Federal Practitioner

A simple urine test can accurately diagnose urothelial carcinoma as well as predict the risk for recurrence for those under surveillance, according to findings from a recent validation study.

The urinary comprehensive genomic profiling (uCGP) assay (UroAmp, Convergent Genomics) had a specificity of 95% and sensitivity of 90% for an initial diagnosis of urothelial carcinoma in patients with hematuria – identifying 95 of 100 people with urothelial carcinoma and 90 of 100 patients without the disease.

For patients under surveillance for urothelial cancer recurrence, the test was six times more accurate than traditional clinical risk factors for predicting recurrence.

“Considering its performance in multiple areas of urothelial carcinoma diagnosis and monitoring, uCGP shows great promise to enhance delivery of risk-stratified care,” Keyan Salari, MD, PhD, director of the prostate cancer genetics program at Massachusetts General Hospital in Boston, and colleagues wrote in a study published in Clinical Cancer Research.

“The idea is that this could be used as kind of a first-pass screening tool for patients with hematuria that could potentially obviate the need for undergoing imaging such as CT scans or cystoscopy,” Dr. Salari said in an interview.

The uCGP test is a next-generation sequencing assay that identifies mutations in 60 genes associated with bladder cancer. An earlier analysis evaluating the test as a potential screening tool focused on 10 key genes covered in the assay. The study found the test accurately predicted future bladder cancer in 66% of urine samples, including some that had been collected more than a decade prior to being tested.

In the current case-control study, Dr. Salari and colleagues used a total of 581 samples – 333 samples for classifying disease and developing algorithms for initial diagnosis, surveillance, and molecular-grade prediction, as well as 248 samples for blinded validation. The test’s performance was evaluated by calculating sensitivity, specificity, positive predictive value, and negative predictive value.

Overall, the test demonstrated a specificity of 95% and sensitivity of 90% for an initial urothelial carcinoma diagnosis, but performed even better for the most aggressive tumors, with 100% sensitivity for diagnosing high-grade urothelial carcinoma and muscle-invasive tumors.

On the diagnosis front, the test had a positive predictive value of 88% and a negative predictive value of 99%.

Among patients under surveillance, the test predicted the risk of recurrence significantly better than standard clinical risk factors (hazard ratio, 6.2). The test demonstrated a positive predictive value similar to that observed for cytology (45% vs. 42%) but a much higher sensitivity (79% vs. 25%). The test also demonstrated a negative predictive value of 91% for recurrence.

The molecular-grade algorithm performed well, with a positive predictive value for high-grade disease of 88% and a specificity of 95% in the validation cohort.

Overall, “uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients,” the authors concluded. The test is not currently reimbursed by Medicare, but negotiations with third-party payers are reportedly underway.

The study was supported by the National Cancer Institute. Dr. Salari reported grants from Convergent Genomics during the conduct of the study as well as grants from Urology Care Foundation and Prostate Cancer Foundation, and personal fees from OrigiMed outside the submitted work. Several coauthors are employees and stockholders of Convergent Genomics.

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

A simple urine test can accurately diagnose urothelial carcinoma as well as predict the risk for recurrence for those under surveillance, according to findings from a recent validation study.

The urinary comprehensive genomic profiling (uCGP) assay (UroAmp, Convergent Genomics) had a specificity of 95% and sensitivity of 90% for an initial diagnosis of urothelial carcinoma in patients with hematuria – identifying 95 of 100 people with urothelial carcinoma and 90 of 100 patients without the disease.

For patients under surveillance for urothelial cancer recurrence, the test was six times more accurate than traditional clinical risk factors for predicting recurrence.

“Considering its performance in multiple areas of urothelial carcinoma diagnosis and monitoring, uCGP shows great promise to enhance delivery of risk-stratified care,” Keyan Salari, MD, PhD, director of the prostate cancer genetics program at Massachusetts General Hospital in Boston, and colleagues wrote in a study published in Clinical Cancer Research.

“The idea is that this could be used as kind of a first-pass screening tool for patients with hematuria that could potentially obviate the need for undergoing imaging such as CT scans or cystoscopy,” Dr. Salari said in an interview.

The uCGP test is a next-generation sequencing assay that identifies mutations in 60 genes associated with bladder cancer. An earlier analysis evaluating the test as a potential screening tool focused on 10 key genes covered in the assay. The study found the test accurately predicted future bladder cancer in 66% of urine samples, including some that had been collected more than a decade prior to being tested.

In the current case-control study, Dr. Salari and colleagues used a total of 581 samples – 333 samples for classifying disease and developing algorithms for initial diagnosis, surveillance, and molecular-grade prediction, as well as 248 samples for blinded validation. The test’s performance was evaluated by calculating sensitivity, specificity, positive predictive value, and negative predictive value.

Overall, the test demonstrated a specificity of 95% and sensitivity of 90% for an initial urothelial carcinoma diagnosis, but performed even better for the most aggressive tumors, with 100% sensitivity for diagnosing high-grade urothelial carcinoma and muscle-invasive tumors.

On the diagnosis front, the test had a positive predictive value of 88% and a negative predictive value of 99%.

Among patients under surveillance, the test predicted the risk of recurrence significantly better than standard clinical risk factors (hazard ratio, 6.2). The test demonstrated a positive predictive value similar to that observed for cytology (45% vs. 42%) but a much higher sensitivity (79% vs. 25%). The test also demonstrated a negative predictive value of 91% for recurrence.

The molecular-grade algorithm performed well, with a positive predictive value for high-grade disease of 88% and a specificity of 95% in the validation cohort.

Overall, “uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients,” the authors concluded. The test is not currently reimbursed by Medicare, but negotiations with third-party payers are reportedly underway.

The study was supported by the National Cancer Institute. Dr. Salari reported grants from Convergent Genomics during the conduct of the study as well as grants from Urology Care Foundation and Prostate Cancer Foundation, and personal fees from OrigiMed outside the submitted work. Several coauthors are employees and stockholders of Convergent Genomics.

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

A simple urine test can accurately diagnose urothelial carcinoma as well as predict the risk for recurrence for those under surveillance, according to findings from a recent validation study.

The urinary comprehensive genomic profiling (uCGP) assay (UroAmp, Convergent Genomics) had a specificity of 95% and sensitivity of 90% for an initial diagnosis of urothelial carcinoma in patients with hematuria – identifying 95 of 100 people with urothelial carcinoma and 90 of 100 patients without the disease.

For patients under surveillance for urothelial cancer recurrence, the test was six times more accurate than traditional clinical risk factors for predicting recurrence.

“Considering its performance in multiple areas of urothelial carcinoma diagnosis and monitoring, uCGP shows great promise to enhance delivery of risk-stratified care,” Keyan Salari, MD, PhD, director of the prostate cancer genetics program at Massachusetts General Hospital in Boston, and colleagues wrote in a study published in Clinical Cancer Research.

“The idea is that this could be used as kind of a first-pass screening tool for patients with hematuria that could potentially obviate the need for undergoing imaging such as CT scans or cystoscopy,” Dr. Salari said in an interview.

The uCGP test is a next-generation sequencing assay that identifies mutations in 60 genes associated with bladder cancer. An earlier analysis evaluating the test as a potential screening tool focused on 10 key genes covered in the assay. The study found the test accurately predicted future bladder cancer in 66% of urine samples, including some that had been collected more than a decade prior to being tested.

In the current case-control study, Dr. Salari and colleagues used a total of 581 samples – 333 samples for classifying disease and developing algorithms for initial diagnosis, surveillance, and molecular-grade prediction, as well as 248 samples for blinded validation. The test’s performance was evaluated by calculating sensitivity, specificity, positive predictive value, and negative predictive value.

Overall, the test demonstrated a specificity of 95% and sensitivity of 90% for an initial urothelial carcinoma diagnosis, but performed even better for the most aggressive tumors, with 100% sensitivity for diagnosing high-grade urothelial carcinoma and muscle-invasive tumors.

On the diagnosis front, the test had a positive predictive value of 88% and a negative predictive value of 99%.

Among patients under surveillance, the test predicted the risk of recurrence significantly better than standard clinical risk factors (hazard ratio, 6.2). The test demonstrated a positive predictive value similar to that observed for cytology (45% vs. 42%) but a much higher sensitivity (79% vs. 25%). The test also demonstrated a negative predictive value of 91% for recurrence.

The molecular-grade algorithm performed well, with a positive predictive value for high-grade disease of 88% and a specificity of 95% in the validation cohort.

Overall, “uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients,” the authors concluded. The test is not currently reimbursed by Medicare, but negotiations with third-party payers are reportedly underway.

The study was supported by the National Cancer Institute. Dr. Salari reported grants from Convergent Genomics during the conduct of the study as well as grants from Urology Care Foundation and Prostate Cancer Foundation, and personal fees from OrigiMed outside the submitted work. Several coauthors are employees and stockholders of Convergent Genomics.

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

This transcript from Impact Factor has been edited for clarity.

If you are my age or older, and like me, you are something of a rule follower, then you’re getting screened for various cancers.

Colonoscopies, mammograms, cervical cancer screening, chest CTs for people with a significant smoking history. The tests are done and usually, but not always, they are negative. And if positive, usually, but not always, follow-up tests are negative, and if they aren’t and a new cancer is diagnosed you tell yourself, Well, at least we caught it early. Isn’t it good that I’m a rule follower? My life was just saved.

But it turns out, proving that cancer screening actually saves lives is quite difficult. Is it possible that all this screening is for nothing?

The benefits, risks, or perhaps futility of cancer screening is in the news this week because of this article, appearing in JAMA Internal Medicine.

It’s a meta-analysis of very specific randomized trials of cancer screening modalities and concludes that, with the exception of sigmoidoscopy for colon cancer screening, none of them meaningfully change life expectancy.

Now – a bit of inside baseball here – I almost never choose to discuss meta-analyses on Impact Factor. It’s hard enough to dig deep into the methodology of a single study, but with a meta-analysis, you’re sort of obligated to review all the included studies, and, what’s worse, the studies that were not included but might bear on the central question.

In this case, though, the topic is important enough to think about a bit more, and the conclusions have large enough implications for public health that we should question them a bit.

First, let’s run down the study as presented.

The authors searched for randomized trials of cancer screening modalities. This is important, and I think appropriate. They wanted studies that took some people and assigned them to screening, and some people to no screening – avoiding the confounding that would come from observational data (rule followers like me tend to live longer owing to a variety of healthful behaviors, not just cancer screening).

Dr. F. Perry Wilson

JAMA Internal Medicine

Dr. F. Perry Wilson

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and his new book, How Medicine Works and When It Doesn’t, is available now. He has disclosed no relevant financial relationships.

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

This transcript from Impact Factor has been edited for clarity.

If you are my age or older, and like me, you are something of a rule follower, then you’re getting screened for various cancers.

Colonoscopies, mammograms, cervical cancer screening, chest CTs for people with a significant smoking history. The tests are done and usually, but not always, they are negative. And if positive, usually, but not always, follow-up tests are negative, and if they aren’t and a new cancer is diagnosed you tell yourself, Well, at least we caught it early. Isn’t it good that I’m a rule follower? My life was just saved.

But it turns out, proving that cancer screening actually saves lives is quite difficult. Is it possible that all this screening is for nothing?

The benefits, risks, or perhaps futility of cancer screening is in the news this week because of this article, appearing in JAMA Internal Medicine.

It’s a meta-analysis of very specific randomized trials of cancer screening modalities and concludes that, with the exception of sigmoidoscopy for colon cancer screening, none of them meaningfully change life expectancy.

Now – a bit of inside baseball here – I almost never choose to discuss meta-analyses on Impact Factor. It’s hard enough to dig deep into the methodology of a single study, but with a meta-analysis, you’re sort of obligated to review all the included studies, and, what’s worse, the studies that were not included but might bear on the central question.

In this case, though, the topic is important enough to think about a bit more, and the conclusions have large enough implications for public health that we should question them a bit.

First, let’s run down the study as presented.

The authors searched for randomized trials of cancer screening modalities. This is important, and I think appropriate. They wanted studies that took some people and assigned them to screening, and some people to no screening – avoiding the confounding that would come from observational data (rule followers like me tend to live longer owing to a variety of healthful behaviors, not just cancer screening).

