial relationships.

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

In patients with acute ischemic stroke who have not received thrombolysis or thrombectomy, early antihypertensive treatment compared with delayed antihypertensive treatment did not reduce the likelihood of death and major disability at 3 months in the CATIS-2 trial.

The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.

But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.

Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”

But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”

Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.

“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.

In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.

In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.

Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.

The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.

Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).

The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.

BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).

At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).

The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).

There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).

There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.

Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.

Dr. Liu has disclosed no relevant financial relationships.

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

In patients with acute ischemic stroke who have not received thrombolysis or thrombectomy, early antihypertensive treatment compared with delayed antihypertensive treatment did not reduce the likelihood of death and major disability at 3 months in the CATIS-2 trial.

The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.

But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.

Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”

But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”

Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.

“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.

In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.

In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.

Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.

The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.

Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).

The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.

BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).

At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).

The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).

There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).

There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.

Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.

Dr. Liu has disclosed no relevant financial relationships.

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

In patients with acute ischemic stroke who have not received thrombolysis or thrombectomy, early antihypertensive treatment compared with delayed antihypertensive treatment did not reduce the likelihood of death and major disability at 3 months in the CATIS-2 trial.

The trial was presented by Liping Liu, MD, Beijing Tiantan Hospital, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Antihypertensive treatment can be delayed for at least 7 days following ischemic stroke onset, unless there are severe acute comorbidities that demand emergency blood pressure reduction to prevent serious complications,” Dr. Liu concluded.

But he acknowledged that the optimal BP management strategy in these patients remains uncertain and should be the focus of future research.

Discussing the trial at an ISC 2023 Highlights session, Lauren Sansing, MD, Yale University, New Haven, Conn., and ISC program vice chair, said: “These results seem to support waiting for a week or so before treating blood pressure in these patients.”

But Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., and ISC program chair, countered: “To me, it’s kind of a neutral result, so what I take home from this is that you don’t necessarily have to wait.”

Dr. Jovin continued: “We used to think that it was mandatory not to treat blood pressure early because of the risk of deceasing the perfusion pressure, but this trial suggests the effects are neutral and there is probably as much benefit from lowering blood pressure for other reasons that offsets the potential harm.

“I think these are good data to rely on when we make these kinds of treatment decisions. Personally, I am a bit more aggressive with early blood pressure management and it’s good to see that you don’t get punished for that,” he added.

In his presentation, Dr. Liu explained that increased BP is common in acute stroke and is strongly associated with poor functional outcome and recurrence of ischemic stroke, but the optimal blood pressure management strategy in acute ischemic stroke remains controversial.

In the first CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke), which compared antihypertensive treatment within 48 hours of stroke onset with no antihypertensive treatment in ischemic stroke patients not receiving thrombolysis, the main results suggested that BP reduction with antihypertensive medications did not reduce the likelihood of death and major disability at 14 days or hospital discharge. But a subgroup analysis found that initiating antihypertensive treatment between 24 and 48 hours of stroke onset showed a beneficial effect on reducing death or major disability.

Current AHA/ASA guidelines suggest that, in patients with BP greater than 220/120 mm Hg who have not received thrombolysis or thrombectomy and have no comorbid conditions requiring urgent antihypertensive treatment, the benefit of initiating or reinitiating antihypertensive treatment within the first 48-72 hours is uncertain, although the guidelines say it might be reasonable to lower BP by around 15% during the first 24 hours after stroke onset, Dr. Liu noted.

The CATIS-2 trial was a multicenter, randomized, open-label, blinded-endpoints trial conducted at 106 centers in China that enrolled 4810 patients within 24-48 hours of onset of acute ischemic stroke who had elevated BP. Patients had not received thrombolytic therapy or mechanical thrombectomy.

Patients were randomly assigned to early antihypertensive therapy (initiated after randomization and aiming for a 10%-20% reduction in systolic BP) or delayed antihypertensive therapy (restarted antihypertensive therapy on day 8 of randomization, aiming for a BP of < 140/90 mm Hg).

The median age of the patients was 64 years, 65% were male, 80% had a history of hypertension, and the median National Institutes of Health Stroke Scale score was 3. Baseline BP averaged 163/92 mm Hg in both groups. The median time from stroke onset to antihypertensive treatment was 1.5 days in the early group and 8.5 days in the delayed group.

BP results showed that, at 24 hours after randomization, mean systolic pressure was reduced by 16.4 mm Hg (9.7%) in the early-treatment group and by 8.6 mm Hg (4.9%) in the delayed-treatment group (difference, –7.8 mm Hg; P < .0001).

At day 7, mean systolic pressure was 139.1 mm Hg in the early-treatment group, compared with 150.9 mm Hg in the delayed-treatment group, with a net difference in systolic BP of –11.9 mm Hg (P < .0001).