Dr. F. Perry Wilson

JAMA Internal Medicine

Dr. F. Perry Wilson

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and his new book, How Medicine Works and When It Doesn’t, is available now. He has disclosed no relevant financial relationships.

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

This transcript from Impact Factor has been edited for clarity.

If you are my age or older, and like me, you are something of a rule follower, then you’re getting screened for various cancers.

Colonoscopies, mammograms, cervical cancer screening, chest CTs for people with a significant smoking history. The tests are done and usually, but not always, they are negative. And if positive, usually, but not always, follow-up tests are negative, and if they aren’t and a new cancer is diagnosed you tell yourself, Well, at least we caught it early. Isn’t it good that I’m a rule follower? My life was just saved.

But it turns out, proving that cancer screening actually saves lives is quite difficult. Is it possible that all this screening is for nothing?

The benefits, risks, or perhaps futility of cancer screening is in the news this week because of this article, appearing in JAMA Internal Medicine.

It’s a meta-analysis of very specific randomized trials of cancer screening modalities and concludes that, with the exception of sigmoidoscopy for colon cancer screening, none of them meaningfully change life expectancy.

Now – a bit of inside baseball here – I almost never choose to discuss meta-analyses on Impact Factor. It’s hard enough to dig deep into the methodology of a single study, but with a meta-analysis, you’re sort of obligated to review all the included studies, and, what’s worse, the studies that were not included but might bear on the central question.

In this case, though, the topic is important enough to think about a bit more, and the conclusions have large enough implications for public health that we should question them a bit.

First, let’s run down the study as presented.

The authors searched for randomized trials of cancer screening modalities. This is important, and I think appropriate. They wanted studies that took some people and assigned them to screening, and some people to no screening – avoiding the confounding that would come from observational data (rule followers like me tend to live longer owing to a variety of healthful behaviors, not just cancer screening).

Dr. F. Perry Wilson

JAMA Internal Medicine

Dr. F. Perry Wilson

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and on Medscape. He tweets @fperrywilson and his new book, How Medicine Works and When It Doesn’t, is available now. He has disclosed no relevant financial relationships.

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

People on Medicare may in 2026 see prices drop for 10 medicines, including pricey diabetes, cancer, blood clot, and arthritis treatments, if advocates for federal drug-price negotiations can implement their plans amid tough opposition.

The Biden administration on Aug. 29 revealed the first 10 drugs selected for direct Medicare price negotiations in accordance with a process mandated by the Inflation Reduction Act of 2022.

It’s unclear at this time, though, how these negotiations will play out. The Chamber of Commerce has sided with pharmaceutical companies in bids to block direct Medicare negotiation of drug prices. Many influential Republicans in Congress oppose this plan, which has deep support from both Democrats and AARP.

While facing strong opposition to negotiations, the Centers for Medicare & Medicaid Services sought in its announcement to illustrate the high costs of the selected medicines.

CMS provided data on total Part D costs for selected medicines for the period from June 2022 to May 2023, along with tallies of the number of people taking these drugs. The 10 selected medicines are as follows:
 

• Eliquis (generic name: apixaban), used to prevent and treat serious blood clots. It is taken by about 3.7 million people through Part D plans. The estimated cost is $16.4 billion.
• Jardiance (generic name: empagliflozin), used for diabetes and heart failure. It is taken by almost 1.6 million people through Part D plans. The estimated cost is $7.06 billion.
• Xarelto (generic name: rivaroxaban), used for blood clots. It is taken by about 1.3 million people through Part D plans. The estimated cost is $6 billion.
• Januvia (generic name: sitagliptin), used for diabetes. It is taken by about 869,00 people through Part D plans. The estimated cost is $4.1 billion.
• Farxiga (generic name: dapagliflozin), used for diabetes, heart failure, and chronic kidney disease. It is taken by about 799,000 people through Part D plans. The estimated cost is almost $3.3 billion.
• Entresto (generic name: sacubitril/valsartan), used to treat heart failure. It is taken by 587,000 people through Part D plans. The estimated cost is $2.9 billion.
• Enbrel( generic name: etanercept), used for rheumatoid arthritis, psoriasis, and psoriatic arthritis. It is taken by 48,000 people through Part D plans. The estimated cost is $2.8 billion.
• Imbruvica (generic name: ibrutinib), used to treat some blood cancers. It is taken by about 20,000 people in Part D plans. The estimated cost is $2.7 billion.
• Stelara (generic name: ustekinumab), used to treat plaque psoriasis, psoriatic arthritis, or certain bowel conditions (Crohn’s disease, ulcerative colitis). It is used by about 22,000 people through Part D plans. The estimated cost is $2.6 billion.
• Fiasp; Fiasp FlexTouch; Fiasp PenFill; NovoLog; NovoLog FlexPen; NovoLog PenFill. These are forms of insulin used to treat diabetes. They are used by about 777,000 people through Part D plans. The estimated cost is $2.6 billion.

A vocal critic of Medicare drug negotiations, Joel White, president of the Council for Affordable Health Coverage, called the announcement of the 10 drugs selected for negotiation “a hollow victory lap.” A former Republican staffer on the House Ways and Means Committee, Mr. White aided with the development of the Medicare Part D plans and has kept tabs on the pharmacy programs since its launch in 2006.

“No one’s costs will go down now or for years because of this announcement” about Part D negotiations, Mr. White said in a statement.

According to its website, CAHC includes among its members the American Academy of Ophthalmology as well as some patient groups, drugmakers, such as Johnson & Johnson, and insurers and industry groups, such as the National Association of Manufacturers.

Separately, the influential Chamber of Commerce is making a strong push to at least delay the implementation of the Medicare Part D drug negotiations. On Aug. 28, the chamber released a letter sent to the Biden administration, raising concerns about a “rush” to implement the provisions of the Inflation Reduction Act.

The chamber also has filed suit to challenge the drug negotiation provisions of the Inflation Reduction Act, requesting that the court issue a preliminary injunction by Oct. 1, 2023.

Other pending legal challenges to direct Medicare drug negotiations include suits filed by Merck, Bristol-Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, and AstraZeneca, according to an email from Pharmaceutical Research and Manufacturers of America. PhRMA also said it is a party to a case.

In addition, the three congressional Republicans with most direct influence over Medicare policy issued on Aug. 29 a joint statement outlining their objections to the planned negotiations on drug prices.

This drug-negotiation proposal is “an unworkable, legally dubious scheme that will lead to higher prices for new drugs coming to market, stifle the development of new cures, and destroy jobs,” said House Energy and Commerce Committee Chair Cathy McMorris Rodgers (R-Wash.), House Ways and Means Committee Chair Jason Smith (R-Mo.), and Senate Finance Committee Ranking Member Mike Crapo (R-Idaho).

Democrats were equally firm and vocal in their support of the negotiations. Senate Finance Chairman Ron Wyden (D-Ore.) issued a statement on Aug. 29 that said the release of the list of the 10 drugs selected for Medicare drug negotiations is part of a “seismic shift in the relationship between Big Pharma, the federal government, and seniors who are counting on lower prices.

“I will be following the negotiation process closely and will fight any attempt by Big Pharma to undo or undermine the progress that’s been made,” Mr. Wyden said.

In addition, AARP issued a statement of its continued support for Medicare drug negotiations.

“The No. 1 reason seniors skip or ration their prescriptions is because they can’t afford them. This must stop,” said AARP executive vice president and chief advocacy and engagement officer Nancy LeaMond in the statement. “The big drug companies and their allies continue suing to overturn the Medicare drug price negotiation program to keep up their price gouging. We can’t allow seniors to be Big Pharma’s cash machine anymore.”

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

People on Medicare may in 2026 see prices drop for 10 medicines, including pricey diabetes, cancer, blood clot, and arthritis treatments, if advocates for federal drug-price negotiations can implement their plans amid tough opposition.

The Biden administration on Aug. 29 revealed the first 10 drugs selected for direct Medicare price negotiations in accordance with a process mandated by the Inflation Reduction Act of 2022.

It’s unclear at this time, though, how these negotiations will play out. The Chamber of Commerce has sided with pharmaceutical companies in bids to block direct Medicare negotiation of drug prices. Many influential Republicans in Congress oppose this plan, which has deep support from both Democrats and AARP.

While facing strong opposition to negotiations, the Centers for Medicare & Medicaid Services sought in its announcement to illustrate the high costs of the selected medicines.

CMS provided data on total Part D costs for selected medicines for the period from June 2022 to May 2023, along with tallies of the number of people taking these drugs. The 10 selected medicines are as follows:
 

• Eliquis (generic name: apixaban), used to prevent and treat serious blood clots. It is taken by about 3.7 million people through Part D plans. The estimated cost is $16.4 billion.
• Jardiance (generic name: empagliflozin), used for diabetes and heart failure. It is taken by almost 1.6 million people through Part D plans. The estimated cost is $7.06 billion.
• Xarelto (generic name: rivaroxaban), used for blood clots. It is taken by about 1.3 million people through Part D plans. The estimated cost is $6 billion.
• Januvia (generic name: sitagliptin), used for diabetes. It is taken by about 869,00 people through Part D plans. The estimated cost is $4.1 billion.
• Farxiga (generic name: dapagliflozin), used for diabetes, heart failure, and chronic kidney disease. It is taken by about 799,000 people through Part D plans. The estimated cost is almost $3.3 billion.
• Entresto (generic name: sacubitril/valsartan), used to treat heart failure. It is taken by 587,000 people through Part D plans. The estimated cost is $2.9 billion.
• Enbrel( generic name: etanercept), used for rheumatoid arthritis, psoriasis, and psoriatic arthritis. It is taken by 48,000 people through Part D plans. The estimated cost is $2.8 billion.
• Imbruvica (generic name: ibrutinib), used to treat some blood cancers. It is taken by about 20,000 people in Part D plans. The estimated cost is $2.7 billion.
• Stelara (generic name: ustekinumab), used to treat plaque psoriasis, psoriatic arthritis, or certain bowel conditions (Crohn’s disease, ulcerative colitis). It is used by about 22,000 people through Part D plans. The estimated cost is $2.6 billion.
• Fiasp; Fiasp FlexTouch; Fiasp PenFill; NovoLog; NovoLog FlexPen; NovoLog PenFill. These are forms of insulin used to treat diabetes. They are used by about 777,000 people through Part D plans. The estimated cost is $2.6 billion.

A vocal critic of Medicare drug negotiations, Joel White, president of the Council for Affordable Health Coverage, called the announcement of the 10 drugs selected for negotiation “a hollow victory lap.” A former Republican staffer on the House Ways and Means Committee, Mr. White aided with the development of the Medicare Part D plans and has kept tabs on the pharmacy programs since its launch in 2006.

“No one’s costs will go down now or for years because of this announcement” about Part D negotiations, Mr. White said in a statement.

According to its website, CAHC includes among its members the American Academy of Ophthalmology as well as some patient groups, drugmakers, such as Johnson & Johnson, and insurers and industry groups, such as the National Association of Manufacturers.

Separately, the influential Chamber of Commerce is making a strong push to at least delay the implementation of the Medicare Part D drug negotiations. On Aug. 28, the chamber released a letter sent to the Biden administration, raising concerns about a “rush” to implement the provisions of the Inflation Reduction Act.

The chamber also has filed suit to challenge the drug negotiation provisions of the Inflation Reduction Act, requesting that the court issue a preliminary injunction by Oct. 1, 2023.

Other pending legal challenges to direct Medicare drug negotiations include suits filed by Merck, Bristol-Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, and AstraZeneca, according to an email from Pharmaceutical Research and Manufacturers of America. PhRMA also said it is a party to a case.

In addition, the three congressional Republicans with most direct influence over Medicare policy issued on Aug. 29 a joint statement outlining their objections to the planned negotiations on drug prices.

This drug-negotiation proposal is “an unworkable, legally dubious scheme that will lead to higher prices for new drugs coming to market, stifle the development of new cures, and destroy jobs,” said House Energy and Commerce Committee Chair Cathy McMorris Rodgers (R-Wash.), House Ways and Means Committee Chair Jason Smith (R-Mo.), and Senate Finance Committee Ranking Member Mike Crapo (R-Idaho).

Democrats were equally firm and vocal in their support of the negotiations. Senate Finance Chairman Ron Wyden (D-Ore.) issued a statement on Aug. 29 that said the release of the list of the 10 drugs selected for Medicare drug negotiations is part of a “seismic shift in the relationship between Big Pharma, the federal government, and seniors who are counting on lower prices.

“I will be following the negotiation process closely and will fight any attempt by Big Pharma to undo or undermine the progress that’s been made,” Mr. Wyden said.

In addition, AARP issued a statement of its continued support for Medicare drug negotiations.

“The No. 1 reason seniors skip or ration their prescriptions is because they can’t afford them. This must stop,” said AARP executive vice president and chief advocacy and engagement officer Nancy LeaMond in the statement. “The big drug companies and their allies continue suing to overturn the Medicare drug price negotiation program to keep up their price gouging. We can’t allow seniors to be Big Pharma’s cash machine anymore.”

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

People on Medicare may in 2026 see prices drop for 10 medicines, including pricey diabetes, cancer, blood clot, and arthritis treatments, if advocates for federal drug-price negotiations can implement their plans amid tough opposition.

The Biden administration on Aug. 29 revealed the first 10 drugs selected for direct Medicare price negotiations in accordance with a process mandated by the Inflation Reduction Act of 2022.

It’s unclear at this time, though, how these negotiations will play out. The Chamber of Commerce has sided with pharmaceutical companies in bids to block direct Medicare negotiation of drug prices. Many influential Republicans in Congress oppose this plan, which has deep support from both Democrats and AARP.

While facing strong opposition to negotiations, the Centers for Medicare & Medicaid Services sought in its announcement to illustrate the high costs of the selected medicines.

CMS provided data on total Part D costs for selected medicines for the period from June 2022 to May 2023, along with tallies of the number of people taking these drugs. The 10 selected medicines are as follows:
 

• Eliquis (generic name: apixaban), used to prevent and treat serious blood clots. It is taken by about 3.7 million people through Part D plans. The estimated cost is $16.4 billion.
• Jardiance (generic name: empagliflozin), used for diabetes and heart failure. It is taken by almost 1.6 million people through Part D plans. The estimated cost is $7.06 billion.
• Xarelto (generic name: rivaroxaban), used for blood clots. It is taken by about 1.3 million people through Part D plans. The estimated cost is $6 billion.
• Januvia (generic name: sitagliptin), used for diabetes. It is taken by about 869,00 people through Part D plans. The estimated cost is $4.1 billion.
• Farxiga (generic name: dapagliflozin), used for diabetes, heart failure, and chronic kidney disease. It is taken by about 799,000 people through Part D plans. The estimated cost is almost $3.3 billion.
• Entresto (generic name: sacubitril/valsartan), used to treat heart failure. It is taken by 587,000 people through Part D plans. The estimated cost is $2.9 billion.
• Enbrel( generic name: etanercept), used for rheumatoid arthritis, psoriasis, and psoriatic arthritis. It is taken by 48,000 people through Part D plans. The estimated cost is $2.8 billion.
• Imbruvica (generic name: ibrutinib), used to treat some blood cancers. It is taken by about 20,000 people in Part D plans. The estimated cost is $2.7 billion.
• Stelara (generic name: ustekinumab), used to treat plaque psoriasis, psoriatic arthritis, or certain bowel conditions (Crohn’s disease, ulcerative colitis). It is used by about 22,000 people through Part D plans. The estimated cost is $2.6 billion.
• Fiasp; Fiasp FlexTouch; Fiasp PenFill; NovoLog; NovoLog FlexPen; NovoLog PenFill. These are forms of insulin used to treat diabetes. They are used by about 777,000 people through Part D plans. The estimated cost is $2.6 billion.

A vocal critic of Medicare drug negotiations, Joel White, president of the Council for Affordable Health Coverage, called the announcement of the 10 drugs selected for negotiation “a hollow victory lap.” A former Republican staffer on the House Ways and Means Committee, Mr. White aided with the development of the Medicare Part D plans and has kept tabs on the pharmacy programs since its launch in 2006.

“No one’s costs will go down now or for years because of this announcement” about Part D negotiations, Mr. White said in a statement.

According to its website, CAHC includes among its members the American Academy of Ophthalmology as well as some patient groups, drugmakers, such as Johnson & Johnson, and insurers and industry groups, such as the National Association of Manufacturers.

Separately, the influential Chamber of Commerce is making a strong push to at least delay the implementation of the Medicare Part D drug negotiations. On Aug. 28, the chamber released a letter sent to the Biden administration, raising concerns about a “rush” to implement the provisions of the Inflation Reduction Act.

The chamber also has filed suit to challenge the drug negotiation provisions of the Inflation Reduction Act, requesting that the court issue a preliminary injunction by Oct. 1, 2023.

Other pending legal challenges to direct Medicare drug negotiations include suits filed by Merck, Bristol-Myers Squibb, Johnson & Johnson, Boehringer Ingelheim, and AstraZeneca, according to an email from Pharmaceutical Research and Manufacturers of America. PhRMA also said it is a party to a case.

In addition, the three congressional Republicans with most direct influence over Medicare policy issued on Aug. 29 a joint statement outlining their objections to the planned negotiations on drug prices.

This drug-negotiation proposal is “an unworkable, legally dubious scheme that will lead to higher prices for new drugs coming to market, stifle the development of new cures, and destroy jobs,” said House Energy and Commerce Committee Chair Cathy McMorris Rodgers (R-Wash.), House Ways and Means Committee Chair Jason Smith (R-Mo.), and Senate Finance Committee Ranking Member Mike Crapo (R-Idaho).

Democrats were equally firm and vocal in their support of the negotiations. Senate Finance Chairman Ron Wyden (D-Ore.) issued a statement on Aug. 29 that said the release of the list of the 10 drugs selected for Medicare drug negotiations is part of a “seismic shift in the relationship between Big Pharma, the federal government, and seniors who are counting on lower prices.

“I will be following the negotiation process closely and will fight any attempt by Big Pharma to undo or undermine the progress that’s been made,” Mr. Wyden said.

In addition, AARP issued a statement of its continued support for Medicare drug negotiations.

“The No. 1 reason seniors skip or ration their prescriptions is because they can’t afford them. This must stop,” said AARP executive vice president and chief advocacy and engagement officer Nancy LeaMond in the statement. “The big drug companies and their allies continue suing to overturn the Medicare drug price negotiation program to keep up their price gouging. We can’t allow seniors to be Big Pharma’s cash machine anymore.”

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

Depression and anxiety were not associated with outcomes for most cancer types, including breast cancer, prostate cancer, and alcohol-related cancer, according to findings from a large, individual participant data meta-analysis.

An exception was for lung and smoking-related cancers, but key covariates appeared to explain the relationship between depression, anxiety, and these cancer types, the investigators reported.

The findings challenge a common theory that depression and anxiety increase cancer risk and should “change current thinking,” they argue.

“Our results may come as a relief to many patients with cancer who believe their diagnosis is attributed to previous anxiety or depression,” first author Lonneke A. van Tuijl, PhD, of the University of Groningen and Utrecht University, the Netherlands, noted in a press release.

Analyses included data from up to nearly 320,000 individuals from the 18 prospective cohorts included in the international Psychosocial Factors and Cancer Incidence (PSY-CA) consortium. The cohorts are from studies conducted in the Netherlands, United Kingdom, Norway, and Canada, and included 25,803 patients with cancer. During follow-up of up to 26 years and more than 3.2 million person-years, depression and anxiety symptoms and diagnoses showed no association with overall breast, prostate, colorectal, and alcohol-related cancers (hazard ratios, 0.98-1.05).

For the specific cancer types, the investigators “found no evidence for an association between depression or anxiety and the incidence of colorectal cancer (HRs, 0.88-1.13), prostate cancer (HRs, 0.97-1.17), or alcohol-related cancers (HRs, 0.97-1.06).”

“For breast cancer, all pooled HRs were consistently negative but mean pooled HRs were close to 1 (HRs, 0.92-0.98) and the upper limit of the 95% confidence intervals all exceeded 1 (with the exception of anxiety symptoms),” they noted.

An increase in risk observed between depression and anxiety symptoms and diagnoses and lung cancer (HRs, 1.12-1.60) and smoking-related cancers (HRs, 1.06-1.60), in minimally adjusted models, was substantially attenuated after adjusting for known risk factors such as smoking, alcohol use, and body mass index (HRs, 1.04-1.08), the investigators reported.

The findings were published online in Cancer.

“Depression and anxiety have long been hypothesized to increase the risk for cancer. It is thought that the increased cancer risk can occur via several pathways, including health behaviors, or by influencing mutation, viral oncogenes, cell proliferation, or DNA repair,” the authors explained, noting that “[c]onclusions drawn in meta-analyses vary greatly, with some supporting an association between depression, anxiety, and cancer incidence and others finding no or a negligible association.”

The current findings “may help health professionals to alleviate feelings of guilt and self-blame in patients with cancer who attribute their diagnosis to previous depression or anxiety,” they said, noting that the findings “also underscore the importance of addressing tobacco smoking and other unhealthy behaviors – including those that may develop as a result of anxiety or depression.”

“However, further research is needed to understand exactly how depression, anxiety, health behaviors, and lung cancer are related,” said Dr. Tuijl.

Dr. Tuijl has received grants and travel support from the Dutch Cancer Society (KWF).
 

Depression and anxiety were not associated with outcomes for most cancer types, including breast cancer, prostate cancer, and alcohol-related cancer, according to findings from a large, individual participant data meta-analysis.

An exception was for lung and smoking-related cancers, but key covariates appeared to explain the relationship between depression, anxiety, and these cancer types, the investigators reported.

The findings challenge a common theory that depression and anxiety increase cancer risk and should “change current thinking,” they argue.

“Our results may come as a relief to many patients with cancer who believe their diagnosis is attributed to previous anxiety or depression,” first author Lonneke A. van Tuijl, PhD, of the University of Groningen and Utrecht University, the Netherlands, noted in a press release.

Analyses included data from up to nearly 320,000 individuals from the 18 prospective cohorts included in the international Psychosocial Factors and Cancer Incidence (PSY-CA) consortium. The cohorts are from studies conducted in the Netherlands, United Kingdom, Norway, and Canada, and included 25,803 patients with cancer. During follow-up of up to 26 years and more than 3.2 million person-years, depression and anxiety symptoms and diagnoses showed no association with overall breast, prostate, colorectal, and alcohol-related cancers (hazard ratios, 0.98-1.05).

For the specific cancer types, the investigators “found no evidence for an association between depression or anxiety and the incidence of colorectal cancer (HRs, 0.88-1.13), prostate cancer (HRs, 0.97-1.17), or alcohol-related cancers (HRs, 0.97-1.06).”

“For breast cancer, all pooled HRs were consistently negative but mean pooled HRs were close to 1 (HRs, 0.92-0.98) and the upper limit of the 95% confidence intervals all exceeded 1 (with the exception of anxiety symptoms),” they noted.

An increase in risk observed between depression and anxiety symptoms and diagnoses and lung cancer (HRs, 1.12-1.60) and smoking-related cancers (HRs, 1.06-1.60), in minimally adjusted models, was substantially attenuated after adjusting for known risk factors such as smoking, alcohol use, and body mass index (HRs, 1.04-1.08), the investigators reported.

The findings were published online in Cancer.

“Depression and anxiety have long been hypothesized to increase the risk for cancer. It is thought that the increased cancer risk can occur via several pathways, including health behaviors, or by influencing mutation, viral oncogenes, cell proliferation, or DNA repair,” the authors explained, noting that “[c]onclusions drawn in meta-analyses vary greatly, with some supporting an association between depression, anxiety, and cancer incidence and others finding no or a negligible association.”

The current findings “may help health professionals to alleviate feelings of guilt and self-blame in patients with cancer who attribute their diagnosis to previous depression or anxiety,” they said, noting that the findings “also underscore the importance of addressing tobacco smoking and other unhealthy behaviors – including those that may develop as a result of anxiety or depression.”

“However, further research is needed to understand exactly how depression, anxiety, health behaviors, and lung cancer are related,” said Dr. Tuijl.

Dr. Tuijl has received grants and travel support from the Dutch Cancer Society (KWF).
 

Depression and anxiety were not associated with outcomes for most cancer types, including breast cancer, prostate cancer, and alcohol-related cancer, according to findings from a large, individual participant data meta-analysis.