The primary outcome was the composite of death and major disability (modified Rankin Scale ≥ 3) at 3 months. This did not differ between the groups, occurring in 12.1% in the early antihypertensive treatment group versus 10.5% in the delayed antihypertensive treatment group (risk ratio, 1.15; P = .08).

There was also no difference in the major secondary outcome of shift in scores of mRS at 3 months, with a common odds ratio of 1.05 (95% confidence interval, 0.95-1.17).

There was no interaction with the composite outcome of death or major disability at 90 days in the prespecified subgroups.

Dr. Liu pointed out several limitations of the study. These included an observed primary outcome rate substantially lower than expected; the BP reduction seen within the first 7 days in the early-treatment group was moderate; and the results of the study cannot be applied to patients treated with thrombolysis or thrombectomy.

Dr. Liu has disclosed no relevant financial relationships.

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

Among Chinese patients with minor nondisabling stroke who presented within 4.5 hours of symptom onset, dual antiplatelet treatment was noninferior to thrombolysis with intravenous alteplase with regard to functional outcome at 90 days in the ARAMIS trial.

The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.

In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.

Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”

She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”

Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.

A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.

This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.

In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.

In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.

The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.

The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).

The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.

In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).

“Therefore, this was a positive trial,” Dr. Nguyen stated.

About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.

Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.

In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.

Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).

Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.

Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.

In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.

“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.

“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.

In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”

But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”

The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.

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

Among Chinese patients with minor nondisabling stroke who presented within 4.5 hours of symptom onset, dual antiplatelet treatment was noninferior to thrombolysis with intravenous alteplase with regard to functional outcome at 90 days in the ARAMIS trial.

The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.

In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.

Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”

She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”

Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.

A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.

This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.

In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.

In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.

The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.

The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).

The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.

In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).

“Therefore, this was a positive trial,” Dr. Nguyen stated.

About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.

Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.

In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.

Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).

Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.

Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.

In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.

“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.

“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.

In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”

But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”

The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.

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

Among Chinese patients with minor nondisabling stroke who presented within 4.5 hours of symptom onset, dual antiplatelet treatment was noninferior to thrombolysis with intravenous alteplase with regard to functional outcome at 90 days in the ARAMIS trial.

The trial was presented by Thanh Nguyen, MD, Boston Medical Center, at the International Stroke Conference presented by the American Stroke Association, a division of the American Heart Association.

“Given the ease of administration, less intensive monitoring, low cost, and safety profile of dual antiplatelet therapy, the current findings support the use of dual antiplatelet in this population,” Dr. Nguyen concluded.

In a comment on the trial, Pooja Khatri, MD, professor of neurology at the University of Cincinnati, and lead investigator of the previous PRISMS study of tissue plasminogen activator (tPA) or alteplase in mild stroke, said the results reinforced the current recommendations of giving dual antiplatelet therapy but not alteplase to these patients.

Noting that the standard of care is now to give dual antiplatelet therapy to these patients, Dr. Khatri said: “These data reassure that this remains the right way to go.”

She added that her take-home message from the study would be: “Keep giving dual antiplatelet therapy, and we may be doing more harm than good with alteplase in this patient population.”

Introducing her presentation, Dr. Nguyen explained that mild ischemic stroke, defined as having a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less, comprises half of ischemic stroke patients in the United States. But the benefit of thrombolysis in patients with minor ischemic stroke that is not disabling is unknown.

A subgroup analysis of one of the major thrombolysis trials (IST-3) found that a higher proportion of patients with mild ischemic stroke who were treated within 3 hours of symptom onset were alive and independent at 6 months if they had been given thrombolysis (84%), compared to 65% in the control group who received standard medical treatment.

This led to the first randomized trial (PRISMS) dedicated to patients with mild nondisabling stroke, which found that alteplase given within 3 hours of symptom onset did not increase the likelihood of a good functional outcome at 90 days in comparison with single-agent aspirin. The study was unfortunately terminated early for administrative reasons, and no definitive conclusions could be drawn on the basis of these results, Dr. Nguyen reported.

In 2018, the American Heart Association/American Stroke Association guidelines indicated that for patients who present within 3 hours of symptom onset with mild ischemic stroke that was judged to be nondisabling, thrombolysis with intravenous alteplase could be considered, she noted.

In the meantime, dual antiplatelet therapy was shown to be safe and effective in the POINT and CHANCE trials in patients presenting with minor stroke within 12 or 24 hours, and the CHANCE trial also found a benefit in reducing recurrent stroke that was most effective in the first 2 weeks.