An exception was for lung and smoking-related cancers, but key covariates appeared to explain the relationship between depression, anxiety, and these cancer types, the investigators reported.

The findings challenge a common theory that depression and anxiety increase cancer risk and should “change current thinking,” they argue.

“Our results may come as a relief to many patients with cancer who believe their diagnosis is attributed to previous anxiety or depression,” first author Lonneke A. van Tuijl, PhD, of the University of Groningen and Utrecht University, the Netherlands, noted in a press release.

Analyses included data from up to nearly 320,000 individuals from the 18 prospective cohorts included in the international Psychosocial Factors and Cancer Incidence (PSY-CA) consortium. The cohorts are from studies conducted in the Netherlands, United Kingdom, Norway, and Canada, and included 25,803 patients with cancer. During follow-up of up to 26 years and more than 3.2 million person-years, depression and anxiety symptoms and diagnoses showed no association with overall breast, prostate, colorectal, and alcohol-related cancers (hazard ratios, 0.98-1.05).

For the specific cancer types, the investigators “found no evidence for an association between depression or anxiety and the incidence of colorectal cancer (HRs, 0.88-1.13), prostate cancer (HRs, 0.97-1.17), or alcohol-related cancers (HRs, 0.97-1.06).”

“For breast cancer, all pooled HRs were consistently negative but mean pooled HRs were close to 1 (HRs, 0.92-0.98) and the upper limit of the 95% confidence intervals all exceeded 1 (with the exception of anxiety symptoms),” they noted.

An increase in risk observed between depression and anxiety symptoms and diagnoses and lung cancer (HRs, 1.12-1.60) and smoking-related cancers (HRs, 1.06-1.60), in minimally adjusted models, was substantially attenuated after adjusting for known risk factors such as smoking, alcohol use, and body mass index (HRs, 1.04-1.08), the investigators reported.

The findings were published online in Cancer.

“Depression and anxiety have long been hypothesized to increase the risk for cancer. It is thought that the increased cancer risk can occur via several pathways, including health behaviors, or by influencing mutation, viral oncogenes, cell proliferation, or DNA repair,” the authors explained, noting that “[c]onclusions drawn in meta-analyses vary greatly, with some supporting an association between depression, anxiety, and cancer incidence and others finding no or a negligible association.”

The current findings “may help health professionals to alleviate feelings of guilt and self-blame in patients with cancer who attribute their diagnosis to previous depression or anxiety,” they said, noting that the findings “also underscore the importance of addressing tobacco smoking and other unhealthy behaviors – including those that may develop as a result of anxiety or depression.”

“However, further research is needed to understand exactly how depression, anxiety, health behaviors, and lung cancer are related,” said Dr. Tuijl.

Dr. Tuijl has received grants and travel support from the Dutch Cancer Society (KWF).
 

Written exposure therapy (WET) for posttraumatic stress disorder was just as effective as prolonged exposure therapy (PE), results of a new randomized clinical trial show.

Investigators also found that participants randomly assigned to receive WET were significantly less likely to drop out of treatment than those receiving PE.

Written exposure therapy involves writing about thoughts and feelings during a specific traumatic event during five supervised, 30-minute sessions and discussing the writing process with the therapist supervising the sessions.

In the latter sessions, the participant talks about how the event affected them.

“Clinicians should consider using WET in their practices as some clients would prefer a shorter treatment approach, and it may be the only option for some clients – for instance, those who have limited time for therapy and may not be able to do a longer treatment,” study investigator Denise Sloan, PhD, said in an interview.

She also noted that WET is covered by insurance and that “most providers I know indicate that they list it as CBT [cognitive-behavioral therapy] code to insurance companies.”

Sloan is senior clinician investigator of the National Center for PTSD at VA Boston Healthcare System and professor of psychiatry at Boston University.

The findings were published online in JAMA Psychiatry.
 

High attrition rates

The disadvantage to the three major types of therapy used most often to treat PTSD in veterans – eye movement desensitization and reprocessing, cognitive processing therapy (CPT), and PE – are the dropout rates, that range from 18% to as high as 50%.

Prior studies have shown that WET is briefer and just as effective as CPT, but investigators noted that it had never been tested against PE in a randomized clinical trial.

To find out how the two types of therapy compare, Dr. Sloan and associates randomized 178 veterans with PTSD from three VA centers – Boston; Charleston, S.C.; and Madison, Wisc. – to receive either WET or PE.

PE consisted of 8-15 90-minute therapy sessions during which participants imagine the most distressing aspect of their traumatic memory, and between sessions, they confront the people, places, or situations they have been avoiding because of the trauma.

The investigators used the Structured Clinical Interview for DSM-5 at baseline to screen participants at high risk for suicide, comorbid substance use disorder, and unstable bipolar disorder, who were excluded from the study.

At baseline, 10, 20, and 30 weeks after the first treatment session, the investigators measured the severity of each patient’s PTSD symptoms with the Clinician-Administered PTSD Scale for DSM-5, which has a range of 0 (no PTSD symptoms) to 80 (most severe PTSD symptoms).

Of the 178 veterans, 134 were men, and their mean age was 45 years. The majority (63%) was White, while 21% were Black.

The researchers found that study participants were not significantly more likely to meet PTSD diagnostic criteria in the WET or PE conditions at any assessment.
 

WET briefer, better retention

Investigators noted the largest difference in PTSD scores in favor of WET at the 10-month assessment: The mean score for those receiving WET was 27.7, and the mean score for those receiving PE was 30.1 (odds ratio, 0.72; 95% CI, 0.35-1.46).

Among those who finished treatment, the mean number of treatment sessions was 12.5 for PE and 6 for WET.

Participants assigned to receive PE were significantly more likely to drop out of the study prematurely; 32 (35.6%) dropped out, compared with 11 (12.5%) participants assigned to WET.

Notably, of the 32 participants who dropped out of PE, 30 did so by session 7, so the increased dropout in PE was not related to the greater number of sessions, the investigators noted.

They added that findings could have been limited by stressors related to the global COVID-19 pandemic, which was taking place during the treatment, and the fact that all of the participants were veterans, which could limit the generalizability of the findings.

In an editorial, Charles Taylor, PhD, and Murray Stein, MD, MPH, both from the department of psychiatry at the University of California, San Diego, wrote that “WET achieved comparable reductions in PTSD symptoms through fewer sessions, shorter duration sessions, less therapist involvement, and no explicit prescription of homework.

“These findings should galvanize the psychotherapy field to design parsimonious treatments from the start, systematically testing the effects of different dose parameters,” they concluded.

The study was supported by the VA. Dr. Sloan reported receiving royalty payments for the published Written Exposure Therapy manual from the American Psychological Association outside the submitted work.

A version of this article appeared on Medscape.com.

Written exposure therapy (WET) for posttraumatic stress disorder was just as effective as prolonged exposure therapy (PE), results of a new randomized clinical trial show.

Investigators also found that participants randomly assigned to receive WET were significantly less likely to drop out of treatment than those receiving PE.

Written exposure therapy involves writing about thoughts and feelings during a specific traumatic event during five supervised, 30-minute sessions and discussing the writing process with the therapist supervising the sessions.

In the latter sessions, the participant talks about how the event affected them.

“Clinicians should consider using WET in their practices as some clients would prefer a shorter treatment approach, and it may be the only option for some clients – for instance, those who have limited time for therapy and may not be able to do a longer treatment,” study investigator Denise Sloan, PhD, said in an interview.

She also noted that WET is covered by insurance and that “most providers I know indicate that they list it as CBT [cognitive-behavioral therapy] code to insurance companies.”

Sloan is senior clinician investigator of the National Center for PTSD at VA Boston Healthcare System and professor of psychiatry at Boston University.

The findings were published online in JAMA Psychiatry.
 

High attrition rates

The disadvantage to the three major types of therapy used most often to treat PTSD in veterans – eye movement desensitization and reprocessing, cognitive processing therapy (CPT), and PE – are the dropout rates, that range from 18% to as high as 50%.

Prior studies have shown that WET is briefer and just as effective as CPT, but investigators noted that it had never been tested against PE in a randomized clinical trial.

To find out how the two types of therapy compare, Dr. Sloan and associates randomized 178 veterans with PTSD from three VA centers – Boston; Charleston, S.C.; and Madison, Wisc. – to receive either WET or PE.

PE consisted of 8-15 90-minute therapy sessions during which participants imagine the most distressing aspect of their traumatic memory, and between sessions, they confront the people, places, or situations they have been avoiding because of the trauma.

The investigators used the Structured Clinical Interview for DSM-5 at baseline to screen participants at high risk for suicide, comorbid substance use disorder, and unstable bipolar disorder, who were excluded from the study.

At baseline, 10, 20, and 30 weeks after the first treatment session, the investigators measured the severity of each patient’s PTSD symptoms with the Clinician-Administered PTSD Scale for DSM-5, which has a range of 0 (no PTSD symptoms) to 80 (most severe PTSD symptoms).

Of the 178 veterans, 134 were men, and their mean age was 45 years. The majority (63%) was White, while 21% were Black.

The researchers found that study participants were not significantly more likely to meet PTSD diagnostic criteria in the WET or PE conditions at any assessment.
 

WET briefer, better retention

Investigators noted the largest difference in PTSD scores in favor of WET at the 10-month assessment: The mean score for those receiving WET was 27.7, and the mean score for those receiving PE was 30.1 (odds ratio, 0.72; 95% CI, 0.35-1.46).

Among those who finished treatment, the mean number of treatment sessions was 12.5 for PE and 6 for WET.

Participants assigned to receive PE were significantly more likely to drop out of the study prematurely; 32 (35.6%) dropped out, compared with 11 (12.5%) participants assigned to WET.

Notably, of the 32 participants who dropped out of PE, 30 did so by session 7, so the increased dropout in PE was not related to the greater number of sessions, the investigators noted.

They added that findings could have been limited by stressors related to the global COVID-19 pandemic, which was taking place during the treatment, and the fact that all of the participants were veterans, which could limit the generalizability of the findings.

In an editorial, Charles Taylor, PhD, and Murray Stein, MD, MPH, both from the department of psychiatry at the University of California, San Diego, wrote that “WET achieved comparable reductions in PTSD symptoms through fewer sessions, shorter duration sessions, less therapist involvement, and no explicit prescription of homework.

“These findings should galvanize the psychotherapy field to design parsimonious treatments from the start, systematically testing the effects of different dose parameters,” they concluded.

The study was supported by the VA. Dr. Sloan reported receiving royalty payments for the published Written Exposure Therapy manual from the American Psychological Association outside the submitted work.

A version of this article appeared on Medscape.com.

Written exposure therapy (WET) for posttraumatic stress disorder was just as effective as prolonged exposure therapy (PE), results of a new randomized clinical trial show.

Investigators also found that participants randomly assigned to receive WET were significantly less likely to drop out of treatment than those receiving PE.

Written exposure therapy involves writing about thoughts and feelings during a specific traumatic event during five supervised, 30-minute sessions and discussing the writing process with the therapist supervising the sessions.

In the latter sessions, the participant talks about how the event affected them.

“Clinicians should consider using WET in their practices as some clients would prefer a shorter treatment approach, and it may be the only option for some clients – for instance, those who have limited time for therapy and may not be able to do a longer treatment,” study investigator Denise Sloan, PhD, said in an interview.

She also noted that WET is covered by insurance and that “most providers I know indicate that they list it as CBT [cognitive-behavioral therapy] code to insurance companies.”

Sloan is senior clinician investigator of the National Center for PTSD at VA Boston Healthcare System and professor of psychiatry at Boston University.

The findings were published online in JAMA Psychiatry.
 

High attrition rates

The disadvantage to the three major types of therapy used most often to treat PTSD in veterans – eye movement desensitization and reprocessing, cognitive processing therapy (CPT), and PE – are the dropout rates, that range from 18% to as high as 50%.

Prior studies have shown that WET is briefer and just as effective as CPT, but investigators noted that it had never been tested against PE in a randomized clinical trial.

To find out how the two types of therapy compare, Dr. Sloan and associates randomized 178 veterans with PTSD from three VA centers – Boston; Charleston, S.C.; and Madison, Wisc. – to receive either WET or PE.

PE consisted of 8-15 90-minute therapy sessions during which participants imagine the most distressing aspect of their traumatic memory, and between sessions, they confront the people, places, or situations they have been avoiding because of the trauma.

The investigators used the Structured Clinical Interview for DSM-5 at baseline to screen participants at high risk for suicide, comorbid substance use disorder, and unstable bipolar disorder, who were excluded from the study.

At baseline, 10, 20, and 30 weeks after the first treatment session, the investigators measured the severity of each patient’s PTSD symptoms with the Clinician-Administered PTSD Scale for DSM-5, which has a range of 0 (no PTSD symptoms) to 80 (most severe PTSD symptoms).

Of the 178 veterans, 134 were men, and their mean age was 45 years. The majority (63%) was White, while 21% were Black.

The researchers found that study participants were not significantly more likely to meet PTSD diagnostic criteria in the WET or PE conditions at any assessment.
 

WET briefer, better retention

Investigators noted the largest difference in PTSD scores in favor of WET at the 10-month assessment: The mean score for those receiving WET was 27.7, and the mean score for those receiving PE was 30.1 (odds ratio, 0.72; 95% CI, 0.35-1.46).

Among those who finished treatment, the mean number of treatment sessions was 12.5 for PE and 6 for WET.

Participants assigned to receive PE were significantly more likely to drop out of the study prematurely; 32 (35.6%) dropped out, compared with 11 (12.5%) participants assigned to WET.

Notably, of the 32 participants who dropped out of PE, 30 did so by session 7, so the increased dropout in PE was not related to the greater number of sessions, the investigators noted.

They added that findings could have been limited by stressors related to the global COVID-19 pandemic, which was taking place during the treatment, and the fact that all of the participants were veterans, which could limit the generalizability of the findings.

In an editorial, Charles Taylor, PhD, and Murray Stein, MD, MPH, both from the department of psychiatry at the University of California, San Diego, wrote that “WET achieved comparable reductions in PTSD symptoms through fewer sessions, shorter duration sessions, less therapist involvement, and no explicit prescription of homework.

“These findings should galvanize the psychotherapy field to design parsimonious treatments from the start, systematically testing the effects of different dose parameters,” they concluded.

The study was supported by the VA. Dr. Sloan reported receiving royalty payments for the published Written Exposure Therapy manual from the American Psychological Association outside the submitted work.

A version of this article appeared on Medscape.com.

The largest study to date of chronic traumatic encephalopathy (CTE) in young athletes shows that 41% had the neurodegenerative disease, caused by repetitive head impacts (RHIs).

Analysis of brain tissue from athletes who were exposed to RHIs and died before the age of 30 revealed neuropathological evidence of shrinkage of the brain and microscopic changes that indicate a breach of the blood-brain barrier. The case series also identified the first known American female athlete with CTE.

Nearly all of those with CTE had a mild form of the disease and 71% played only at the amateur level in youth, high school, or college sports.

“A lot of people think CTE is a result of high-level, professional play such as football, ice hockey, and boxing, but it can affect amateur athletes and can affect people at a young age,” lead author Ann McKee, MD, professor of neurology and pathology and director of the Chronic Traumatic Encephalopathy Center at Boston University, said in an interview.

The findings were published online in JAMA Neurology.
 

A rare look

Brain donation at younger ages is rare, so most of what is known about CTE comes from studies in older athletes.

“We’ve always known that young people could develop this disease early after just amateur high school, youth, and college exposure, but this is the largest study of donor brains at this age,” Dr. McKee said.

The case series included 152 brains of athletes who played contact sports, experienced RHIs, and died before age 30. The tissues are part of the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank and were donated between February 2008 and September 2022.

Researchers reviewed the donors’ medical records and conducted retrospective interviews with the donors’ next of kin to assess cognitive symptoms, mood disturbances, and neurobehavioral issues.

Donors died between the ages of 13 and 29 years, 92.8% were male and 73% were White. In 57.2% of the cases, suicide was the cause of death, with no difference between those with or without CTE.

CTE was neuropathologically diagnosed in 41.4% of athletes, using diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke. 

More than 95% had mild CTE. Diagnosis was associated with older age (mean difference, 3.92 years; P < .001) and significantly more years of exposure to contact sports (11.6 vs. 8.8 years).

Among those with CTE, 71.4% played amateur sports, including football (60.9%), soccer (17.2%), hockey (7.8%), and wrestling (7%).

The cohort includes the first known American female athlete with CTE. Recruiting female brain donors has always been a challenge, Dr. McKee said. In this study, females comprised about 7% of the entire cohort and tended to be younger and play fewer years of a sport, compared with their male counterparts. All of that could lower their risk for CTE, Dr. McKee said.

“We don’t have enough brain donations to make any comments about differences between the genders, but we’ve always known that women can develop CTE,” she said. “It’s been reported after domestic violence and in an autistic woman who was a headbanger, so it was just a matter of time before we found our first case.”
 

Early stage of CTE?

Neuropathological analysis revealed neuronal p-tau aggregates in all CTE cases, a hallmark of the disease.

Young athletes with CTE had significantly more ventricular dilatation, suggesting atrophy or shrinkage of the brain, and more cavum septum pellucidum.

“I was surprised that even at this very young age group we could see structural changes to the gross pathology,” Dr. McKee said.

Investigators also found evidence of perivascular macrophages in the deep white matter, a microscopic change that correlated with CTE and years of play and indicates a breach of the blood-brain barrier that could allow pro-inflammatory molecules to enter the brain, setting up a neuroinflammatory response.

“Neuroinflammation is a very early change after repetitive head impacts, as well as in CTE,” Dr. McKee said. “This may be one of the mechanisms by which the inflammation starts, meaning microvascular injury might be an integral part of the pathogenesis of CTE.”
 

A message for clinicians

All athletes had symptoms of mood and neurobehavioral dysfunction common in people with RHIs. There were no significant differences in those clinical symptoms based on CTE diagnosis, which is likely related to the retrospective nature of the clinical evaluations, Dr. McKee said.

While the study leaves many questions about CTE in younger athletes unanswered, there is a message for clinicians and for patients in the findings, she said.

For clinicians, it’s important to note that “this young population of amateur athletes can be very symptomatic, and in all likelihood, a lot of these symptoms are reversible with proper care and management,” Dr. McKee said.

“For individual athletes, it’s important to note that 58% of this cohort did not have CTE, so just because you have these symptoms is not an indication that you have a neurodegenerative disease,” she added.

The study was funded by Andlinger Foundation, the National Football League, Mac Parkman Foundation, National Operating Committee on Standards for Athletic Equipment, and the Nick and Lynn Buoniconti Foundation, World Wrestling Entertainment, Alzheimer’s Association, National Institutes of Health, Concussion Legacy Foundation, U.S. Department of Defense and the U.S. Department of Veterans Affairs. Dr. McKee is a member of the Mackey-White Health and Safety Committee of the National Football League Players Association and reported receiving grants from the NIH and Department of Veteran Affairs and other funding from the Buoniconti Foundation and Mac Parkman Foundation during the conduct of the study.

A version of this article appeared on Medscape.com.

The largest study to date of chronic traumatic encephalopathy (CTE) in young athletes shows that 41% had the neurodegenerative disease, caused by repetitive head impacts (RHIs).

Analysis of brain tissue from athletes who were exposed to RHIs and died before the age of 30 revealed neuropathological evidence of shrinkage of the brain and microscopic changes that indicate a breach of the blood-brain barrier. The case series also identified the first known American female athlete with CTE.

Nearly all of those with CTE had a mild form of the disease and 71% played only at the amateur level in youth, high school, or college sports.

“A lot of people think CTE is a result of high-level, professional play such as football, ice hockey, and boxing, but it can affect amateur athletes and can affect people at a young age,” lead author Ann McKee, MD, professor of neurology and pathology and director of the Chronic Traumatic Encephalopathy Center at Boston University, said in an interview.

The findings were published online in JAMA Neurology.
 

A rare look

Brain donation at younger ages is rare, so most of what is known about CTE comes from studies in older athletes.

“We’ve always known that young people could develop this disease early after just amateur high school, youth, and college exposure, but this is the largest study of donor brains at this age,” Dr. McKee said.

The case series included 152 brains of athletes who played contact sports, experienced RHIs, and died before age 30. The tissues are part of the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank and were donated between February 2008 and September 2022.

Researchers reviewed the donors’ medical records and conducted retrospective interviews with the donors’ next of kin to assess cognitive symptoms, mood disturbances, and neurobehavioral issues.

Donors died between the ages of 13 and 29 years, 92.8% were male and 73% were White. In 57.2% of the cases, suicide was the cause of death, with no difference between those with or without CTE.

CTE was neuropathologically diagnosed in 41.4% of athletes, using diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke. 

More than 95% had mild CTE. Diagnosis was associated with older age (mean difference, 3.92 years; P < .001) and significantly more years of exposure to contact sports (11.6 vs. 8.8 years).

Among those with CTE, 71.4% played amateur sports, including football (60.9%), soccer (17.2%), hockey (7.8%), and wrestling (7%).

The cohort includes the first known American female athlete with CTE. Recruiting female brain donors has always been a challenge, Dr. McKee said. In this study, females comprised about 7% of the entire cohort and tended to be younger and play fewer years of a sport, compared with their male counterparts. All of that could lower their risk for CTE, Dr. McKee said.

“We don’t have enough brain donations to make any comments about differences between the genders, but we’ve always known that women can develop CTE,” she said. “It’s been reported after domestic violence and in an autistic woman who was a headbanger, so it was just a matter of time before we found our first case.”
 

Early stage of CTE?

Neuropathological analysis revealed neuronal p-tau aggregates in all CTE cases, a hallmark of the disease.

Young athletes with CTE had significantly more ventricular dilatation, suggesting atrophy or shrinkage of the brain, and more cavum septum pellucidum.

“I was surprised that even at this very young age group we could see structural changes to the gross pathology,” Dr. McKee said.

Investigators also found evidence of perivascular macrophages in the deep white matter, a microscopic change that correlated with CTE and years of play and indicates a breach of the blood-brain barrier that could allow pro-inflammatory molecules to enter the brain, setting up a neuroinflammatory response.

“Neuroinflammation is a very early change after repetitive head impacts, as well as in CTE,” Dr. McKee said. “This may be one of the mechanisms by which the inflammation starts, meaning microvascular injury might be an integral part of the pathogenesis of CTE.”
 

A message for clinicians

All athletes had symptoms of mood and neurobehavioral dysfunction common in people with RHIs. There were no significant differences in those clinical symptoms based on CTE diagnosis, which is likely related to the retrospective nature of the clinical evaluations, Dr. McKee said.

While the study leaves many questions about CTE in younger athletes unanswered, there is a message for clinicians and for patients in the findings, she said.

For clinicians, it’s important to note that “this young population of amateur athletes can be very symptomatic, and in all likelihood, a lot of these symptoms are reversible with proper care and management,” Dr. McKee said.

“For individual athletes, it’s important to note that 58% of this cohort did not have CTE, so just because you have these symptoms is not an indication that you have a neurodegenerative disease,” she added.

The study was funded by Andlinger Foundation, the National Football League, Mac Parkman Foundation, National Operating Committee on Standards for Athletic Equipment, and the Nick and Lynn Buoniconti Foundation, World Wrestling Entertainment, Alzheimer’s Association, National Institutes of Health, Concussion Legacy Foundation, U.S. Department of Defense and the U.S. Department of Veterans Affairs. Dr. McKee is a member of the Mackey-White Health and Safety Committee of the National Football League Players Association and reported receiving grants from the NIH and Department of Veteran Affairs and other funding from the Buoniconti Foundation and Mac Parkman Foundation during the conduct of the study.

A version of this article appeared on Medscape.com.

The largest study to date of chronic traumatic encephalopathy (CTE) in young athletes shows that 41% had the neurodegenerative disease, caused by repetitive head impacts (RHIs).

Analysis of brain tissue from athletes who were exposed to RHIs and died before the age of 30 revealed neuropathological evidence of shrinkage of the brain and microscopic changes that indicate a breach of the blood-brain barrier. The case series also identified the first known American female athlete with CTE.

Nearly all of those with CTE had a mild form of the disease and 71% played only at the amateur level in youth, high school, or college sports.