The current ARAMIS trial was therefore conducted to evaluate dual antiplatelet therapy in comparison with thrombolysis for patients with acute minor stroke (NIHSS 5 or less) who presented within 4.5 hours of symptom onset and were without clearly disabling deficit.

The trial was conducted in 38 hospitals in China and included 760 patients (median NIHSS score of 2) who were randomly assigned to receive intravenous alteplase at the standard dose of 0.9 mg/kg, followed by guideline-based antiplatelet treatment, or dual antiplatelet therapy (clopidogrel 300 mg plus 100 mg aspirin loading dose followed by 10 to 14 days of aspirin 100 mg and clopidogrel 75 mg).

The trial was designed to assess noninferiority of dual antiplatelet therapy to alteplase with noninferiority margin of –4.5%.

In the modified intention-to-treat analysis, which included 722 patients, the primary outcome (excellent functional outcome, defined as a Modified Rankin Scale score of 0 or 1 at 90 days) occurred in 93.8% of patients in the dual antiplatelet therapy group and in 91.4% of the alteplase group. This gave a difference of 2.4%, which fell within the limits for noninferiority (P = .0002 for noninferiority test).

“Therefore, this was a positive trial,” Dr. Nguyen stated.

About 20% of patients crossed over from the dual antiplatelet group to the thrombolysis group, and about 16% of patients crossed over from the thrombolysis group to the dual antiplatelet group. But a per-protocol and an “as treated” analysis showed results similar to those of the main intention-to-treat analysis.

Secondary outcomes were largely similar between the two groups other than early neurologic deterioration, which was less common in the dual antiplatelet therapy group.

In terms of safety, symptomatic intracranial hemorrhage occurred in 0.3% (1/369) in the dual antiplatelet group and in 0.9% (3/350) in the alteplase group, a nonsignificant difference.

Events of “any bleeding” occurred in more patients in the thrombolysis group (5.4%) than in the dual antiplatelet therapy group (1.6%), and this difference was significant (P = .01).

Subgroup analysis showed a trend toward benefit of alteplase for patients with higher NIHSS score at baseline (NIHSS > 3). Otherwise, the other subgroups looked similar to the main results.

Dr. Nguyen pointed out one limitation of the study – that dual antiplatelet therapy was updated to standard treatment in this target population in the 2019 AHA/ASA guidelines.

In her discussion of the study, Dr. Khatri suggested that the ARAMIS results were what might have been expected.

“Dual antiplatelet therapy is designed to prevent stroke. Even in the POINT trial, dual antiplatelet therapy showed no effect on 90-day functional outcome. It was really about prevention. The PRISMS trial suggested that alteplase was also unlikely to improve 90-day functional outcome in this population of patients with mild and not clearly disabling stroke. So, it is not surprising that dual antiplatelet therapy was noninferior to alteplase for 90-day functional outcome for both those reasons,” she explained.

“That being said, while designed as a noninferiority study, it is interesting to note that alteplase again showed no evidence of treatment effect compared to antiplatelet therapy, affirming what was observed in the prematurely terminated PRISMS trial,” Dr. Khatri added.

In a discussion of the study at an ISC 2023 highlights session, ISC program chair Tudor Jovin, MD, Cooper Neurological Institute, Cherry Hill, N.J., said: “This is very important data and it’s actually the first completed trial that examines this question.”

But, he added, “I think we need to refine our knowledge about what a nondisabling stroke actually is. You could argue that every stroke is disabling. I think we need more clarity on this definition, as in practice, many clinicians still give tPA on account of these mild strokes still being disabling.”

The ARAMIS trial was funded by the National Key R&D Program of China and the Science and Technology Project Plan of Liaoning Province. Dr. Nguyen reports research support from Medtronic that was not related to the current study.

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

Treatment with the thiazolidinedione pioglitazone may offer the greatest protection against dementia for older adults with newly diagnosed type 2 diabetes mellitus (T2DM) who have a history of stroke or ischemic heart disease, new research suggests.

Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.

However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.

“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.

However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.

This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.

The results were published online in Neurology.
 

Dose-response relationship

Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.

This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.

Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.

Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.

Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.

There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).

A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
 

Several limitations

The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).

The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.

The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.

However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.

The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.

There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
 

More data needed

In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”

However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.

They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.

They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.

“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.

For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.

The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.

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

Treatment with the thiazolidinedione pioglitazone may offer the greatest protection against dementia for older adults with newly diagnosed type 2 diabetes mellitus (T2DM) who have a history of stroke or ischemic heart disease, new research suggests.

Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.

However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.

“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.

However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.

This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.

The results were published online in Neurology.
 

Dose-response relationship

Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.

This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.

Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.

Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.

Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.

There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).

A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
 

Several limitations

The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).

The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.

The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.

However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.

The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.

There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
 

More data needed

In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”

However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.