“A lot of people think CTE is a result of high-level, professional play such as football, ice hockey, and boxing, but it can affect amateur athletes and can affect people at a young age,” lead author Ann McKee, MD, professor of neurology and pathology and director of the Chronic Traumatic Encephalopathy Center at Boston University, said in an interview.

The findings were published online in JAMA Neurology.
 

A rare look

Brain donation at younger ages is rare, so most of what is known about CTE comes from studies in older athletes.

“We’ve always known that young people could develop this disease early after just amateur high school, youth, and college exposure, but this is the largest study of donor brains at this age,” Dr. McKee said.

The case series included 152 brains of athletes who played contact sports, experienced RHIs, and died before age 30. The tissues are part of the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank and were donated between February 2008 and September 2022.

Researchers reviewed the donors’ medical records and conducted retrospective interviews with the donors’ next of kin to assess cognitive symptoms, mood disturbances, and neurobehavioral issues.

Donors died between the ages of 13 and 29 years, 92.8% were male and 73% were White. In 57.2% of the cases, suicide was the cause of death, with no difference between those with or without CTE.

CTE was neuropathologically diagnosed in 41.4% of athletes, using diagnostic criteria developed by the National Institute of Neurological Disorders and Stroke. 

More than 95% had mild CTE. Diagnosis was associated with older age (mean difference, 3.92 years; P < .001) and significantly more years of exposure to contact sports (11.6 vs. 8.8 years).

Among those with CTE, 71.4% played amateur sports, including football (60.9%), soccer (17.2%), hockey (7.8%), and wrestling (7%).

The cohort includes the first known American female athlete with CTE. Recruiting female brain donors has always been a challenge, Dr. McKee said. In this study, females comprised about 7% of the entire cohort and tended to be younger and play fewer years of a sport, compared with their male counterparts. All of that could lower their risk for CTE, Dr. McKee said.

“We don’t have enough brain donations to make any comments about differences between the genders, but we’ve always known that women can develop CTE,” she said. “It’s been reported after domestic violence and in an autistic woman who was a headbanger, so it was just a matter of time before we found our first case.”
 

Early stage of CTE?

Neuropathological analysis revealed neuronal p-tau aggregates in all CTE cases, a hallmark of the disease.

Young athletes with CTE had significantly more ventricular dilatation, suggesting atrophy or shrinkage of the brain, and more cavum septum pellucidum.

“I was surprised that even at this very young age group we could see structural changes to the gross pathology,” Dr. McKee said.

Investigators also found evidence of perivascular macrophages in the deep white matter, a microscopic change that correlated with CTE and years of play and indicates a breach of the blood-brain barrier that could allow pro-inflammatory molecules to enter the brain, setting up a neuroinflammatory response.

“Neuroinflammation is a very early change after repetitive head impacts, as well as in CTE,” Dr. McKee said. “This may be one of the mechanisms by which the inflammation starts, meaning microvascular injury might be an integral part of the pathogenesis of CTE.”
 

A message for clinicians

All athletes had symptoms of mood and neurobehavioral dysfunction common in people with RHIs. There were no significant differences in those clinical symptoms based on CTE diagnosis, which is likely related to the retrospective nature of the clinical evaluations, Dr. McKee said.

While the study leaves many questions about CTE in younger athletes unanswered, there is a message for clinicians and for patients in the findings, she said.

For clinicians, it’s important to note that “this young population of amateur athletes can be very symptomatic, and in all likelihood, a lot of these symptoms are reversible with proper care and management,” Dr. McKee said.

“For individual athletes, it’s important to note that 58% of this cohort did not have CTE, so just because you have these symptoms is not an indication that you have a neurodegenerative disease,” she added.

The study was funded by Andlinger Foundation, the National Football League, Mac Parkman Foundation, National Operating Committee on Standards for Athletic Equipment, and the Nick and Lynn Buoniconti Foundation, World Wrestling Entertainment, Alzheimer’s Association, National Institutes of Health, Concussion Legacy Foundation, U.S. Department of Defense and the U.S. Department of Veterans Affairs. Dr. McKee is a member of the Mackey-White Health and Safety Committee of the National Football League Players Association and reported receiving grants from the NIH and Department of Veteran Affairs and other funding from the Buoniconti Foundation and Mac Parkman Foundation during the conduct of the study.

A version of this article appeared on Medscape.com.

AMSTERDAM – Intravenous iron supplementation showed modest benefits in recently hospitalized patients with heart failure and iron deficiency in the HEART-FID trial, but the study failed to meet the specified more rigorous definition of significance (P = .01) on the primary hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.

The trial, which investigated intravenous ferric carboxymaltose treatment vs. placebo, also showed no statistical difference in the main secondary endpoint: time to cardiovascular death or first heart failure hospitalization.

It was hoped that HEART-FID, the largest study to date to look at intravenous iron supplementation in heart failure, would confirm benefits suggested in previous smaller studies, but its modest results seem to have, if anything, caused more uncertainly on whether supplementing iron is actually worthwhile.

The HEART-FID trial was presented at the annual congress of the European Society of Cardiology and simultaneously published online in the New England Journal of Medicine.

Another presentation at the ESC Congress reported a pooled meta-analysis of all the intravenous iron supplementation studies, including HEART-FID. This showed a significant reduction in one coprimary endpoint (cardiovascular hospitalization/CV death) but not in the other (heart failure hospitalization/CV death), which is the more traditional and well-recognized endpoint in heart failure trials.

The meta-analysis was also published online in the European Heart Journal.

HEART-FID lead investigator, Robert J. Mentz, MD, Duke University, Durham, N.C., said the totality of the evidence showed clinical benefits of intravenous iron supplementation with intravenous ferric carboxymaltose.

“I worry that people will focus on a P value rather than the actual clinical benefits seen across all the studies,” Dr. Mentz said in an interview. “Technically, this study was neutral in respect to the primary endpoint, but when we look at all the evidence with respect to ferric carboxymaltose, including this new pooled analysis, this does support clinical benefits.”

Comoderator of the ESC Hotline session at which the trial was presented, John McMurray, MD, University of Glasgow (Scotland), thought the trial had “muddied the waters a bit” on the issue of iron supplementation in heart failure.

“I would say we are in a less clear position on iron supplementation now than we were a few months ago. Those clinicians who have believed that checking iron levels and supplementing iron in those who are low is the right thing to do may now be wondering about that,” he told this news organization.  

Dr. McMurray noted that initial impressions of the data from both HEART-FID and the meta-analysis suggested some benefit of intravenous iron on CV death/heart failure hospitalization in the first year, but on longer term follow-up, that benefit was less evident.

“We need to look further into why there is that discrepancy,” he said. “This could be a statistical phenomenon or could be something to do with the frequency of redosing over the longer term.”

He explained that several previous studies of intravenous iron supplementation in heart failure have reported apparent convincing benefits on quality of life and functional capacity, but there has been some uncertainty on this because of the difficulty in producing a placebo for intravenous iron.

“So, it would have been great to have some additional confirmation of these benefits and on harder endpoints,” he said, “but even in HEART-FID, there was only a small nonsignificant benefit in walking distance.”
 

HEART-FID

The HEART-FID trial randomly assigned 3,065 ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency to intravenous ferric carboxymaltose or placebo, given every 6 months as needed on the basis of iron indexes and hemoglobin levels, in addition to standard therapy for heart failure.

The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at .01.

Results showed that death by month 12 occurred in 8.6% of the ferric carboxymaltose group and 10.3% of the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean change from baseline to 6 months in the 6-minute walk distance was 8 meters in the ferric carboxymaltose group and 4 meters with placebo. The P value for the primary composite was .02.

The trial also used another method (unmatched win ratio) to analyze the hierarchical composite outcome in the ferric carboxymaltose group as compared with the placebo group that gave a result of 1.10 (99% confidence interval, 0.99-1.23).

During the follow-up period, CV death or hospitalization for heart failure (the main secondary outcome) occurred in 31.0% of the ferric carboxymaltose group and in 32.2% of the placebo group (hazard ratio, 0.93; 96% CI, 0.81-1.06).

Repeated dosing of ferric carboxymaltose appeared to be safe, with an acceptable adverse-event profile in most patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (27.0% in the ferric carboxymaltose group and 26.2% in the placebo group).
 

‘It’s hard to argue that we are not disappointed’

Designated discussant of the HEART-FID study at the ESC HOTLINE session, Scott Solomon, MD, Brigham and Women’s Hospital, Boston, described HEART-FID as “an extremely important and well-conducted trial.”

He noted that iron deficiency is extremely common in patients with heart failure, affecting at least about a third of patients, and is associated with reduced New York Heart Association class and reduced survival. Previous smaller studies have suggested benefit but have narrowly missed their primary endpoints. HEART-FID was a larger and sufficiently well-powered trial to test the hypothesis that iron supplementation can improve harder clinical endpoints.

Dr. Solomon said that the primary endpoint could be difficult to interpret, with a hierarchical composite, and a win ratio. “But I think it’s fair to say that the results are modest at best,” he added.

“When we look at the traditional cardiovascular death/heart failure hospitalization endpoint, one of the hard endpoints that we care about most in heart failure, it’s hard to argue that we are not disappointed,” he commented.

Referring to the P value of .01 threshold set for significance, which is based on new U.S. Food and Drug Administration regulatory standards, Dr. Solomon noted, “If they had used a standard P = .05 threshold, then they would be able to claim that this trial had met its primary endpoint. But, nevertheless, whatever threshold for significance we look at, the benefit was clearly modest.”

“As with all trials that show modest results, it will be useful to look at subgroups that are most likely to respond to the greatest extent to this therapy, and I look forward to learning more on this from further analyses,” Dr. Solomon concluded.

In an accompanying editorial in the New England Journal of Medicine, Pieter Martens, MD, and Wilfried Mullens, MD, PhD, Ziekenhuis Oost-Limburg, Genk, Belgium, and Hasselt (Belgium) University, point out that analyses from previous trials have suggested that intravenous iron did not have a treatment effect in patients with a transferrin saturation of more than 20%.

They note that, in the ferric carboxymaltose group in the HEART-FID trial, the mean transferrin saturation was 23.9% at baseline, higher than in previous studies.

Future analyses should assess the importance of the transferrin saturation value at baseline, which “could help redefine the definition of iron deficiency in patients with heart failure and, we hope, help clinicians determine which patients might benefit from intravenous iron supplementation,” they write.
 

Meta-analysis of trials

The meta-analysis of intravenous iron supplementation trials in heart failure was presented by Piotr Ponikowski, MD, Medical University Wroclaw (Poland).

The analysis pooled individual patient data from three double-blind, placebo-controlled trials – CONFIRM-HF 2, AFFIRM-AHF 3, and HEART-FID – giving a total of 4,475 patients, with 2,241 receiving ferric carboxymaltose and 2,234 receiving placebo.

The two prespecified composite primary endpoints were CV hospitalizations/CV death and heart failure hospitalizations/CV death.

These showed similar 13%-14% relative risk reductions with ferric carboxymaltose, but only the former was statistically significant.

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

AMSTERDAM – Intravenous iron supplementation showed modest benefits in recently hospitalized patients with heart failure and iron deficiency in the HEART-FID trial, but the study failed to meet the specified more rigorous definition of significance (P = .01) on the primary hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.

The trial, which investigated intravenous ferric carboxymaltose treatment vs. placebo, also showed no statistical difference in the main secondary endpoint: time to cardiovascular death or first heart failure hospitalization.

It was hoped that HEART-FID, the largest study to date to look at intravenous iron supplementation in heart failure, would confirm benefits suggested in previous smaller studies, but its modest results seem to have, if anything, caused more uncertainly on whether supplementing iron is actually worthwhile.

The HEART-FID trial was presented at the annual congress of the European Society of Cardiology and simultaneously published online in the New England Journal of Medicine.

Another presentation at the ESC Congress reported a pooled meta-analysis of all the intravenous iron supplementation studies, including HEART-FID. This showed a significant reduction in one coprimary endpoint (cardiovascular hospitalization/CV death) but not in the other (heart failure hospitalization/CV death), which is the more traditional and well-recognized endpoint in heart failure trials.

The meta-analysis was also published online in the European Heart Journal.

HEART-FID lead investigator, Robert J. Mentz, MD, Duke University, Durham, N.C., said the totality of the evidence showed clinical benefits of intravenous iron supplementation with intravenous ferric carboxymaltose.

“I worry that people will focus on a P value rather than the actual clinical benefits seen across all the studies,” Dr. Mentz said in an interview. “Technically, this study was neutral in respect to the primary endpoint, but when we look at all the evidence with respect to ferric carboxymaltose, including this new pooled analysis, this does support clinical benefits.”

Comoderator of the ESC Hotline session at which the trial was presented, John McMurray, MD, University of Glasgow (Scotland), thought the trial had “muddied the waters a bit” on the issue of iron supplementation in heart failure.

“I would say we are in a less clear position on iron supplementation now than we were a few months ago. Those clinicians who have believed that checking iron levels and supplementing iron in those who are low is the right thing to do may now be wondering about that,” he told this news organization.  

Dr. McMurray noted that initial impressions of the data from both HEART-FID and the meta-analysis suggested some benefit of intravenous iron on CV death/heart failure hospitalization in the first year, but on longer term follow-up, that benefit was less evident.

“We need to look further into why there is that discrepancy,” he said. “This could be a statistical phenomenon or could be something to do with the frequency of redosing over the longer term.”

He explained that several previous studies of intravenous iron supplementation in heart failure have reported apparent convincing benefits on quality of life and functional capacity, but there has been some uncertainty on this because of the difficulty in producing a placebo for intravenous iron.

“So, it would have been great to have some additional confirmation of these benefits and on harder endpoints,” he said, “but even in HEART-FID, there was only a small nonsignificant benefit in walking distance.”
 

HEART-FID

The HEART-FID trial randomly assigned 3,065 ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency to intravenous ferric carboxymaltose or placebo, given every 6 months as needed on the basis of iron indexes and hemoglobin levels, in addition to standard therapy for heart failure.

The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at .01.

Results showed that death by month 12 occurred in 8.6% of the ferric carboxymaltose group and 10.3% of the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean change from baseline to 6 months in the 6-minute walk distance was 8 meters in the ferric carboxymaltose group and 4 meters with placebo. The P value for the primary composite was .02.

The trial also used another method (unmatched win ratio) to analyze the hierarchical composite outcome in the ferric carboxymaltose group as compared with the placebo group that gave a result of 1.10 (99% confidence interval, 0.99-1.23).

During the follow-up period, CV death or hospitalization for heart failure (the main secondary outcome) occurred in 31.0% of the ferric carboxymaltose group and in 32.2% of the placebo group (hazard ratio, 0.93; 96% CI, 0.81-1.06).

Repeated dosing of ferric carboxymaltose appeared to be safe, with an acceptable adverse-event profile in most patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (27.0% in the ferric carboxymaltose group and 26.2% in the placebo group).
 

‘It’s hard to argue that we are not disappointed’

Designated discussant of the HEART-FID study at the ESC HOTLINE session, Scott Solomon, MD, Brigham and Women’s Hospital, Boston, described HEART-FID as “an extremely important and well-conducted trial.”

He noted that iron deficiency is extremely common in patients with heart failure, affecting at least about a third of patients, and is associated with reduced New York Heart Association class and reduced survival. Previous smaller studies have suggested benefit but have narrowly missed their primary endpoints. HEART-FID was a larger and sufficiently well-powered trial to test the hypothesis that iron supplementation can improve harder clinical endpoints.

Dr. Solomon said that the primary endpoint could be difficult to interpret, with a hierarchical composite, and a win ratio. “But I think it’s fair to say that the results are modest at best,” he added.

“When we look at the traditional cardiovascular death/heart failure hospitalization endpoint, one of the hard endpoints that we care about most in heart failure, it’s hard to argue that we are not disappointed,” he commented.

Referring to the P value of .01 threshold set for significance, which is based on new U.S. Food and Drug Administration regulatory standards, Dr. Solomon noted, “If they had used a standard P = .05 threshold, then they would be able to claim that this trial had met its primary endpoint. But, nevertheless, whatever threshold for significance we look at, the benefit was clearly modest.”

“As with all trials that show modest results, it will be useful to look at subgroups that are most likely to respond to the greatest extent to this therapy, and I look forward to learning more on this from further analyses,” Dr. Solomon concluded.

In an accompanying editorial in the New England Journal of Medicine, Pieter Martens, MD, and Wilfried Mullens, MD, PhD, Ziekenhuis Oost-Limburg, Genk, Belgium, and Hasselt (Belgium) University, point out that analyses from previous trials have suggested that intravenous iron did not have a treatment effect in patients with a transferrin saturation of more than 20%.

They note that, in the ferric carboxymaltose group in the HEART-FID trial, the mean transferrin saturation was 23.9% at baseline, higher than in previous studies.

Future analyses should assess the importance of the transferrin saturation value at baseline, which “could help redefine the definition of iron deficiency in patients with heart failure and, we hope, help clinicians determine which patients might benefit from intravenous iron supplementation,” they write.
 

Meta-analysis of trials

The meta-analysis of intravenous iron supplementation trials in heart failure was presented by Piotr Ponikowski, MD, Medical University Wroclaw (Poland).

The analysis pooled individual patient data from three double-blind, placebo-controlled trials – CONFIRM-HF 2, AFFIRM-AHF 3, and HEART-FID – giving a total of 4,475 patients, with 2,241 receiving ferric carboxymaltose and 2,234 receiving placebo.

The two prespecified composite primary endpoints were CV hospitalizations/CV death and heart failure hospitalizations/CV death.

These showed similar 13%-14% relative risk reductions with ferric carboxymaltose, but only the former was statistically significant.

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

AMSTERDAM – Intravenous iron supplementation showed modest benefits in recently hospitalized patients with heart failure and iron deficiency in the HEART-FID trial, but the study failed to meet the specified more rigorous definition of significance (P = .01) on the primary hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance.

The trial, which investigated intravenous ferric carboxymaltose treatment vs. placebo, also showed no statistical difference in the main secondary endpoint: time to cardiovascular death or first heart failure hospitalization.

It was hoped that HEART-FID, the largest study to date to look at intravenous iron supplementation in heart failure, would confirm benefits suggested in previous smaller studies, but its modest results seem to have, if anything, caused more uncertainly on whether supplementing iron is actually worthwhile.

The HEART-FID trial was presented at the annual congress of the European Society of Cardiology and simultaneously published online in the New England Journal of Medicine.

Another presentation at the ESC Congress reported a pooled meta-analysis of all the intravenous iron supplementation studies, including HEART-FID. This showed a significant reduction in one coprimary endpoint (cardiovascular hospitalization/CV death) but not in the other (heart failure hospitalization/CV death), which is the more traditional and well-recognized endpoint in heart failure trials.

The meta-analysis was also published online in the European Heart Journal.

HEART-FID lead investigator, Robert J. Mentz, MD, Duke University, Durham, N.C., said the totality of the evidence showed clinical benefits of intravenous iron supplementation with intravenous ferric carboxymaltose.

“I worry that people will focus on a P value rather than the actual clinical benefits seen across all the studies,” Dr. Mentz said in an interview. “Technically, this study was neutral in respect to the primary endpoint, but when we look at all the evidence with respect to ferric carboxymaltose, including this new pooled analysis, this does support clinical benefits.”

Comoderator of the ESC Hotline session at which the trial was presented, John McMurray, MD, University of Glasgow (Scotland), thought the trial had “muddied the waters a bit” on the issue of iron supplementation in heart failure.

“I would say we are in a less clear position on iron supplementation now than we were a few months ago. Those clinicians who have believed that checking iron levels and supplementing iron in those who are low is the right thing to do may now be wondering about that,” he told this news organization.  

Dr. McMurray noted that initial impressions of the data from both HEART-FID and the meta-analysis suggested some benefit of intravenous iron on CV death/heart failure hospitalization in the first year, but on longer term follow-up, that benefit was less evident.

“We need to look further into why there is that discrepancy,” he said. “This could be a statistical phenomenon or could be something to do with the frequency of redosing over the longer term.”

He explained that several previous studies of intravenous iron supplementation in heart failure have reported apparent convincing benefits on quality of life and functional capacity, but there has been some uncertainty on this because of the difficulty in producing a placebo for intravenous iron.

“So, it would have been great to have some additional confirmation of these benefits and on harder endpoints,” he said, “but even in HEART-FID, there was only a small nonsignificant benefit in walking distance.”
 

HEART-FID

The HEART-FID trial randomly assigned 3,065 ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency to intravenous ferric carboxymaltose or placebo, given every 6 months as needed on the basis of iron indexes and hemoglobin levels, in addition to standard therapy for heart failure.

The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at .01.

Results showed that death by month 12 occurred in 8.6% of the ferric carboxymaltose group and 10.3% of the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean change from baseline to 6 months in the 6-minute walk distance was 8 meters in the ferric carboxymaltose group and 4 meters with placebo. The P value for the primary composite was .02.

The trial also used another method (unmatched win ratio) to analyze the hierarchical composite outcome in the ferric carboxymaltose group as compared with the placebo group that gave a result of 1.10 (99% confidence interval, 0.99-1.23).

During the follow-up period, CV death or hospitalization for heart failure (the main secondary outcome) occurred in 31.0% of the ferric carboxymaltose group and in 32.2% of the placebo group (hazard ratio, 0.93; 96% CI, 0.81-1.06).

Repeated dosing of ferric carboxymaltose appeared to be safe, with an acceptable adverse-event profile in most patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (27.0% in the ferric carboxymaltose group and 26.2% in the placebo group).
 

‘It’s hard to argue that we are not disappointed’

Designated discussant of the HEART-FID study at the ESC HOTLINE session, Scott Solomon, MD, Brigham and Women’s Hospital, Boston, described HEART-FID as “an extremely important and well-conducted trial.”

He noted that iron deficiency is extremely common in patients with heart failure, affecting at least about a third of patients, and is associated with reduced New York Heart Association class and reduced survival. Previous smaller studies have suggested benefit but have narrowly missed their primary endpoints. HEART-FID was a larger and sufficiently well-powered trial to test the hypothesis that iron supplementation can improve harder clinical endpoints.

Dr. Solomon said that the primary endpoint could be difficult to interpret, with a hierarchical composite, and a win ratio. “But I think it’s fair to say that the results are modest at best,” he added.

“When we look at the traditional cardiovascular death/heart failure hospitalization endpoint, one of the hard endpoints that we care about most in heart failure, it’s hard to argue that we are not disappointed,” he commented.

Referring to the P value of .01 threshold set for significance, which is based on new U.S. Food and Drug Administration regulatory standards, Dr. Solomon noted, “If they had used a standard P = .05 threshold, then they would be able to claim that this trial had met its primary endpoint. But, nevertheless, whatever threshold for significance we look at, the benefit was clearly modest.”

“As with all trials that show modest results, it will be useful to look at subgroups that are most likely to respond to the greatest extent to this therapy, and I look forward to learning more on this from further analyses,” Dr. Solomon concluded.

In an accompanying editorial in the New England Journal of Medicine, Pieter Martens, MD, and Wilfried Mullens, MD, PhD, Ziekenhuis Oost-Limburg, Genk, Belgium, and Hasselt (Belgium) University, point out that analyses from previous trials have suggested that intravenous iron did not have a treatment effect in patients with a transferrin saturation of more than 20%.

They note that, in the ferric carboxymaltose group in the HEART-FID trial, the mean transferrin saturation was 23.9% at baseline, higher than in previous studies.

Future analyses should assess the importance of the transferrin saturation value at baseline, which “could help redefine the definition of iron deficiency in patients with heart failure and, we hope, help clinicians determine which patients might benefit from intravenous iron supplementation,” they write.
 

Meta-analysis of trials

The meta-analysis of intravenous iron supplementation trials in heart failure was presented by Piotr Ponikowski, MD, Medical University Wroclaw (Poland).

The analysis pooled individual patient data from three double-blind, placebo-controlled trials – CONFIRM-HF 2, AFFIRM-AHF 3, and HEART-FID – giving a total of 4,475 patients, with 2,241 receiving ferric carboxymaltose and 2,234 receiving placebo.

The two prespecified composite primary endpoints were CV hospitalizations/CV death and heart failure hospitalizations/CV death.