They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.

They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.

“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.

For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.

The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.

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

Treatment with the thiazolidinedione pioglitazone may offer the greatest protection against dementia for older adults with newly diagnosed type 2 diabetes mellitus (T2DM) who have a history of stroke or ischemic heart disease, new research suggests.

Overall, in a large cohort study from South Korea, patients who took pioglitazone were 16% less likely to develop dementia over an average of 10 years than peers who did not take the drug.

However, the dementia risk reduction was 54% among those with ischemic heart disease and 43% among those with a history of stroke.

“Our study was to see the association between pioglitazone use and incidence of dementia, not how (with what mechanisms) this drug can suppress dementia pathology,” coinvestigator Eosu Kim, MD, PhD, Yonsei University, Seoul, South Korea, said in an interview.

However, “as we found this drug is more effective in diabetic patients who have blood circulation problems in the heart or brain than in those without such problems, we speculate that pioglitazone’s antidementia action may be related to improving blood vessel’s health,” Dr. Kim said.

This finding suggests that pioglitazone could be used as a personalized treatment approach for dementia prevention in this subgroup of patients with diabetes, the researchers noted.

The results were published online in Neurology.
 

Dose-response relationship

Risk for dementia is doubled in adults with T2DM, the investigators wrote. Prior studies have suggested that pioglitazone may protect against dementia, as well as a first or recurrent stroke, in patients with T2DM.

This led Dr. Kim and colleagues to examine the effects of pioglitazone on dementia risk overall and in relation to stroke and ischemic heart disease.

Using the national Korean health database, the researchers identified 91,218 adults aged 50 and older with new-onset T2DM who did not have dementia. A total of 3,467 were treated with pioglitazone.

Pioglitazone exposure was defined as a total cumulative daily dose of 90 or more calculated from all dispensations during 4 years after T2DM diagnosis, with outcomes assessed after this period.

Over an average of 10 years, 8.3% of pioglitazone users developed dementia, compared with 10.0% of nonusers.

There was a statistically significant 16% lower risk for developing all-cause dementia among pioglitazone users than among nonusers (adjusted hazard ratio, 0.84; 95% confidence interval, 0.75-0.95).

A dose-response relationship was evident; pioglitazone users who received the highest cumulative daily dose were at lower risk for dementia (aHR, 0.72; 95% CI, 0.55-0.94).
 

Several limitations

The reduced risk for dementia was more pronounced among patients who used pioglitazone for 4 years in comparison with patients who did not use the drug (aHR, 0.63; 95% CI, 0.44-0.90).

The apparent protective effect of pioglitazone with regard to dementia was greater among those with a history of ischemic heart disease (aHR, 0.46; 95% CI, 0.24-0.90) or stroke (aHR, 0.57; 95% CI, 0.38-0.86) before diabetes diagnosis.

The incidence of stroke was also reduced with pioglitazone use (aHR, 0.81; 95% CI, 0.66-1.0).

“These results provide valuable information on who could potentially benefit from pioglitazone use for prevention of dementia,” Dr. Kim said in a news release.

However, “the risk and benefit balance of long-term use of this drug to prevent dementia should be prospectively assessed,” he said in an interview.

The researchers cautioned that the study was observational; hence, the reported associations cannot address causal relationships. Also, because of the use of claims data, drug compliance could not be guaranteed, and exposure may have been overestimated.

There is also the potential for selection bias, and no information on apolipoprotein E was available, they noted.
 

More data needed

In an accompanying editorial, Colleen J. Maxwell, PhD, University of Waterloo (Ont.), and colleagues wrote that the results “not only support previous studies showing the potential cognitive benefit of pioglitazone but also extend our understanding of this benefit through the mediating effect of reducing ischemic stroke.”

However, because of their associated risks, which include fractures, weight gain, heart failure, and bladder cancer, thiazolidinediones are not currently favored in diabetes management guidelines – and their use has significantly declined since the mid to late 2000s, the editorialists noted.

They agreed that it will be important to reassess the risk-benefit profile of pioglitazone in T2DM as additional findings emerge.

They also noted that sodium-glucose cotransporter-2 inhibitors, which have significant cardiovascular and renal benefits and minimal side effects, may also lower the risk for dementia.

“As both pioglitazone and SGLT-2 inhibitors are second-line options for physicians, the current decision would easily be in favor of SGLT-2 inhibitors given their safety profile,” Dr. Maxwell and colleagues wrote.

For now, pioglitazone “should not be used to prevent dementia in patients with T2DM,” they concluded.

The study was supported by grants from the National Research Foundation of Korea funded by the Korean government and the Ministry of Health and Welfare. The investigators and editorialists report no relevant financial relationships.

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