These showed similar 13%-14% relative risk reductions with ferric carboxymaltose, but only the former was statistically significant.

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

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.

When added to guideline-directed therapies for heart failure with reduced ejection fraction (HFrEF), a traditional Chinese medicine called qiliqiangxin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by more than 20%, results of a large placebo-controlled trial show.

“The risk reductions in both cardiovascular death and heart failure hospitalization were substantial, clinically important, and consistent across all subgroups,” reported Xinli Li, MD, PhD, First Affiliated Hospital, Nanjing Medical University, China.

Qiliqiangxin, a commonly used therapy in China for cardiovascular disease, is not a single chemical entity but a treatment composed of 11 plant-based substances that together are associated with diuretic effects, vasodilation, and “cardiotonic” activity, Dr. Li said. He also cited studies showing an upregulation effect on peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1-beta).

The results were presented at the annual congress of the European Society of Cardiology.
 

Hard endpoints pursued in rigorous design

There have been numerous studies of qiliqiangxin for cardiovascular diseases, including a double-blind study that associated this agent with a greater than 30% reduction in the surrogate endpoint of N-terminal pro–B-type natriuretic peptide (NT-proBNP).

In the newly completed multicenter trial, called QUEST, the goal was to determine whether this therapy could reduce hard endpoints relative to placebo in a rigorously conducted trial enrolling patients receiving an optimized triple-therapy heart failure regimen.

Few patients in the study received a sodium glucose cotransporter-2 (SGLT-2 inhibitor), which was not a standard at the time the study was designed but is now part of the quadruple guideline-directed medical therapy in most European and North American guidelines.

In this trial, 3,119 patients were randomly assigned at 133 centers in China to take four capsules of qiliqiangxin or placebo three times per day. At a median follow-up of 18.3 months, outcomes were evaluable in nearly all 1,561 patients randomly assigned to the experimental therapy and 1,555 patients randomly assigned to placebo.

The key inclusion criteria were a left ventricular ejection fraction of 40% or less and a serum NT-proBNP level of at least 450 pg/mL. Patients in New York Heart Association class IV heart failure were excluded.

At enrollment, more than 80% of patients in both arms were receiving a renin-angiotensin system (RAS) inhibitor (angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor neprilysin inhibitor), more than 80% were receiving a mineralocorticoid receptor antagonist, and more than 85% were receiving a beta-blocker.
 

Death and hospitalization reduced 22%

By hazard ratio, the primary composite endpoint of CV death and heart failure hospitalization was reduced by 22% relative to placebo (HR, 0.78; P < .001). When evaluated separately, the relative reductions in these respective endpoints were 17% (HR, 0.83; P = .045) and 24% (HR, 0.76; P = .002).

The risk reduction was robust (HR, 0.76; P < .001) in patients with an ischemic cause but nonsignificant in those without (HR, 0.92; P = .575). A significant benefit was sustained in patients receiving an angiotensin receptor neprilysin inhibitor (HR, 0.84; P = .041), as well as those who did not receive this class of drug (HR, 0.77; P = .012).

However, the benefit of qiliqiangxin among patients receiving all components of guideline-directed triple therapy (RAS inhibitor, beta-blocker, and mineralocorticoid antagonist) was only a trend (HR, 0.86; P = .079).

All-cause mortality, a secondary endpoint, was lower among patients randomly assigned to qiliqiangxin than to those assigned to placebo, but this difference fell just short of statistical significance (14.21% vs. 16.85%; P = .058).

Qiliqiangxin was well tolerated. The proportion of patients with a serious adverse event was numerically lower with qiliqiangxin than with placebo (17.43% vs. 19.74%), whereas discontinuations associated with an adverse event were numerically higher in the qiliqiangxin group (1.03% vs. 0.58%), albeit still very low in both study arms.
 

Overlap of drug benefits suspected

Given the safety of this drug and its highly significant reduction in a composite endpoint used in other major HFrEF trials, the ESC-invited discussant, Carolyn S.P. Lam, MBBS, PhD, National Heart Centre, Singapore, called the outcome “remarkable” and a validation for “the millions of people” who are already taking qiliqiangxin in China and other Asian countries.

Using the DAPA-HF trial as a point of reference, Dr. Lam noted that relative reduction in the composite endpoint of cardiovascular death for the SGLT-2 inhibitor dapagliflozin relative to placebo on top of triple guideline-directed medical therapy was lower (17% vs. 24%), but there were significant reductions in each of the components, as well as a nonsignificant signal of a mortality benefit.

However, Dr. Lam pointed out that there does seem to be more of an overlap for the benefits of qiliqiangxin than dapagliflozin relative to other components of triple therapy based on the lower rate of benefit when patients were optimized on triple therapy.

“The subgroup analysis [of this study] is very important,” Dr. Lam said. Qiliqiangxin may be best in patients who cannot take one or more of the components of triple therapy, she suggested, even though she called for further studies to test this theory. She also cautioned that the pill burden of four capsules taken three times per day might be onerous for some patients.

Of the many questions still to be answered, Dr. Lam noted that the low rate of enrollment for patients (< 10%) taking SGLT-2 inhibitors makes the contribution of qiliqiangxin unclear among those receiving the current standard of quadruple guideline-directed medical therapy.

She also suggested that it will be important to dissect the relative contribution of the different active ingredients of qiliqiangxin.

“This is not a purified compound that we are used to in Western medicine,” Dr. Lam said. While she praised the study as “scientifically rigorous” and indicated that the results support a clinical benefit from qiliqiangxin, she thinks an exploration of the mechanism or mechanisms of benefit is a next step in understanding where this therapy fits in HFrEF management.

Dr. Li reports financial relationships with AstraZeneca, Bayer, Novartis, Roche, and Yiling. Dr. Lam reports financial relationships with more than 25 pharmaceutical or device manufacturers, many of which produce therapies for heart failure, as well as with Medscape/WebMD Global LLC. The study was supported by the Chinese National Key Research and Development Project and Yiling Pharmaceuticals.

A version of this article appeared on Medscape.com.

A new trial testing perioperative treatment with colchicine has shown no significant benefit on the co-primary outcomes of clinically important atrial fibrillation (AFib) or myocardial injury after noncardiac surgery (MINS) in patients undergoing thoracic surgery.

Trends were seen with reductions in events, but these did not reach significance. However, benefit was seen in a post-hoc analysis looking at a composite of both of those endpoints, the researchers note, as well as a composite of vascular death, nonfatal MINS, nonfatal stroke, and clinically important perioperative AFib, the researchers report.

“We interpret that as there is a trend that is promising, a trend that needs to be further explored,” lead author David Conen, MD, Population Health Research Institute, Hamilton, Ont., said in an interview. “We think that further studies are needed to tease out which patients can benefit from colchicine and in what setting it can be used.”

Treatment was safe, with no effect on the risk for sepsis or infection, but it did cause an increase in noninfectious diarrhea. “These events were mostly benign and did not increase length of stay, and only one patient was readmitted because of diarrhea,” Dr. Conen noted.

Results of the COP-AF trial were presented at the annual congress of the European Society of Cardiology, Amsterdam, and published online  in The Lancet .
 

Inflammation and perioperative AFib

AFib and MINS are common complications in patients undergoing major thoracic surgery, Dr. Conen explained. The literature suggests AFib occurs in about 10% and MINS in about 20% of these patients, “and patients with these complications have a much higher risk of additional complications, such as stroke or MI [myocardial infarction],” Dr. Conen said.

Both disorders are associated with high levels of inflammatory biomarkers, so they set out to test colchicine, a well-known anti-inflammatory drug used in higher doses to treat common clinical disorders, such as gout and pericarditis. Small, randomized trials had shown it reduced the incidence of perioperative AFib after cardiac surgery, he noted.

Low-dose colchicine (LoDoCo, Agepha Pharma) was recently approved by the U.S. Food and Drug Administration to reduce the risk for MI, stroke, coronary revascularization, or death in patients with established atherosclerotic disease or multiple risk factors for cardiovascular disease. It was approved on the basis of the LoDoCo 2 trial in patients with stable coronary artery disease and the COLCOT trial in patients with recent MI.

COP-AF was a randomized trial, conducted at 45 sites in 11 countries, and enrolled 3,209 patients aged 55 years or older (51.6% male) undergoing major noncardiac thoracic surgery. Patients were excluded if they had previous AFib, had any contraindications to colchicine, or required colchicine on a clinical basis.

Patients were randomly assigned 1:1 to receive oral colchicine at a dose of 0.5 mg twice daily (1,608 patients) or placebo (1,601 patients). Treatment was begun within 4 hours before surgery and continued for 10 days. Health care providers and patients, as well as data collectors and adjudicators, were blinded to treatment assignment.

The co-primary outcomes were clinically important perioperative AFib or MINS over 14 days of follow-up. The trial was originally looking only at clinically important AFib, Dr. Conen noted, but after the publication of LoDoCo 2 and COLCOT, “MINS was added as an independent co-primary outcome,” requiring more patients to achieve adequate power.

The main safety outcomes were a composite of sepsis or infection, along with noninfectious diarrhea.

Clinically important AFib was defined as AFib that results in angina, heart failure, or symptomatic hypotension or required treatment with a rate-controlling drug, antiarrhythmic drug, or electrical cardioversion. “This definition was chosen because of its prognostic relevance, and to avoid adding short, asymptomatic AFib episodes of uncertain clinical relevance to the primary outcome,” Dr. Conen said during his presentation.

MINS was defined as an MI or any postoperative troponin elevation that was judged by an adjudication panel to be of ischemic origin.

At 14 days, there was no significant difference between groups on either of the co-primary end points.

Low-risk patients

Jean-Claude Tardif, MD, Montreal Heart Institute and Université de Montréal, was the invited discussant for the COP-AF presentation and congratulated the researchers on “a job well done.”

He made the point that the risk for perioperative AFib has decreased substantially with the greater use of thoracoscopic rather than open surgical approaches. The population of this trial was relatively young, with an average age of 68 years; the presence of concomitant CVD was low, at about 9%; by design, patients with previous AFib were excluded; and only about 20% of patients had surgery with an open approach.

“So that population of patients were probably at relatively low risk of atrial fibrillation, and sure enough, the incidence of perioperative AFib in that population at 7.5% was lower than the assumed rate in the statistical powering of the study at 9%,” Dr. Tardif noted.

The post-hoc analyses showed a “nominally significant effect on the composite of MINS and AFib; however, that combination is fairly difficult to justify given the different pathophysiology and clinical consequences of both outcomes,” he pointed out.

The incidence of postoperative MI as a secondary outcome was low, less than 1%, as was the incidence of postoperative stroke in that study, Dr. Tardif added. “Given the link between presence of blood in the pericardium as a trigger for AFib, it would be interesting to know the incidence of perioperative pericarditis in COP-AF.”

In conclusion, he said, “when trying to put these results into the bigger picture of colchicine in cardiovascular disease, I believe we need large, well-powered clinical trials to determine the value of colchicine to reduce the risk of AFib after cardiac surgery and after catheter ablation,” Dr. Tardif said.

“We all know that colchicine represents the first line of therapy for the treatment of acute and recurrent pericarditis, and finally, low-dose colchicine, at a lower dose than was used in COP-AF, 0.5 mg once daily, is the first anti-inflammatory agent approved by both U.S. FDA and Health Canada to reduce the risk of atherothombotic events in patients with ASCVD [atherosclerotic cardiovascular disease], I believe offering a new pillar of treatment for the prevention of ischemic events in such patients.”

Session co-moderator Franz Weidinger, MD, Landstrasse Clinic, Vienna, Austria, called the COP-AF results “very important” but also noted that they show “the challenge of doing well-powered randomized trials these days when we have patients so well treated for a wide array of cardiovascular disease.”

The study was supported by the Canadian Institutes of Health Research (CIHR); Accelerating Clinical Trials Consortium; Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario; Population Health Research Institute; Hamilton Health Sciences; Division of Cardiology at McMaster University, Canada; Hanela Foundation, Switzerland; and General Research Fund, Research Grants Council, Hong Kong. Dr. Conen reports receiving research grants from CIHR, speaker fees from Servier outside the current study, and advisory board fees from Roche Diagnostics and Trimedics outside the current study.

A version of this article appeared on Medscape.com.